FitSugar

ACTivism: Breast Cancer Three-Day Walk

FitSugar — Fri, 22 Feb 2008 13:30:00 -0800

October may be Breast Cancer Awareness Month, but the battle against the disease is fought daily. One great way to join the fight is to raise funds for the Susan G. Komen Foundation by participating in the Breast Cancer Three-Day Walk.

This walk sounds incredible. After raising a minimum of $2,200 for breast cancer research and initiatives, you walk 60 miles over the course of three days - about 15 to 22 miles a day. There are events in 14 cities starting in August and running through November. It might seem early to start planning for something happening at the end of Summer, but informational meetings are happening now (here's the link to the calendar of informational meetings). Plus you are going to want to train because that is half the fun. Plus we all know there are great health benefits to regular walking. Sugar user kscincotta lost 8 lbs. while training last year for her walk! She also raised $8,000 - wow! Good work all the way around!

Want to see if your city is participating? Then just read more.

Chicago – August 8-10
Boston – August 15-17
Cleveland – August 22-24
San Francisco Bay Area – September 5-7
Seattle – September 12-14
Twin Cities – September 19-21
Michigan – September 26-28
Washington, DC – October 3-5
Philadelphia – October 17-19
Atlanta – October 24-26
Tampa Bay – October 31 - November 2
Dallas/Fort Worth – November 7-9
Arizona – November 14-16
San Diego – November 21-23

Do you think you are going to do one? Do the miles seem daunting, or the money? Tell me in the comments section below.

Breast cancer

FitSugar — Wed, 08 Oct 2008 17:34:59 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approvals

In September 2007, Evista (raloxifene) was approved for prevention of breast cancer in postmenopausal women with osteoporosis, and postmenopausal women at high risk for invasive breast cancer. Raloxifene and tamoxifen are the only two drugs approved for breast cancer prevention in high-risk women.
In March 2007, lapatinib (Tykerb) was approved in combination with capecitabine (Xeloda) for treatment of advanced HER2-positive breast cancer.
In November 2006, trastuzumab (Herceptin) was approved for treatment of early-stage HER2-positive breast cancer. Trastuzumab is also approved for advanced HER2-positive breast cancer.

Screening

The American College of Physicians’ 2007 guidelines recommend that women with a low risk for breast cancer talk to their doctor before starting to have mammogram screening at age 40. Other associations, including the American Cancer Society, continue to recommend annual mammograms for women age 40 and older.
Women at high risk for breast cancer should have an MRI scan along with their annual mammogram, according to 2007 guidelines from the American Cancer Society.
For women who have been diagnosed with cancer in one breast, an MRI can help detect tumors in the other breast, indicates a 2007 study in the New England Journal of Medicine.

Post-Treatment Guidelines

The American Society of Clinical Oncology (ASCO)’s 2006 post-treatment guidelines recommend regular physical exams, breast self-exam, mammograms, and genetic counseling. Know how to recognize the signs of breast cancer recurrence. ASCO does not recommend blood and imaging tests for routine recurrence screening.

Hormone Replacement Therapy (HRT) and Breast Cancer Risk

Fewer women are using HRT, which may explain why new cases of breast cancer among postmenopausal women have declined, suggests a recent New England Journal of Medicine study.

Aromatase Inhibitors

Drug treatment with aromatase inhibitors is improving survival in women with hormone-sensitive advanced breast cancer, suggest recent studies. Switching from tamoxifen to an aromatase inhibitor may help improve the odds for survival.

Introduction

Breast cancers are potentially life-threatening malignancies that develop in one or both breasts. The structure of the female breast is important in understanding this cancer:

The interior of the female breast consists mostly of fatty and fibrous connective tissues.
It is divided into about 20 sections called lobes.
Each lobe is further subdivided into a collection of lobules, structures that contain small milk-producing glands.
These glands secrete milk into a complex system of tiny ducts. The ducts carry the milk through the breast and converge in a collecting chamber located just below the nipple.
Breast cancer is either noninvasive (referred to as in situ, confined to the site of origin) or invasive (spreading).

The female breast is either of two mammary glands (organs of milk secretion) on the chest.

Noninvasive breast cancers include:

Ductal carcinoma in situ (also called intraductal carcinoma or DCIS). DCIS consist of cancer cells in the lining of the duct. DCIS is a non-invasive, early cancer, but if left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer.
Lobular carcinoma in situ, or LCIS. Although noninvasive, lobular carcinoma in situ is a marker for an increased risk of invasive cancer in both breasts. (Some experts prefer to call this condition lobular neoplasia rather than refer to it as a cancer.) According to a 2001 report, for patients with LCIS the risk for developing invasive cancer in the same breast is about 18% -- and 14% in the other breast -- after 20 years. These invasive cancers can be either lobular or ductal.

At the time of diagnosis of these early cancers (DCIS and LCIS), there is no evidence of invasion.

Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. This tissue is rich in blood vessels and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancers include the following:

Infiltrating ductal carcinoma. This is invasive breast cancer that penetrates the wall of a duct. It comprises between 70 - 80% of all breast cancer cases.
Infiltrating lobular carcinoma. This invasive cancer has spread through the wall of a lobule. It accounts for 10 - 15% of all breast cancers. It may sometimes appear in both breasts, sometimes in several separate locations.

Click the icon to see an image of the breast.

There are other less common breast cancers that are not discussed in this report.

Risk Factors

About 12 - 13% of women develop breast cancer in their lifetime. Experts estimate that about 178,480 women will be newly diagnosed with invasive breast cancer in the United States in 2007. Another 2,030 men will be diagnosed with breast cancer during the year. Although breast cancer in men is rare, the incidence has been increasing, and men are diagnosed at a later stage than women. An estimated 40,460 women and 450 men will die from breast cancer in 2007. The earlier breast cancer is diagnosed, the earlier the opportunity for treatment. According to the American Cancer Society, over 2 million women who have been treated for breast cancer are alive today.

Age is a major identifiable risk factor. More than 80% of breast cancer cases occur in women over age 50, and especially in women over age 65. The odds by age are as follows:

From ages 30 - 39, a woman’s chance for being diagnosed with breast cancer is 1 in 233
Ages 40 - 49, the odds are 1 in 69
Ages 50 - 59, the odds are 1 in 38
Ages 60 - 69, the odds are 1 in 27
Ages 70 - 79, the odds are 1 in 11
After age 80, the odds are 1 in 8

Breast cancer is more prevalent among Jewish women of Eastern European (Ashkenazi) descent. Meanwhile, African-American women tend to get breast cancer at an earlier age than Caucasians. Although African-American women have lower overall rates of breast cancer, they represent the highest proportion of women who are diagnosed with the disease before age 45. Comparative studies of breast cancer rates among sub-Saharan Africans suggest a genetic component, as African women are diagnosed most frequently between ages 35 - 45.

The mortality rate in African-Americans is twice that of Caucasians, although it is declining. Social and economic factors make it less likely that African-American women will be screened, so they are more likely to be diagnosed at a later stage. They are also less likely to have access to effective treatments. However, there also appears to be a biological basis for African-American women’s poorer prognosis. According to research presented at the 2007 Breast Cancer Symposium, African-American women are more likely to have estrogen receptor-negative tumors, a type of breast cancer that is more difficult to treat.

An estimated 10% of all women with breast cancer have a very strong family history of the disease. Inherited forms of breast cancer often appear in young women under the age of 50. In such families, some members may also be at higher risk for ovarian cancer. These mutations can be inherited from either a mother or father.

Prior to menopause, a mass on the ovary that is smaller than 2 centimeters is probably a follicle cyst that will go away on its own. However, if the growth is larger and doesn't go away over the course of a few menstrual cycles, then it may need to be removed.

BRCA Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are responsible for 30 - 50% of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers. According to some studies, the risk each gene carries is:

Between 25 - 35% of BRCA1 carriers develop breast cancer by age 70.
Between 35 - 50% of BRCA2 carriers develop the disease. BRCA2 genes also increase the lifetime risk of breast cancer in men.

These mutations are present in only about 0.5% of the overall population. However, certain ethnic groups -- such as Jewish women of Eastern European (Ashkenazi) descent -- have a higher prevalence (2.5%) of BRCA gene mutations. BRCA gene mutations are also seen in some African-American and Hispanic women.

Screening Guidelines for BRCA Genes. In 2005, the U.S. Preventive Services Task Force (USPSTF) released updated guidelines for BRCA testing. While women at high risk should be tested, the USPSTF does not recommend routine genetic counseling or testing for BRCA genes in low-risk women (no family history of BRCA 1 or 2 genetic mutations).

ESR Genes. Genetic variations in estrogen receptor genes (ESRs) may increase the risk for some women but offer protection to others. Mutations in the ESR1 and ESR2 genes may be associated with breast cancer susceptibility for Ashkenazi women over age 50 years.

Other Genetic Factors. Mutations in the tumor suppressor gene p53 are more common in the breast cancer tumors of African-American women than in Caucasian women. Researchers have also identified other defective genes that contribute to breast cancer, such as NOEY2 (which is inherited from the father), CHEK2, and ATM, a mutant gene for the rare disorder ataxia-telangiectasia. (The disease itself is rare, but 1% of the population carries a single copy -- enough to increase the risk for breast cancer.) Cowden's syndrome is an inherited disorder caused by a defective PTEN gene that is associated with a higher risk of breast cancer.

Not all genetic mutations are inherited. In 2007, scientists announced they had located a genetic mutation found in as many as 30 - 40% of breast cancers. The IKBKE mutation appears to occur during the course of a women’s lifetime. It causes overproduction of a kinase protein (IKK-epsilon) that fuels cell growth and tumor development. By identifying this genetic mutation, scientists hope they can develop drugs that will target and block IKK-epsilon production.

Because growth of breast tissue is highly sensitive to estrogens, the more estrogen a woman is exposed to over her lifetime, the higher her risk for breast cancer.

Duration of Estrogen Exposure. Early age at menarche (first menstrual period) or later age at menopause may slightly increase a women’s risk for breast cancer.

Pregnancy. Women who have never had children or who had their first child after age 30 may have a slightly increased breast cancer risk. Having children at an early age, and having multiple pregnancies, reduces breast cancer risk.

Although a few studies have suggested a slightly increased risk for breast cancer in women who have had abortions, the weight of evidence does not support an association between abortion and breast cancer. A large-scale 2007 study found that neither induced abortions nor spontaneous abortions (miscarriages) increases breast cancer risk. However, interrupting a pregnancy does reduce the protective features of a full-term pregnancy.

Studies have been mixed on whether breast-feeding decreases breast cancer risk. Breast-feeding reduces a woman’s total number of menstrual cycles, and thereby estrogen exposure, which may account for its possible protective effects. Some studies suggest that the longer a woman breast-feeds, the lower her risk.

Oral Contraception. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer. Some studies have found no evidence that oral contraceptive use increases the risk for breast cancer, even in women who have taken birth control pills for 15 years or more or had taken them at young ages. In contrast, other studies have reported a slightly higher risk in women who are current or recent users and in women who take them for more than 4 years before a first full-term pregnancy.

Hormone Replacement Therapy. Many studies have reported a higher risk for breast cancer in postmenopausal women who take hormone replacement therapy (HRT) that contains both estrogen and progestin. A combination of estrogen and testosterone also increases breast cancer risk. A 2005 study suggested that HRT with no or low progestin is safer than standard estrogen-progestin combination therapy.

Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take estrogen for 10 - 15 years or more do have an increased risk, especially women who are already at higher risk for breast cancer. In addition, HRT increases breast cancer density, making mammograms more difficult to read. This can cause cancer to be diagnosed at a later stage. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.

As further evidence of the association between HRT and breast cancer, a 2007 New England Journal of Medicine study noted that breast cancer rates have fallen as HRT use has declined. The decline in rates occurred among women over the age of 50 and was particularly associated with cancers that were estrogen receptor-positive. This type of cancer requires estrogen for growth. Experts think that postmenopausal women’s discontinuation of estrogen-containing HRT may explain the decrease in rates of new cases of estrogen receptor-positive cancer.

A 2007 position statement from the North American Menopause Society recommends that women who are at risk for breast cancer should avoid hormone therapy and try other options to manage menopausal symptoms such as hot flashes. At this time, most experts recommend that women use HRT only for short-term relief of menopausal symptoms. [See In-Depth Report #40: Menopause.]

Infertility and Infertility Treatments. There has been concern that infertility treatments using the drug clomiphene may increase the risk for breast cancer. A reassuring 2006 study indicated that ovulation induction with clomiphene does not increase breast cancer risk, and may actually decrease it. (Clomphine is related to tamoxifen, a drug that is used for breast cancer prevention in high-risk women.) The study also suggested that women who are infertile because of ovulatory dysfunction have a 25% lower risk for breast cancer than fertile women.

Abnormalities or Breast Conditions Suggesting a Higher Risk. Certain factors and breast conditions may increase the risk for breast cancer:

Dense breast tissue is associated with a higher risk for breast cancer. Studies suggest that women with highly dense tissue have 2 - 6 times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density. In addition, dense breasts make mammograms more difficult to read, which increases the likelihood of missing early signs of cancer.
Benign proliferative breast disease, or unusual cell growth known as atypical hyperplasia, is a significant risk factor for breast cancer.

Some common benign breast abnormalities that pose few or no risks include the following:

Cysts. These mostly occur in women in their middle-to-late reproductive years and can be eliminated simply by aspirating fluid from them.

Click the icon to see an image of cysts in the breast.

Fibroadenoma. These are solid benign lumps that occur in women ages 15 - 30.
Breast abscesses during breast-feeding.

Click the icon to see an image of a breast abscess.

Nipple discharge. Discharge from the nipple is worrisome to patients, but is unlikely to be a sign of cancer. Unexplained discharge still warrants evaluation, however.

Click the icon to see an image of nipple discharge.

Mastalgia. This is breast pain that occurs in association with, or independently from, the menstrual cycle. About 8 - 10% of women experience moderate-to-severe breast pain associated with their menstrual cycle. In general, breast pain does not need assessment unless it is severe and prolonged.

The following physical characteristics have been associated with increased risk:

Obesity increases the risk for all types of estrogen receptor-positive breast cancers. Women who gain weight after menopause are most at risk. (On a positive note, losing weight after menopause decreases breast cancer risk.) In postmenopausal women, estrogen is produced in fat tissue. High amounts of fatty tissue increase levels of estrogen in the body, leading to faster growth of estrogen-sensitive cancers.
Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to be at greater risk for breast cancer.
Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth. In one study, regardless of their actual height, women who reached their full height at age 13 or younger had a higher risk than those who attained maximum height at age 18, reflecting higher estrogen levels at an earlier age.

Exposure to Estrogen-like Industrial Chemicals. Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (DDT and its metabolites, such as dieldrin) and pyrethroids (permethrin), but at this time evidence of any causal association is very weak.

Exposure to Diethylstilbestrol. Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. Recent studies also suggest a slightly increased risk for their daughters (commonly called "DES daughters"), who were exposed to the drug when their mothers took it during pregnancy.

Radiation Exposure. Heavy exposure to radiation is a significant risk factor for breast cancer. Girls who received high-dose radiation therapy face an increased risk for breast cancer in adulthood. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations.

Researchers theorize that viruses may be involved in some types of breast cancers. A study of breast cancer samples taken from Tunisian women in North Africa found similarities with a virus known to cause breast cancer in mice. The samples were compared with those taken from women living in other global regions. The researchers suggested that a human breast cancer virus may be more prevalent in specific parts of the world.

Prevention and Lifestyle Factors

Evidence indicates that regular exercise, particularly vigorous exercise, may offer some modest protection against breast cancer. Exercise can help reduce body fat, which in turn lowers levels of cancer-promoting hormones such as estrogen. In fact, a 2006 study suggested that physical activity may help women reduce the risk for developing estrogen receptor-positive tumors.

Exercise can also help women who have been diagnosed with breast cancer. Studies indicate that both aerobic and weight training exercises benefit the body and the mind, and improve quality of life for breast cancer survivors. Even moderate exercise can help improve survival. A 2005 study in the Journal of the American Medical Association reported survival benefits for women diagnosed with breast cancer who walked 3 – 5 hours per week at an average pace. The American Cancer Society recommends engaging in 45 - 60 minutes of physical activity at least 5 days a week. A recent study indicated that diet and exercise can reduce the risk of breast cancer recurrence.

Physical activity contributes to health by reducing the heart rate, decreasing the risk for cardiovascular disease, and reducing the amount of bone loss that is associated with age and osteoporosis. Physical activity also helps the body use calories more efficiently, thereby helping in weight loss and maintenance. It can increase basal metabolic rate, reduces appetite, and helps in the reduction of body fat.

Despite much research on the association between diet and breast cancer, there is still little consensus. The best advice is to eat a well-balanced diet and avoid focusing on one "cancer-fighting" food. The American Cancer Society’s dietary guidelines for cancer prevention recommend that people:

Choose foods and amounts that promote a healthy weight.
Eat 5 or more servings of fruits and vegetables each day.
Choose whole grains instead of refined grain products.
Limit consumption of processed and red meat.
Women should limit alcohol consumption to 1 drink per day (women at high risk for breast cancer should consider not drinking alcohol at all).

For breast cancer survivors, the American Cancer Society recommends diets that include lots of fruits and vegetables, low amounts of saturated fat (from meat and high-fat dairy products), moderation in soy foods, and moderate or no alcohol consumption.

Here are results from recent studies evaluating diet and breast cancer, for preventing both the development of cancer and its recurrence:

Fats. Research is still mixed on the role that fats, and which specific types of fats, play in breast cancer risk and prevention. Several studies have indicated that red meat, which is high in saturated fat, may increase breast cancer risk when eaten in large quantities on a daily basis. (Red meat is also high in iron, which in itself may increase breast cancer risk.) According to results from the 2006 Women’s Health Initiative study of dietary fat and breast cancer, experts cannot yet definitely say that a low-fat diet will help prevent breast cancer. However, the study suggested that women who normally eat a very high-fat diet may benefit by reducing their fat intake. In the study, the low-fat diet reduced blood estrogen levels by 15%. The low-fat diet also appeared to reduce the risk for developing progesterone receptor-negative tumors.

Fruits and Vegetables. Fruits and vegetables are important sources of antioxidants, which may help protect against the tissue damage linked to increased cancer risk. Antioxidants include vitamin C, vitamin E, and carotenoids such as beta-carotene and lycopene. Richly colored fruits and vegetables -- not supplements -- are the best sources for these nutrients. These fiber-rich foods are an essential part of a healthy diet. However, it is not clear whether fruits and vegetables can specifically prevent breast cancer development or recurrence. According to a 2007 study of women with early-stage breast cancer, a low-fat diet very high in vegetables, fruit, and fiber does not work any better in preventing breast cancer recurrence than the standard 5 servings a day of fruits and vegetables. (However, a combination of diet and exercise may help.)

Calcium and Vitamin D. Eating lots of foods rich in calcium and vitamin D (such as yogurt and milk) may modestly reduce the risk of breast cancer for premenopausal -- but not postmenopausal -- women, according to a 2007 study. Low-fat or non-fat dairy products are a healthier choice than high-fat ones.

Click the icon to see an image of vitamin D sources.

Soy. Soy is an excellent low-fat protein alternative to meat. Soy contains phytoestrogens, which are estrogen-like plant chemicals. In particular, soy contains a type of phytoestrogen called isoflavones. Because many soy foods (such as tofu) are eaten in Asian countries where women tend to have a lower incidence of breast cancer, research has focused on whether soy may have a protective effect. To date, the evidence does not indicate that soy foods or supplements can reduce breast cancer risk. In addition, some studies suggest that high intakes of soy may actually increase the risk of estrogen-responsive cancers such as breast cancer. Some animal studies have suggested that the isoflavone compound genistein may reduce the protective properties of tamoxifen, a drug used to prevent breast cancer in high-risk women. The American Cancer Society recommends that women with breast cancer eat only moderate amounts of soy foods and avoid taking dietary supplements that contain high amounts of isoflavones.

Click the icon to see an image of phytochemicals.

Lifestyle Factors. Premenopausal women at higher risk, usually because of family history, should take as many preventive measures as possible, starting at an early age. The following lifestyle choices may be beneficial:

Exercising and eating healthily is the first essential rule.
High-risk premenopausal women may choose alternatives to oral contraceptives and, if feasible, consider having children early in their life.
High-risk postmenopausal women may want to forego hormone replacement therapy.
Any woman at high risk for breast cancer should consider avoiding alcohol or drinking it very sparingly.

In spite of some rumors published in the popular press, antiperspirants or use of deodorants after shaving have not been linked with any higher risk for breast cancer.

Tamoxifen and Raloxifene. Drugs known as selective estrogen-receptor modulators (SERMs) act like estrogen in some tissues but behave like estrogen blockers (anti-estrogens) in others. Two SERMs -- tamoxifen (Nolvadex) and raloxifene (Evista) -- are approved for breast cancer prevention for high-risk women. Tamoxifen and raloxifene are not recommended as prevention for women at low risk for breast cancer or its recurrence. Women at high risk for breast cancer should discuss with their doctors the risks and benefits of SERMs.

Tamoxifen (Nolvadex) is the most studied of these drugs. It is currently used to treat breast cancer and was the first drug approved for prevention. Evidence strongly suggests that it halves the risk for estrogen receptor-positive cancers in high-risk women, including those with BRCA2 mutations (although possibly not BRCA1). It also helps prevent recurrence in women who have been treated for breast cancers. However, it has no protective effects against estrogen receptor-negative (hormone-insensitive) cancers.

Tamoxifen can increase the risk for uterine (endometrial) cancers. It can also increase the risk for blood clots, strokes, and endometriosis. Less serious side effects include hot flashes and vaginal discharge.

Raloxifene (Evista) was approved in 2007 for prevention of breast cancer in postmenopausal women with osteoporosis and postmenopausal women at high risk for invasive breast cancer. Raloxifene was previously approved for prevention and treatment of osteoporosis in postmenopausal women. One of raloxifene’s main benefits is that it has a lower risk than tamoxifen of causing uterine cancer. However, raloxifene also has some serious risks.

According to the prescribing information from the Food and Drug Administration (FDA), raloxifene can increase the risk of blood clots. Women with a history of blood clots in the legs, lungs, or eyes should not take this medicine. Although studies indicate raloxifene does not increase the risk of stroke, it can increase the risk of dying from a stroke. Women with a history of stroke or current risk factors for stroke should discuss with their doctors whether raloxifene is an appropriate choice. Less serious side effects of raloxifene include hot flashes, leg cramps, swelling of the legs and feet, flu-like symptoms, joint pain, and sweating. Raloxifene can cause birth defects and is approved only for postmenopausal women. It should not be taken with the cholesterol-lowering drug cholestyramine (Questran) or with estrogens.

The FDA based its approval of raloxifene on results from several major studies. The comparison trial Study of Tamoxifen and Raloxifene (STAR), published in 2006 in the Journal of the American Medical Association, indicated that raloxifene works as well as tamoxifen in reducing the risk of invasive breast cancer, and has a lower risk of causing blood clots. However, the Raloxifene Use for the Heart (RUTH) trial, published in 2006 in the New England Journal of Medicine, suggested that raloxifene carries its own risks for blood clots and fatal strokes and may not be a safe choice for women at high risk of heart disease.

Investigational Drugs for Breast Cancer Prevention.

Aromatase inhibitors. Aromatase inhibitors such as anastrazole (Armidex), letrozole (Femara), and exemestane (Aromasin) are effective treatments for hormone-receptor positive breast cancer. Like tamoxifen, they are also being investigated for protection in high-risk women. However, these drugs may decrease bone mineral density and cognitive function, and increase the risk for falls.
Retinoids. Analogues of vitamin A called retinoids are being studied for protection against breast cancer. One retinoid, fenretinide, appears to offer some protection against a second breast cancer in previously diagnosed, premenopausal women (but not in postmenopausal women). It can cause birth defects and should not be used during pregnancy.

Symptoms

Breast cancers in their early stages are usually painless. Often the first symptom is the discovery of a hard lump. Fifty percent of such masses are found in the upper outer quarter of the breast. The lump may make the affected breast appear elevated or asymmetric. The nipple may be retracted or scaly. Sometimes the skin of the breast is dimpled like the skin of an orange. In some cases there is a bloody or clear discharge from the nipple. Many cancers, however, produce no symptoms and cannot be felt on examination. They can be detected only with a mammogram.

Monthly breast self-exams should always include: visual inspection (with and without a mirror) to note any changes in contour or texture, and manual inspection in standing and reclining positions to note any unusual lumps or thicknesses.

Diagnosis

Breast Examination by a Health Professional. Early detection of breast cancer significantly reduces the risk of death. Women ages 20 - 49 should have a physical examination by a health professional every 1 - 2 years. Those over age 50 should be examined annually. A breast exam by a health professional can find 10 - 25% of breast cancers that are missed by mammograms. Between 6 - 46% of the lumps detected by examination are malignant. (The yield is lowest in younger women and highest in older women.)

Self-Examinations. Woman have been encouraged to perform a self-examination each month, but well-conducted studies in 2002 reported no difference in mortality rates between women who were intensively instructed in self-examination and those who were not. This does not mean women should stop attempting self-examinations, but they should not replace the annual examination done by a health professional, which evidence suggests is beneficial.

1. Pick a time of the month that is easy to remember and perform self-examination at that time each month. The breast has normal patterns of thickness and lumpiness that change within a monthly period, and a consistently scheduled examination will help differentiate between what is normal from abnormal.

2. Stand in front of a mirror. Breasts should be basically the same size (one may be slightly larger than the other). Check for changes or redness in the nipple area. Look for changes in the appearance of the skin. With hands on the hips, push the pelvis forward and pull the shoulders back and observe the breasts for irregularities. Repeat the observation with hands behind the head. Move each arm and shoulder forward.

3. Lie down on the back with a rolled towel under one shoulder. Apply lotion or bath oil over the breast area.

The finger action should be as follows: Using the 2nd, 3rd, and 4th finger pads (not tips) held together, make dime-sized circles. Press lightly first to feel the breast area, then press harder using a circular motion.

Using this motion, start from the collarbone and move downward to underneath the breast. Shift the fingers slightly over, slightly overlapping the previously checked region, and work upward back to the collarbone. Repeat this up-and-down examination until the entire breast area has been examined. Be sure to cover the entire area from the collarbone to the bottom of the breast area and from the middle of the chest to the armpits. Move the towel under the other shoulder and repeat the procedure.

Examine the nipple area, by gently lifting and squeezing it and checking for discharge.

4. Repeat step 3 in an upright position. (The shower is the best place for this, using plenty of soap.)

Note: A lump can be any size or shape and can move around or remain fixed. Of special concern are specific or unusual lumps that appear to be different from the normal varying thicknesses in the breast.

Click the icon to see an image of a breast self-exam.

Current Recommendations for Screening. Mammograms are very effective low-radiation screening methods for breast cancer. At this time, the U.S. Preventive Services Task Force recommends screening mammograms, with or without breast examination, every 1 - 2 years for all women over age 40.

Guidelines from the American College of Physicians (ACP), however, debate whether women with a low risk for breast cancer should begin mammogram screening at age 40. The 2007 guidelines, instead, recommend that women in their 40s ask their doctor when they should begin having the test. In contrast, the American Cancer Society and the U.S. National Cancer Institute continue to endorse annual screening for women age 40 and older.

The ACP's guidelines have created controversy within the medical community. Supporters of the guidelines believe that these new recommendations reflect some of the risks involved in screening younger women. These risks include radiation exposure and unnecessary biopsies. Mammographies in younger women produce a relatively high rate of false-positive results (when the test falsely indicates breast cancer). Scientists are working on new technologies to improve mammography's accuracy, but more work is needed. For example, a 2007 New England Journal of Medicine study reported that computer-aided detection software, which is used to help radiologists interpret mammograms, may instead make readings less accurate.

Opponents of the ACP guidelines argue that mammograms help catch tumors while they are in their earliest and most treatable stages, and that the most deadly types of breast cancer tend to occur in women in their 40s.

In addition, according to a review in the American Cancer Society's journal, mammography rates have declined since 2000. In fact, while many experts believe that the recent decline in new cases of breast cancer is partially due to reduced use of hormone replacement therapy, other experts are concerned that fewer cases of breast cancer are being detected because fewer mammographies are being performed.

After age 50, all guidelines recommend annual screenings. The older a women gets, the greater her risk for developing breast cancer. (Women over age 65 account for most new cases of breast cancer.) Women with risk factors for breast cancer, including a close family member with the disease, should consider having annual mammograms starting 10 years earlier than the age at which the relative was diagnosed.

Click the icon to see an image of a mammogram.

Magnetic Resonance Imaging and Ultrasound. Magnetic resonance imaging (MRI) and ultrasound techniques can detect very small tumors (less than half an inch). However, they are expensive and time-consuming procedures. Nevertheless, some doctors believe they are important in identifying small tumors missed on mammography in women who are receiving lumpectomy or breast-conserving surgeries. Such findings would allow the surgeons to remove the optimal amount of abnormal tissue. Ultrasound may also be particularly important for women with dense breast tissue who show signs of breast cancer.

In a report published in 2007, the American Cancer Society recommended that high-risk women have an MRI of their breast with their annual mammogram, including those who have:

A BRCA1 or BRCA2 mutation
A first-degree relative (parent, sibling, child) with a BRCA1 or BRCA2 mutation, even if they have yet to be tested themselves
A lifetime risk of breast cancer that has been scored at 20 - 25% or greater
Had radiation to the chest between ages 10 - 30
Li-Fraumeni syndrome, Cowden syndrome, or Bannayan-Riley-Ruvalcaba syndrome, or may have one of these genetic syndromes based on a history in a first-degree relative

For women who have had cancer diagnosed in one breast, MRIs can also be very helpful for detecting hidden tumors in the other breast. A landmark 2007 study in the New England Journal of Medicine reported that MRI scans of women who were diagnosed with cancer in one breast detected over 90% of cancers in the other breast that had been previously missed by mammography or clinical breast exam. Currently, few women who are diagnosed with cancer in one breast are offered an MRI of the other breast. Some experts advocate MRIs for all women newly diagnosed with breast cancer; others oppose this view. MRI scans may be most useful for younger women with breast cancer who have dense breast tissue that may obscure tumors from mammography readings. MRIs are less likely to be helpful for older women with early tumors in one breast and clear mammography readings in the other.

It is very important that women have MRIs at qualified centers that perform many of these procedures each year. MRI is a complicated procedure and requires special equipment and experienced radiologists. MRI facilities should also be able to offer biopsies when suspicious findings are detected.

Scintimammography. In scintimammography, a radioactive chemical is injected into the circulatory system, which is then selectively taken up by the tumor and revealed on mammograms. This method is very accurate in detecting the presence or absence of breast cancer, and some doctors hope that it might eventually reduce the number of unnecessary invasive biopsies. It is used for women who have had abnormal mammograms or for women who have dense breast tissue. It is not used for regular screening or as an alternative to mammography.

A definitive diagnosis of breast cancer can be made only by a biopsy (a microscopic examination of a tissue sample of the suspicious area).

When a lump can be felt and is suspicious for cancer on mammography, an excisional biopsy may be recommended. This biopsy is a surgical procedure for removing the suspicious tissue and typically requires general anesthetic.

Click the icon to see an image of breast biopsy.

A core biopsy involves a small incision and the insertion of a spring-loaded hollow needle that removes several samples. The patient only requires local anesthetic.
A wire localization biopsy may be performed if mammography detects abnormalities but there is no lump. With this procedure, using mammography as a guide, the doctor inserts a small wire hook through a hollow needle and into the suspicious tissue. The needle is withdrawn, and the hook is used by the surgeon to locate and remove the lesion. The patient may receive local or general anesthetic.
A new vacuum-assisted device may be useful for some biopsies. This uses a single probe through which a vacuum is used to draw out tissue. It allows several samples to be taken without having to remove and re-insert the probe.

Final analysis of the breast tissue may take several days.

If breast cancer has been determined, the next diagnostic step is to find out how far it has spread. To do this, the doctor performs a procedure called an axillary lymphadenectomy, which partially or completely removes the lymph nodes in the armpit beside the affected breast (called axillary lymph nodes). It may require a hospital stay of 1 - 2 days.

Click the icon to see an image of the axillary lymph nodes.

Once the lymph nodes are removed, they are analyzed to determine whether subsequent treatment needs to be more or less aggressive:

If no cancer is found in the lymph nodes, the condition is referred to as node negative breast cancer. The chances are good that the cancer has not spread and is still local.
If cancer cells are present in the lymph nodes, the cancer is called node positive. Their presence increases the possibility that the cancer has spread microscopically to other areas of the body. In such cases, however, it is still not known if the cancer has metastasized beyond the lymph nodes or, if so, to what extent. The doctor may perform further tests to see if the cancer has spread to the bone (bone scan), lungs (x-ray or CT scan) or brain (MRI or CT scan).

Side effects of the procedure include increased risk for infection and pain, swelling in the arm from fluid build-up, and impaired sensation and restricted movement in the affected arm. Patients might ask their doctor about the availability of physical therapy or upper-body exercises after treatment. In two studies, such programs resulted in quicker recovery and no fluid build-up in the arm.

A technique known as a sentinel node biopsy is a less invasive alternative to axillary lymph node dissection. This procedure can help determine if cancer has spread beyond the nodes. If the doctor finds no evidence of cancer, the patient may not need to have a complete axillary lymphadenectomy.

Click the icon to see an image of a sentinel node biopsy.

Sentinel node biopsy involves:

The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
The tracer or dye then flows through the lymphatic system into the sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If they do not show any signs of cancer, it is highly likely that the remaining lymph nodes will be cancer free, making further surgery unnecessary.

Patients who have a sentinel node biopsy tend to have better arm function and a shorter hospital stay than those who have an axillary node biopsy. The American Society of Clinical Oncology's 2005 guidelines recommend sentinel node biopsy instead of axillary lymph node dissection for women with early stage breast cancer who do not have nodes that can be felt during a physical exam. It is still not known if the sentinel node biopsy has any survival advantages compared to standard lymph node removal procedures.

Women often have to wait several days for results of sentinel node biopsies to learn whether they will require another surgery to remove additional lymph nodes. In 2007, the Food and Drug Administration approved the GeneSearch BLN Assay to help speed sentinel node biopsy testing. This molecular-based lab test can detect within 40 minutes whether cancer has spread to nearby lymph nodes. Because the test delivers rapid results while the patient is still on the operating table, it may help spare women the discomforts of a second surgical procedure and help them get treatment earlier.

Prognosis

In the U.S., about 40,460 women will die from breast cancer this year, making it the second most lethal cancer in women. (Lung cancer is the leading cancer killer in women.) The good news is that early detection and new treatments have improved survival rates. The 5-year survival rate for women diagnosed with cancer is 80%. About 88% of women diagnosed with breast cancer will survive at least 10 years. Unfortunately, women in lower social and economic groups still have significantly lower survival rates than women in higher groups.

Several factors are used to determine successful treatment and the possibility for a cure. They include:

The location of the tumor and how far it has spread
Whether the tumor is hormone receptor-positive or -negative
Genetic factors
Tumor size and shape
Rate of cell division
Biologic markers

The good news is that women are living longer with breast cancer, and at this time more than 2 million American women are survivors. Due to better treatment options, from 1990 - 2003, breast cancer mortality rates declined by 24%. However, survivors must live with the uncertainties of possible recurrent cancer and some risk for complications from the treatment itself.

Recurrences of cancer usually develop within 5 years of treatment. However, 25% of recurrences and half of new cancers in the opposite breast occur after 5 years. One study suggested that the risk factors for a first breast cancer do not necessarily place a woman at any higher risk for recurrence. (Women with a first cancer, however, do have a higher risk for a new cancer in the opposite breast. The outlook for such new cancers is independent from those of the first one.)

The location of the tumor is a major factor in outlook:

If the cancer is ductal carcinoma in situ (DCIS) or has not spread to the lymph nodes (is node-negative), the 5-year survival rates with treatment are up to 98%. However, cancer recurs in 9 - 30% of women with node-negative cancers. Recurrence is a potentially life-threatening problem, even if the disease relapses locally in the same breast. In one study of DCIS patients with locally invasive recurrence, 8-year mortality rates were only 12%.
If the lymph nodes contain cancer cells (are node positive) then survival rates fall. If the tumor is larger than 5 cm or there is widespread involvement in the lymph nodes, the cancer is sometimes referred to as locally advanced. In such cases, the survival rate drops to about 75% and below.
If the cancer has spread (metastasized) to other sites (most often the lung, liver, and bone), the average survival time is about 2 years (with some patients living for many years). New drug therapies, particularly aromatase inhibitors, have helped prolong survival for women with metastatic cancer.

The location of the tumor within the breast is an important predictor. Tumors that develop toward the outside of the breast tend to be less serious than those that occur more toward the middle of the breast.

Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.

Hormone receptor-positive cancer is also called "hormone sensitive" because it responds to hormone therapy such as tamoxifen or aromatose inhibitors. Hormone receptor-negative tumors are referred to as "hormone insensitive" or "hormone resistant."

Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) A 2007 study in the Journal of Clinical Oncology indicated that recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical tamoxifen therapy.

Determining a "genetic signature" for a tumor may prove to be a very powerful predictor of the aggressive nature of a breast cancer. Researchers have focused on 70 genes whose activity patterns may help make such predictions. In 2007, the Food and Drug Administration approved MammaPrint, a DNA microarray diagnostic test that profiles these 70 genes. The molecular test may help predict how likely it is that breast cancer will recur within 5 - 10 years. However, the accuracy of the test depends on a woman’s risk. It is more accurate when predicting a low risk for recurrence than a high risk.

The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations offer a survival advantage. Others suggest that they make no difference or even worsen prognosis. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively.

Researchers are investigating numerous substances in tumor cells that may indicate whether or not a cancer is likely to spread. Such chemical markers may help doctors determine treatments, and some may even prove to be targets for future drugs. The following are only a few of the more well-researched markers.

HER2. The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2:

Immunohistochemistry (IHC)
Fluorescence in-situ hybridization (FISH)

Some doctors think that FISH is a more accurate test than IHC. According to 2006 HER2 testing guidelines from the American Society of Clinical Oncology and the College of American Pathologists, either test may be used as long as it is performed by an accredited laboratory. Tests that are not clearly positive or negative should be repeated. Treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) may help women who test positive for HER2.

Angiogenesis Factors. Angiogenesis is the growth of new blood vessels. High levels of angiogenesis factors indicate that the tumor is developing its own supply of blood vessels, which enable the tumor to send colonies of cancer cells into the bloodstream and spread to other parts of the body. Specific angiogenesis factors, such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), may turn out to be important markers for determining treatment and prognosis. The monoclonal antibody bevacizumab (Avastin) targets VEGF. The drug is showing promise in clinical trials for prolonging progression-free survival in women with metastatic breast cancer.

Others. Many other markers are being investigated, including p53, cathepsin-D, protein c-erbB-2, bcl-2, Ki-67, telomerase, thymidylate synthase, CA 15-3, and carcinogenic embryonic antigen (CEA). The American Society of Clinical Oncology (ASCO) cautions, however, that the value of many of these factors has not yet been confirmed.

Tumor Size and Shape. Large tumors pose a higher risk than small tumors. Undifferentiated tumors, which have indistinct margins, are more dangerous than those with well-defined margins.

Rate of Cell Division. The more rapidly a tumor grows, the more dangerous it is. Several tests measure aspects of cancer cell division and may eventually prove to predict the disease. For example, the mitotic index (MI) is a measurement of the rate at which cells divide. The higher the MI, the more aggressive the cancer. Another test measures cells at a certain phase of their division.

Recent evidence has not supported early reports of survival benefits for women with metastatic breast cancer who engage in support groups. However, some studies have suggested that psychotherapy, group support, or both may relieve pain and reduce stress, particularly in women who are suffering emotionally.

Stress has been ruled out as a risk factor either for breast cancer itself or for its recurrence.

Treatment

The three major treatments of breast cancer are surgery, radiation, and drug therapy. No one treatment fits every patient, and combination therapy is usually required. The choice is determined by many factors, including the age of the patient, menopausal status, the kind of cancer (ductal vs. lobular), its stage, and whether or not the tumor contains hormone-receptors.

Breast cancer treatments are defined as local or systemic:

Local Treatment. Surgery and radiation are considered local therapies because they directly treat the tumor, breast, lymph nodes, or other specific regions. Surgery is usually the standard initial treatment.
Systemic Treatment. Drug treatment is called systemic therapy, because it affects the whole body.

Any or all of these therapies may be used separately or, most often, in different combinations. For example, radiation alone or with chemotherapy or hormone therapy may be beneficial before surgery, if the tumor is large or not easily removed at prevention. Surgery followed by radiation and hormone therapy is usually recommended for women with early-stage, hormone-sensitive cancer. There are numerous clinical trials investigating new treatments and treatment combinations. Patients, especially those with advanced stages of cancer, may wish to consider enrolling in a clinical trial.

Treatment strategies depend in part on the stage of the cancer.

Stage 0 (Carcinoma in Situ). Stage 0 breast cancer is considered non-invasive (‘in situ"), meaning that the cancer is still confined within breast ducts or lobules and has not yet spread to surrounding tissues. Stage 0 cancer is classified as either:

Ductal carcinoma in situ (DCIS). These are cancer cells in the lining of a duct that have not invaded the surrounding breast tissue.
Lobular carcinoma in situ (LCIS). These are cancer cells in the lobules of the breast. LCIS rarely develops into invasive breast cancer, but having it in one breast increases the risk of developing cancer in the other breast.

Treatment options for DCIS include:

Breast-conserving surgery and radiation therapy (followed by hormone therapy for women with hormone-sensitive cancer)
Total mastectomy (followed by hormone therapy for women with hormone-sensitive cancer)
Breast-conserving surgery without radiation therapy

Treatment options for LCIS include:

Regular exams and mammograms to monitor any potential changes (observation treatment)
Hormone therapy to prevent development of breast cancer (for women with hormone-sensitive cancer)
Mastectomy of both breasts was previously used as treatment, but is now rarely recommended

Stage I and II (Early-Stage Invasive). In stage I cancer, cancer cells have not spread beyond the breast, and the tumor is no more than 2 cm (about 3/4 of an inch) across.

Stage II cancer is classified as either stage IIA or stage IIb.

In stage IIA cancer the tumor is either:

No more than 2 centimeters and has spread to the underarm lymph nodes (axillary lymph nodes)
Between 2 - 5 centimeters and has not spread to the underarm lymph nodes

Treatment options for stage I and stage II breast cancer may include:

Breast-conserving surgery (such as lumpectomy) followed by radiation therapy
Modified radical mastectomy with or without breast reconstruction
Post-surgical therapy (adjuvant therapy), including radiation of lymph nodes, chemotherapy, or hormone therapy
Trastuzumab (Herceptin) given along with or following adjuvant chemotherapy for women with HER2-positive cancer

Stage III (Locally Advanced). Stage III breast cancer is classified into several sub-categories: Stage IIIA, stage IIIB, and stage IIIC (operable or inoperable).

In stage IIIA breast cancer, the tumor is usually confined to the underarm lymph nodes. Treatment options for stage IIIA breast cancer are the same as those for stages I and II.

In stage IIIB breast cancer, the tumor has spread to either:

Tissues near the breast (including the skin or chest wall)
Lymph nodes within the breast or under the arm

Stage IIIB treatment options may include:

Chemotherapy, and possibly hormone therapy (sometimes in combination with chemotherapy)
Chemotherapy followed by surgery (breast-conserving surgery or total mastectomy) with lymph node dissection followed by radiation therapy and possibly more chemotherapy or hormone therapy
Clinical trials

Stage IIIC breast cancer is classified as either operable or inoperable.

In operable stage IIIC, the cancer may be found in:

10 or more of the underarm lymph nodes
Lymph nodes beneath the collarbone and near the neck on the same side of the body as the affected breast
Lymph nodes within the breast as well as underarm lymph nodes

Treatment options for operable stage III breast cancer are the same as those for stage I and II breast cancers.

In inoperable stage III breast cancer, the cancer has spread to lymph nodes above the collarbone and near the neck on the same side of the body as the affected breast. Treatment options are the same as those for stage IIIB.

Stage IV (Advanced Cancer). In stage IV, the cancer has spread (metastasized) from the breast to other parts of the body. In about 75% of cases, the cancer has spread to the bone. The cancer at this stage is considered to be chronic and incurable, and the usefulness of treatments is limited. The goals of treatment for stage IV cancer are to stabilize the disease and slow its progression, as well as to reduce pain and discomfort.

Treatment options for stage IV cancer include:

Surgery or radiation for any localized tumors in the breast. A 2006 study indicated that surgical removal of the primary tumor immediately after metastatic cancer diagnosis can dramatically improve survival.
Chemotherapy, hormone therapy, or both. Targeted therapy with trastuzumab (Herceptin) or lapatinib (Tykerb) should be considered for women with HER2-positive cancer.
Cancer that has spread to the brain may require radiation and high-dose steroids.
Cancer that has spread to the bone may be helped by radiation or bisphosphonate drugs. Such treatments can relieve pain and help prevent bone fractures.
Clinical trials of new drugs or drug combinations, or experimental treatments such as high-dose chemotherapy with stem cell transplant.

In 2006, the American Society of Clinical Oncology (ASCO) released updated guidelines on follow-up care for patients who have been treated for breast cancer. ASCO recommends:

Visit your doctor every 3 - 6 months for the first 3 years after your first cancer treatment, every 6 - 12 months during the fourth and fifth year, and once a year thereafter.
Have a mammogram 1 year after the mammogram that diagnosed your cancer (but no earlier than 6 months after radiation therapy), and every 6 - 12 months thereafter.
Perform a breast self-exam every month (however, this is no substitute for a mammogram).
See your gynecologist regularly (women taking tamoxifen should be sure to report any vaginal bleeding).
A year after diagnosis, you can either continue to see your oncologist or transfer your care to your primary care physician.
If you are on hormone therapy, discuss with your oncologist how often to schedule follow-up visits for re-evaluation of your treatment.

ASCO does not recommend the use of laboratory blood tests (complete blood counts, carcinoembryonic antigen) or imaging tests (bone scans, chest x-rays, liver ultrasound, FDG-PET scan, CT scan) for routine breast cancer follow-up.

Genetic counseling may be helpful if you have:

Ashkenazi Jewish heritage
Personal or family history of ovarian cancer
Personal or family history of cancer in both breasts
Any first-degree female relative (mother, sister, daughter) diagnosed with breast cancer before age 50
Two or more first-degree or second-degree (grandparent, aunt, uncle) diagnosed with breast cancer
History of breast cancer in a male relative

Pregnancy after Breast Cancer Treatment. There are no definite recommendations on how long a woman should wait to become pregnant after breast cancer treatment. Because of the connection between estrogen levels and breast cancer cell growth, some experts recommend delaying pregnancy until 2 years after treatment in order to reduce the risk of cancer recurrence and improve odds for survival. However, a 2007 study indicated that conceiving 6 months after treatment does not negatively affect survival. Discuss with your doctor your risk for recurrence, and when it may be safe to attempt pregnancy.

Recurrent breast cancer is considered to be an advanced cancer. In such cases, the disease has come back in spite of the initial treatment. Most recurrences appear within the first 2 - 3 years after treatment, but breast cancer can recur many years later. Treatment options are based on the stage at which the cancer reappears, whether or not the tumor is hormone responsive, and the age of the patient. Between 10 - 20% of recurring cancers are local. Most recurrent cancers are metastatic. All patients with recurring cancer are candidates for clinical trials.

Because most breast cancer recurrences are discovered by patients in between doctor visits, it is important to notify your doctor if you experience any of the following symptoms. These symptoms may be signs of breast cancer recurrence:

New lumps in the breast
Bone pain
Chest pain
Abdominal pain
Shortness of breath or difficulty breathing
Persistent headaches or coughing
Rash on breast
Nipple discharge

Surgery

Surgery forms a part of nearly every patient's treatment for breast cancer. The initial surgical intervention is often a lumpectomy, the removal of the tumor itself. In the past, mastectomy (the removal of the breast) was the standard treatment for nearly all breast cancers. Now, many patients with early-stage cancers can choose breast-conserving treatment, or lumpectomy followed by radiation, with or without chemotherapy.

For invasive breast cancer, studies indicate that lumpectomy or partial mastectomy combined with radiation therapy works as well as a modified radical mastectomy.

Breast-conserving procedures are now appropriate and as successful as mastectomy in most women with early stage breast cancer. All women should discuss these options fully with their doctor. Recurrence rates with conservative surgery are highest in women under age 45. Some women choose mastectomy over breast-conserving treatment even if the latter is appropriate because it gives them a greater sense of security and allows them to avoid radiation therapy.

Lumpectomy. Lumpectomy is the removal of the tumor, often along with lymph nodes in the armpit. It serves as an opportunity for biopsy, a diagnostic tool, and a primary treatment for small local breast tumors. If invasive cancer is found, the doctor will decide to proceed with breast radiation therapy, to remove additional tissue (should the margins of the specimen show signs of cancer), or to perform a mastectomy. Lumpectomy followed by radiation therapy is appropriate and as effective as mastectomy in most women with Stage I or II breast cancers.

Click the icon to see an illustrated series detailing breast lump removal surgery.

Breast-Conserving Surgery (Quadrantectomy). Breast-conserving surgery (sometimes referred to as quadrantectomy) removes the cancer and a large area of breast tissue, occasionally including some of the lining over the chest muscles. It is less invasive than a full mastectomy, but the cosmetic results are less satisfactory than with a lumpectomy. Excellent studies have found that breast-conserving surgeries plus postoperative radiotherapy offer the same survival rates as radical mastectomy in women with early breast cancer. A new technology called partial breast radiation (MammoSite), approved by the Food and Drug Administration in 2002, confines radiation to the tumor site rather than delivering it to the whole breast, and reduces treatment time from 5 weeks to 5 days in women who undergo breast conserving surgery.

Surgery to remove the breast (mastectomy) is important for women with operable breast cancer who are not candidates for breast conserving surgeries. There are different variations on the procedure:

A total mastectomy involves removal of the whole breast and sometimes lymph nodes under the armpit.
A radical mastectomy removes the breast, chest muscles, all of the lymph nodes under the arm, and some additional fat and skin. (A modified radical mastectomy removes the entire breast and armpit lymph nodes, with the underlying chest wall muscle.) A 25-year study supported other research that observed no survival advantages from radical mastectomy compared to the less invasive mastectomies for the great majority of patients. It is rarely used anymore except when cancer is very advanced.

Click the icon to see an illustrated series detailing mastectomy surgery.

Complications and Side Effects of Surgery. Short-term pain and tenderness occur in the area of the procedure, and pain relievers may be necessary.

The most frequent complication of extensive lymph node removal is edema, or swelling, of the arm, which is usually mild and rarely painful but does increase the risk for infection. The likelihood of edema can be lessened by removing only some of the lymph nodes instead of all of them.

Infrequent complications include poor wound healing, bleeding, or a reaction to the anesthesia.

After mastectomy and lymph node removal, women may experience numbness, tingling, and difficulty in extending the arm fully. These effects can last for months or years afterward.

After a mastectomy, some women choose a breast prosthesis or opt for breast reconstruction, which can be performed during the mastectomy itself, if desired. Several studies have indicated that women who take advantage of cosmetic surgery after breast cancer have a better sense of well-being and a higher quality of life than women who do not choose reconstructive surgery. The breast is reshaped using a saline implant or, for a more cosmetic result, a muscle flap is taken from elsewhere in the body. Muscle flap procedures are more complicated, however, and blood transfusions may be required. (It should be noted that implants, including silicone implants, do not appear to put a woman at risk for breast cancer recurrence.) If the nipple is removed, it is rebuilt from other body tissues and color is applied using tattoo techniques. It is nearly impossible to rebuild a breast that is identical to its partner, and additional operations may be necessary to achieve a desirable effect.

Click the icon to see an illustrated series detailing breast reconstruction surgery.

Numerous studies are investigating minimally invasive techniques that use lasers, deep-freezing of cancer cells (cryosurgery), high-intensity ultrasound, and other experimental approaches to kill cancer cells and reduce severe complications of surgery. Radiofrequency ablation, for example, is an approach that uses an electrode inserted into the tumor. It emits radio waves that produce enough heat to destroy cancer cells. Early trials are promising. These procedures, however, are not considered standard at the present time.

Radiation

Radiation therapy uses high-energy x-rays to kill cancer cells or to shrink the size of a tumor in the breast or surrounding tissue. It is used for several weeks following lumpectomy or partial mastectomy, and sometimes after full mastectomy. Radiation therapy can help reduce the chance of breast cancer recurrence in the breast and chest wall. Radiation is also important in advanced stages of cancer for relief of symptoms and to slow progression. Research shows that radiation therapy is helpful for women of all ages, including those over age 65.

Radiation is generally administered in the following ways:

External Beam Radiation. This type of radiation is administered 4 - 6 weeks after surgery and delivered externally by an x-ray machine that targets radiation to the whole breast. It may be delivered to the chest wall in high-risk patients (large tumors, close surgical margins, or lymph node involvement). The treatment is generally given daily (except for weekends) for about 6 weeks. A follow-up boost of radiation therapy in patients with lumpectomies appears to reduce the risk for recurrence.

Brachytherapy. Less commonly, radiation is delivered in implants (called brachytherapy). Implants are most often used as a radiation boost after whole breast radiation. Studies suggest they improve survival in patients at high risk for local recurrence. Some evidence suggests that implants alone can reduce treatment time and may be as effective as external beam radiation in some patients with early stage breast cancer. A new technology for breast brachytherapy (MammoSite) was approved in 2002. The technique provides 5-year local tumor control rates similar to those of whole-breast radiation for selected patients, with much shorter treatment time and good cosmetic results.

Investigators are also testing other approaches to radiation treatment. One uses a combination of neutrons and protons (mixed-beam) or proton beams rather than the standard photon radiation therapy. Intensity-modulated radiation therapy is a promising technique that delivers different doses to multiple target areas using images of specific regions. Such an approach may improve the coverage of breast cancers while reducing the toxic effects to the heart and lungs.

Side effects of radiation include:

Fatigue is very common and increases with subsequent treatments, but most women are able to continue with normal activities. Exercise may be helpful.
Nausea and lack of appetite may develop and worsen as treatment progresses.
Skin changes and burns can occur on the breast skin. Using a cream that contains a corticosteroid, such as mometasone furoate (MMF), may be helpful. After repeated sessions, the skin may become moist and "weepy." Exposing the treated skin to air as much as possible helps healing. (Washing the affected skin with soap and water does not seem to be harmful and in one study was associated with a lower risk for this side effect.)
Uncommonly, the breast may change color, size, or become permanently firm.
Rarely, the nearest arm may swell and develop impaired mobility or even paralysis.

Future complications include:

Radiation to the left breast may increase the long-term risk for developing heart disease and heart attacks.
There is a very small risk (less than 1%) of lung irritation and scarring.
Some studies have reported a higher risk for future cancer in the opposite breast in younger women who have been given radiation to the chest wall.
Radiation therapy can increase the risk of developing other cancers, such as soft tissue malignancies known as sarcomas.

Current advanced imaging techniques use precise radiation that reduces exposure. These newer techniques are likely to reduce the risks for heart disease and other serious complications.

Medications

The most important advances in the cure of breast cancer have come through the use of drug therapy, also called systemic therapy. Surgery and radiation therapy are effective for treating tumors confined to the breast but not for cancer cells that have spread or are at risk of spreading. In such cases, drug therapy is needed.

Drug treatments for breast cancer include:

Chemotherapy. Chemotherapy drugs are "cytotoxic" (cell-killing) drugs. They are given orally or by injection. They work systemically by killing cancer cells throughout the body. (Unfortunately, they also kill normal cells, which accounts for many of their side effects.) Chemotherapy is always used for advanced breast cancer, but may also be used to treat types of early-stage breast cancer.
Hormone Therapy. The goal of hormone therapy is to prevent estrogen from stimulating breast cancer cells. It is recommended for women whose breast cancers are hormone-receptor positive (either estrogen or progesterone), regardless of the size of the tumor and whether or not it has spread to the lymph nodes. Like chemotherapy, hormone therapy works systemically.
Targeted Therapy. Newer biologic drugs target specific proteins involved in cancer. Because they do not work as systemically as chemotherapy or hormone therapy drugs, they tend to cause fewer widespread side effects. Currently, the monoclonal antibody trastuzumab (Herceptin) and the kinase inhibitor lapatinib (Tykerb) are the two targeted therapies approved for breast cancer. These drugs target the HER2/neu protein and are used to treat HER2-positive breast cancers. Bevacizumab (Avastatin) is a monoclonal antibody that targets vascular endothelial growth factor (VEGF), a protein involved in tumor blood vessel formation (angiogenesis). It is being studied in clinical trials for treatment of metastatic breast cancer.

Drug therapy may be used as:

Primary therapy for patients for whom surgery or radiation therapy is not appropriate.
Neoadjuvant therapy (before surgery or radiation) to shrink tumors to a size that can be treated with local therapy.
Adjuvant therapy (following surgery or radiation) to reduce the risk of cancer recurrence.

For metastatic cancer, drugs are used not to cure but to improve quality of life and prolong survival.

Chemotherapy

Chemotherapy needs to be tailored to the type of cancer involved. Women require different treatments depending on whether the tumor is node-negative or -positive, hormone receptor-positive or -negative, or HER2-positive or -negative. Different treatment approaches are also used for early-stage cancer and advanced cancer.

A 2006 study in the Journal of the American Medical Association indicated that women with hormone receptor-negative cancers respond better to chemotherapy than women with hormone receptor-positive cancer. However, some women with hormone receptor-positive cancer do benefit from chemotherapy, as well as from hormone therapy.

Adjuvant chemotherapy is administered following surgery and before radiation therapy. A 2007 study in the Journal of Clinical Oncology suggested that women with early-stage breast cancer can safely wait for up to 12 weeks after surgery before beginning chemotherapy. However, delaying chemotherapy until more than 12 weeks after surgery significantly increases the risk for breast cancer recurrence and can reduce the odds for survival by as much as 60%.

Many different types of chemotherapy drugs are used to treat breast cancer. Common types of chemotherapy drug classes include:

Anthracyclines include doxorubicin (Adriamycin) and epirubicin (Ellence). Anthracycline-based combination regimens are often used to treat early-stage breast cancer, as well as advanced cancer.
Taxanes include paclitaxel (Taxol) and docetaxel (Taxotere). Two 2003 studies suggested that taxane-based therapy is particularly helpful for node-positive breast cancer. A newer formulation of paclitaxel (Abraxane) is used as a secondary treatment for advanced breast cancer.
Platinum-based drugs include oxaliplatin (Eloxatin) and carboplatin (Paraplatin). These drugs may be used in combination regiments for advanced cancer or for cancers associated with BRCA genes.

Some of the abbreviations used for chemotherapy drug combinations (regimens) refer to drug classes rather than drug names. For example, regimens that contain an anthracycline drug (such as doxorubicin) use the letter "A," and regimens that contain a taxane drug (such as docetaxel) use the letter "T." Cyclophosphamide (Cytoxan), fluorouracil (5-FU), and methotrexate (MTX) are standard cancer drugs used in many breast cancer chemotherapy regimens.

Chemotherapy regimens usually consist of 4 - 6 cycles of treatment given over 3 - 6 months. Common chemotherapy regimens for early-stage breast cancer include:

AC (Doxorubicin and cyclophosphamide)
AC followed by T (Doxorubicin and cylophosphamide followed by paclitaxel)
CAF (Cyclophosphamide, doxorubicin, and 5-FU)
CMF (Cyclophosphamide, methotrexate, and 5-FU)
TAC (Docetaxel, doxorubicin, and cyclophosphamide)

Trastuzumab (Herceptin). Trastuzumab is a monoclonal antibody that targets the HER2 protein on cancer cells. HER2-positive cancers account for 15 - 25% of early-stage breast cancer and are associated with more aggressive disease. Younger women tend to be most affected. In November 2006, the Food and Drug Administration approved trastuzumab for treatment of HER2-positive, early-stage breast cancer (cancer confined to the breasts or lymph nodes that has been surgically removed). Trastuzumab is given along with other chemotherapy drugs following lumpectomy or mastectomy. Research indicates that trastuzumab can help prevent cancer recurrence and death among women with early-stage breast cancer, but it increases the risk of heart problems. Trastuzumab can cause heart failure. Women who have heart failure or weak heart muscle (cardiomyopathy) should not use this drug. Women who take trastuzumab need to have regular heart monitoring, especially if they have already have heart problems.

Patients who develop metastatic disease (cancer that spreads throughout the body) are generally not curable. New advances in drug therapies, however, can help shrink tumors, prolong survival, and improve quality of life.

Chemotherapy regimens for advanced cancer may use a single drug or a combination of drugs. Many chemotherapy regimens used for early-stage breast cancer are also used for advanced breast cancer. Some specific combinations for advanced cancer include:

Gemcitabine and paclitaxel. In 2004, the Food and Drug Administration approved the antimetabolite drug gemcitabine (Gemzar) for use in combination with paclitaxel (Taxol) as a first-line treatment option for women with metastatic breast cancer.
Capecitabine (Xeloda) and docetaxel (Taxotere). Capecitabine is an oral drug that is chemically related to 5-FU. It is also being studied in combination with many other drugs.

Numerous chemotherapy drugs and drug combinations are being tested in clinical trials. Patients with advanced breast cancer may also receive other types of drug treatments. Bisphosphonate drugs, such as zoledronic acid (Zometa) and pamidronate (Aredia), are important supportive drugs for preventing fractures and reducing pain in people whose cancer has spread to the bones.

Two targeted therapy drugs are approved for the treatment of HER2-positive advanced breast cancer

Trastuzumab (Herceptin) was approved in 1998 for treatment of metastatic breast cancer. It is used in adjuvant chemotherapy, along with drugs such as paclitaxel.
Lapatinib (Tykerb) was approved in March 2007 for patients who have not been helped by other cancer drugs, including an anthracycline, a taxane, or trastuzumab. Lapatinib is used in combination with capecitabine (Xeloda). Research suggests it may have fewer risks for heart problems than trastuzumab.

Promising new treatments for advanced breast cancer include:

Ixabepilone (BMS-247550). Ixabepilone is the first of a new class of cancer drugs called epothilones. It is showing encouraging results when combined with capecitabine, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin). Bevacizumab is a targeted therapy anti-angiogenesis drug approved for treatment of colorectal and lung cancers. It is being studied in combination with various chemotherapy drugs for treatment of advanced cancer.

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment.

Common side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects. In one study, a combination of dexamethasone (a corticosteroid) with ondansetron taken within 24 hours of chemotherapy achieved either a major or complete reduction in nausea and vomiting. Aprepitant (Emend), a new drug for preventing chemotherapy-caused nausea and vomiting, was approved in 2006.
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. They include the following:

Anemia. The erythropoietins epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) stimulate red blood cell production and can help reduce or prevent anemia, resulting in significant improvement in quality of life. Aranesp persists longer in the blood than epoetin alfa and may therefore require fewer injections.
Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection.
Liver and kidney damage.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction, particularly to platinum-based drugs.
Menstrual abnormalities and infertility. Premature menopause occurs in about 30% of women, particularly in those over 40. A natural hormone medication called a gonadotropin-releasing hormone analogue, which puts women in a temporary pre-pubescent state during chemotherapy, may preserve fertility in some women. Women may also wish to consider embryo cryopreservation -- the harvesting of eggs, followed by in vitro fertilization and freezing of embryos for later use. The American Society of Clinical Oncology recommends that women being treated for cancer see a reproductive specialist to discuss all available fertility preservation options.
Sexual dysfunction.
Rarely, secondary cancers such as leukemia.
A quarter to a third of women report problems in concentration, motor function, and memory, which can be long-term. In one study, women were having these symptoms 2 years after treatment, although by 4 years they had resolved.
Heart problems. Trastuzumab (Herceptin) may increase the risk for heart failure, particularly in women with pre-existing risk factors. Cumulative doses of anthracyclines (doxorubicin, epirubicin) can also damage heart muscles over time and increase the risk for heart failure.
Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur, more often in taxol than taxotere. Taking a steroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, relievable with corticosteroids.

High-dose chemotherapy along with peripheral-blood stem cell rescue or bone marrow transplantation procedures have been used for cancer that has metastasized and, in some cases, for earlier stages of breast cancer in high-risk patients. The objective of this treatment is to be able to give patients very high toxic doses of cell-killing drugs.

Transplantation procedures are based on stem cells, which are produced in the bone marrow. Stem cells are the early forms for all blood cells in the body (including red, white, and immune cells). Cancer treatments can harm these growing cells as well as cancer cells.

Despite the initial enthusiasm over the use of high-dose therapy for treatment of high risk breast cancer, this approach can no longer be generally recommended and should not be used outside of a clinical trial setting. The results of several randomized studies have failed to show a convincing advantage for the use of high-dose therapy. Nevertheless, some experts believe this approach can still be useful in selected patients, and studies continue. In general, however, transplantation has a limited role in breast cancer management, and its use should be restricted to clinical trials.

Hormone Therapy

Hormone therapy works by blocking estrogen that causes cell proliferation. It is used only for patients with hormone receptor-positive tumors. Different types of hormone therapy work in different ways by:

Blocking estrogen receptors in cancer cells (Tamoxifen)
Suppressing estrogen production in the body (Aromatase inhibitors)
Destroying ovaries, which produce estrogen (Ovarian ablation)

Tamoxifen was the first widely used hormonal therapy drug, but it has been replaced by aromatase inhibitors for some women. Aromatase inhibitors are used only to treat postmenopausal women. Tamoxifen is mainly used as adjuvant therapy for premenopausal women with hormone-sensitive breast cancer.

Tamoxifen (Nolvadex) has been the standard hormonal drug used for breast cancer. It belongs to a class of compounds called selective estrogen receptor modulators (SERMs). SERMs chemically resemble estrogen and trick the breast cancer cells into accepting it in place of estrogen. Unlike estrogen, however, they do not stimulate breast cancer cell growth. Because SERMs block estrogen’s effects on cancer cells, they are sometimes referred to as "anti-estrogen" drugs.

Tamoxifen is used for all cancer stages in women of all ages with hormone receptor-positive cancers. In addition, it is used to prevent breast cancer in high-risk women. Another SERM drug, toremifene (Fareston), is an option for women with advanced cancer, but this drug is rarely used in the United States. A third drug, fulvestrant (Faslodex), works in a similar anti-estrogen way to tamoxifen but belongs to a different drug class. Fulvestrant is approved only for postmenopausal women with hormone-sensitive advanced breast cancer in which tamoxifen or aromatase inhibitors no longer work.

To prevent cancer recurrence, women should take tamoxifen for 5 years following surgery and radiation. Tamoxifen is an effective cancer treatment, but it can cause unpleasant side effects and has small (less than 1%) but serious risks for blood clots and uterine (endometrial) cancer. Immediately report any signs of vaginal bleeding to the doctor, as this may be a symptom of uterine cancer.

Less serious, but discomforting, side effects include hot flashes and mood swings. According to a 2007 study, nearly 25% of women stop taking tamoxifen within 1 year because of these symptoms. By 3.5 years, over 33% stop treatment. Taking tamoxifen for fewer than 5 years, however, increases the risk for cancer recurrence and death. Talk with your doctor about antidepressants or other therapies that may help you cope with tamoxifen’s side effects.

Many doctors now recommend that postmenopausal women switch to an aromatase inhibitor after 2 - 3 years of tamoxifen therapy. Several 2007 studies indicated that switching from tamoxifen to an aromatase inhibitor significantly improves survival rates and reduces the risk of death from breast cancer as well as other causes.

Endometrial cancer is a cancerous growth of the endometrium (lining of the uterus). It is the most common uterine cancer.

Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues, including the breast, muscle, liver, and fat. Aromatase inhibitors work differently than tamoxifen. Tamoxifen interferes with tumors’ ability to use estrogen by blocking their estrogen receptors. Aromatase inhibitors reduce the overall amount of estrogen in the body.

Because these drugs cannot stop the ovaries of premenopausal women from producing estrogen, they are recommended only for postmenopausal women.

There are currently three aromatase inhibitors approved for treating early-stage, hormone receptor-positive breast cancer in postmenopausal women:

Anastrazole (Armidex) for treatment after surgery
Exemestane (Aromasin) for women who have taken tamoxifen for 2 - 3 years
Letrozole (Femara) for treatment after surgery or for women who have completed 5 years of tamoxifen therapy

All of these drugs are also approved for women with advanced (metastatic) hormone-sensitive breast cancer. Studies indicate that the introduction of aromatase inhibitors has helped greatly in prolonging survival for women with advanced cancer.

Compared to tamoxifen, aromatase inhibitors are less likely to cause blood clots and uterine cancer. However, these drugs are more likely to cause osteoporosis, which can lead to bone loss and fractures. In general, recent studies indicate that aromatase inhibitors are better than tamoxifen in improving survival and reducing the risk of cancer recurrence. Unfortunately, like tamoxifen, they can cause hot flashes, as well as joint pain.

Ovarian ablation literally shuts down estrogen production from the ovaries. Medications can accomplish ovarian ablation. Destroying the ovaries with surgery or radiation can also shut down estrogen production. (Osteoporosis is one serious side effect of this approach, but several therapies are available to help prevent bone loss.)

Chemical Ovarian Ablation. Drug treatment (non-chemotherapy drugs) to block ovarian production of estrogen is called chemical ovarian ablation. It is often reversible. The primary drugs used are luteinizing hormone-releasing hormone (LHRH) agonists, such as goserelin (Zoladex). (They are also sometimes called GnRH agonists). These drugs block the release of the reproductive hormones LH-RH, therefore stopping ovulation and estrogen production.

Studies suggest that women with estrogen-positive early stage cancer who take goserelin have similar survival rates to those who take standard chemotherapy. They also experience fewer serious side effects. A major analysis of four trials using LHRH agonists plus tamoxifen suggested that this combination should be the standard for patients with advanced breast cancers that are hormone-receptor positive, although this is an area of controversy. (Chemotherapy is still more effective in women with estrogen-negative tumors.)

Ovariectomy. Ovariectomy, the removal of the ovaries, has modestly improved breast cancer survival rates in some premenopausal women whose tumors are hormone receptor-positive. In these women, combining this procedure with tamoxifen may improve results beyond those of standard chemotherapies. Ovariectomy does not benefit women after menopause, and its advantages can be blunted in women who have received adjuvant chemotherapy. The procedure causes sterility and can have a major negative emotional impact on younger patients.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.asco.org -- American Society of Clinical Oncology
www.oncolink.org -- Oncolink
www.womenshealth.gov -- National Women's Health Information Center
www.nccn.org -- National Comprehensive Cancer Network
www.plwc.org -- People Living With Cancer
www.cancer.gov/clinicaltrials -- Find clinical trials
www.breastcancer.org -- Find clinical trials

References

Bardia A, Hartmann LC, Vachon CM, Vierkant RA, Wang AH, Olson JE, et al. Recreational physical activity and risk of postmenopausal breast cancer based on hormone receptor status. Arch Intern Med. 2006 Dec 11-25;166(22):2478-83.

Barron TI, Connolly R, Bennett K, Feely J, Kennedy MJ. Early discontinuation of tamoxifen: a lesson for oncologists. Cancer. 2007 Mar 1;109(5):832-9.

Boccardo F, Rubagotti A, Aldrighetti D, Buzzi F, Cruciani G, Farris A, et al. Switching to an aromatase inhibitor provides mortality benefit in early breast carcinoma: pooled analysis of 2 consecutive trials. Cancer. 2007 Mar 15;109(6):1060-7.

Boehm JS, Zhao JJ, Yao J, Kim SY, Firestein R, Dunn IF, et al. Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell. 2007 Jun 15;129(6):1065-79.

Boyd NF, Guo H, Martin LJ, Sun L, Stone J, Fishell E, et al. Mammographic density and the risk and detection of breast cancer. N Engl J Med. 2007 Jan 18;356(3):227-36.

Breen N, A Cronin K, Meissner HI, Taplin SH, Tangka FK, Tiro JA, et al. Reported drop in mammography : is this cause for concern? Cancer. 2007 Jun 15;109(12):2405-9.

Chia SK, Speers CH, D'Yachkova Y, Kang A, Malfair-Taylor S, Barnett J, et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer. 2007 Jul 23;110(5):973-979 [Epub ahead of print]

Cho E, Chen WY, Hunter DJ, Stampfer MJ, Colditz GA, Hankinson SE, et al. Red meat intake and risk of breast cancer among premenopausal women. Arch Intern Med. 2006 Nov 13;166(20):2253-9.

Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, et al. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70.

Fenton JJ, Taplin SH, Carney PA, Abraham L, Sickles EA, D'Orsi C, et al. Influence of computer-aided detection on performance of screening mammography. N Engl J Med. 2007 Apr 5;356(14):1399-409.

Geiger AM, Thwin SS, Lash TL, Buist DS, Prout MN, Wei F, et al. Recurrences and second primary breast cancers in older women with initial early-stage disease. Cancer. 2007 Mar 1;109(5):966-74.

Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43.

Ives A, Saunders C, Bulsara M, Semmens J. Pregnancy after breast cancer: population based study. BMJ. 2007 Jan 27;334(7586):194. Epub 2006 Dec 8.

Jatoi I, Chen BE, Anderson WF, Rosenberg PS. Breast cancer mortality trends in the United States according to estrogen receptor status and age at diagnosis. J Clin Oncol. 2007 May 1;25(13):1683-90. Epub 2007 Apr 2.

Kahlenborn C, Modugno F, Potter DM, Severs WB. Oral contraceptive use as a risk factor for premenopausal breast cancer: a meta-analysis. Mayo Clin Proc. 2006 Oct;81(10):1290-302.

Kerlikowske K, Miglioretti DL, Buist DS, Walker R, Carney PA; National Cancer Institute-Sponsored Breast Cancer Surveillance Consortium. Declines in invasive breast cancer and use of postmenopausal hormone therapy in a screening mammography population. J Natl Cancer Inst. 2007 Sep 5;99(17):1335-9. Epub 2007 Aug 14.

Khatcheressian JL, Wolff AC, Smith TJ, Grunfeld E, Muss HB, Vogel VG, et al.American Society of Clinical Oncology 2006 update of the breast cancer follow-up and management guidelines in the adjuvant setting. J Clin Oncol. 2006 Nov 1;24(31):5091-7. Epub 2006 Oct 10.

Lehman CD, Gatsonis C, Kuhl CK, Hendrick RE, Pisano ED, Hanna L, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med. 2007 Mar 29;356(13):1295-303. Epub 2007 Mar 28.

Lin J, Manson JE, Lee IM, Cook NR, Buring JE, Zhang SM. Intakes of calcium and vitamin D and breast cancer risk in women. Arch Intern Med. 2007 May 28;167(10):1050-9.

Lohrisch C, Paltiel C, Gelmon K, Speers C, Taylor S, Barnett J, et al. Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol. 2006 Oct 20;24(30):4888-94. Epub 2006 Oct 2.

Michels KB, Xue F, Colditz GA, Willett WC. Induced and spontaneous abortion and incidence of breast cancer among young women: a prospective cohort study. Arch Intern Med. 2007 Apr 23;167(:814-20.

Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L. Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial. Lancet. 2006 Dec 9;368(9552):2053-60.

North American Menopause Society. Estrogen and progestogen use in peri- and postmenopausal women: March 2007 position statement of The North American Menopause Society. Menopause. 2007 Mar-Apr;14(2):168-82.

Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, et al. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2.

Pierce JP, Natarajan L, Caan BJ, Parker BA, Greenberg ER, Flatt SW, et al. Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women's Healthy Eating and Living (WHEL) randomized trial. JAMA. 2007 Jul 18;298(3):289-98.

Qaseem A, Snow V, Sherif K, Aronson M, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Screening mammography for women 40 to 49 years of age: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007 Apr 3;146(7):511-5.

Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19;356(16):1670-4.

Saslow D, Boetes C, Burke W, Harms S, Leach MO, Lehman CD, et al. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007 Mar-Apr;57(2):75-89.

Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36.

Terry KL, Willett WC, Rich-Edwards JW, Michels KB. A prospective study of infertility due to ovulatory disorders, ovulation induction, and incidence of breast cancer. Arch Intern Med. 2006 Dec 11-25;166(22):2484-9.

Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007 Jan 1;25(1):118-45. Epub 2006 Dec 11.

Review Date:
1/26/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (11/01/07).

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adam.com

Ovarian cancer

FitSugar — Wed, 08 Oct 2008 17:34:58 -0700

In This Report

Highlights
Introduction
Symptoms
Causes
Prevention
Diagnosis
Prognosis
Treatment
Surgery
Medications
Radiation Therapy
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Ovarian Cancer Symptoms

Even early-stage ovarian cancer can produce symptoms, according to a 2007 consensus statement issued by the American Cancer Society, the Gynecologic Cancer Foundation, and the Society of Gynecologic Oncologists. Because ovarian cancer can grow very rapidly, early detection is extremely important. Contact your doctor (preferably a gynecologist) if you experience these symptoms on a daily basis for more than a few weeks:

Bloating
Pelvic or abdominal pain
Difficulty eating or feeling full quickly
Urgent or frequent urination

Hormone Replacement Therapy (HRT) Increases Ovarian Cancer Risk

Post-menopausal women who use hormone replacement therapy (HRT) for more than 5 years are 20% more likely to develop ovarian cancer than women who do not use HRT, suggests a 2007 study in the Lancet. Researchers analyzed data from more than 1 million women.
A similar association between HRT use and ovarian cancer, especially for women who have not had a hysterectomy, was reported in a 2006 study in the Journal of the National Cancer Institute.

Surgery

About 1 in 3 women with ovarian cancer fail to receive recommended surgical treatment, according to a 2007 study in Cancer. The study found that women who are poor, African-American or Hispanic, or over age 70 are least likely to receive adequate care. Another Cancer study suggested that although experienced cancer centers may cost more than other facilities, they are more cost-effective over the long term than less experienced medical facilities.
For optimal ovarian cancer treatment, it is best to seek care from an experienced gynecologic oncologist and specialized cancer center.

Investigational Drugs

Aflibercept (VEGF-TRAP), an experimental anti-angiogenesis drug, may benefit patients with epithelial ovarian cancer who have not been helped by platinum-based chemotherapy, according to interim results of a Phase II study presented at the 2007 annual meeting of the American Society of Clinical Oncology. Anti-angiogenesis drugs prevent tumors from growing and spreading by starving them of their blood supply.

Introduction

The ovaries are two small, almond-shaped organs located on either side of the uterus. They are key components of a woman's reproductive system:

Ovaries store 200,000 - 400,000 follicles, tiny sacs that are present from birth, that nurture immature eggs (ova).
During each normal (usually monthly) reproductive cycle, a follicle in one ovary bursts and releases a mature or "ripened" egg. The egg travels down the fallopian tube into the uterus, where it either is fertilized by a man's sperm or, if unfertilized, breaks down and is excreted as part of the menstrual cycle.
Ovaries also secrete the important reproductive hormones estrogen and progesterone.

The uterus, commonly called the womb, is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Ovarian cancers are potentially life-threatening malignancies that develop in one or both ovaries. Malignant ovarian tumors generally fall into three primary classes:

Epithelial tumors
Germ cell tumors
Stromal tumors

Epithelial Tumors. Epithelial tumors account for up to 90% of all ovarian cancers and therefore are the primary focus of this report. These cancers develop in a layer of cube-shaped cells known as the germinal epithelium, which surrounds the outside of the ovaries.

Germ Cell Tumors. Germ cell tumors, which account for about 3% of all ovarian cancers, are found in the egg-maturation cells of the ovary. They occur most often in teenagers and young women. Although they progress rapidly, they are very sensitive to treatments. About 90% of patients with germ cell malignancies can be cured, often preserving fertility.

Stromal Tumors. Stromal tumors, which account for 6% of all ovarian cancers, develop from connective tissue cells that hold the ovary together and that produce the female hormones, estrogen and progesterone. Stromal tumors do not usually spread, in which case the prognosis is good. If they spread, however, they can be more difficult to treat than others.

Click the icon to see an image of ovarian cancer.

Ovarian cancer is called the silent killer because it progress almost silently, with vague symptoms. By the time symptoms do appear, the ovarian tumor may have grown large enough to shed cancer cells throughout the abdomen. At such an advanced stage, the cancer is more difficult to cure.

Ovarian cancer cells that have spread outside the ovaries are referred to as metastatic ovarian cancers. Ovarian tumors tend to spread to the following locations:

Diaphragm
Intestine
Omentum (a fatty layer that covers and pads organs in the abdomen)

Cancer cells can also spread to other organs through lymph channels and the bloodstream.

Not all ovarian tumors are malignant. Benign cysts, dermoid tumors, and borderline malignant tumors all are distinct from ovarian cancer.

Benign Cysts. Benign cysts are common. They typically develop in one of two ways:

Follicular Cysts. During normal ovulation, follicles (the little sacs in the ovary) expel eggs. If the egg is not expelled, fluids and other substances can build up inside the follicle, forming a follicular cyst.
Corpus Luteum Cysts. Benign cysts may form when an egg has been released, but the emptied follicle (now called the corpus luteum) does not break down normally, instead filling with blood from nearby blood vessels.

Both follicular cysts and corpus luteum cysts are normal parts of the menstrual cycle and nearly always resolve within one or two cycles without treatment.

Dermoid Tumors. Dermoid tumors are benign growths that occur when an egg begins to develop without fertilization by a sperm; they can contain hair, teeth, and cartilage. They are easily removed by surgery.

Borderline Ovarian Tumors. About 15% of ovarian tumors are referred to as "borderline" because their appearance and behavior under the microscope is between benign and malignant. These tumors are often referred to as carcinomas of low malignant potential because they rarely metastasize or cause death. Even when borderline carcinomas do spread outside the ovary, only 10 - 20% are fatal.

Symptoms

Ovarian cancer used to be considered a “silent killer." Symptoms were thought to appear only when the cancer was in an advanced stage. Now, experts know this is not true -- even early-stage ovarian cancer can produce symptoms.

In June 2007, the Gynecologic Cancer Foundation, the Society of Gynecologic Oncologists, and the American Cancer Society released a consensus statement concerning ovarian cancer symptoms. If you have the following symptoms on a daily basis for more than a few weeks, you should see your doctor (preferably a gynecologist):

Bloating
Pelvic or abdominal pain
Difficulty eating or feeling full quickly

Ovarian cancer grows quickly and can progress from early to advanced stages within a year. Paying attention to symptoms can help improve a woman's chances of being diagnosed and treated promptly. Detecting cancer while it is still in its earliest stages can help improve prognosis. Even a few months delay in detection may affect survival.

Other symptoms are also sometimes associated with ovarian cancer. These symptoms include fatigue, indigestion, back pain, pain during intercourse, constipation, and menstrual irregularities. However, according to experts, these symptoms are not as useful in diagnosing ovarian cancer, because they are also commonly experienced by women who do not have cancer.

Based on the symptoms and physical examination, the doctor may order pelvic imaging tests or a CA-125 blood test. If these tests reveal signs of cancer, patients should be referred to a gynecologic oncologist or a surgeon who specializes in female reproductive system cancers.

Causes

About 22,430 new cases of ovarian cancer are expected in the United States in 2007. Evidence suggests that the incidence of ovarian cancer is declining. The average age for the onset of ovarian cancer is about 60, although ovarian cancer can develop in women from the ages of 20 - 90. The lifetime risk of ovarian cancer in women with no family history of the disease is approximately one in 70 (1.4%).

Women with a history of ovarian cancer in one first-degree relative (mother or sister) have an overall 5% risk of developing the disease, but it may be higher in women with specific genetic factors. The majority of women with ovarian cancer have no family history of the disease, however, meaning that genetic inheritance is not the only risk factor.

Genetic mutations causing abnormal cell growth and differentiation are the basis for all cancer. The great majority of genetic defects that cause cancer are due to unknown causes. Most likely overexposure to environmental assaults, or errors that occur during cell division, play a role in many cases.

Several circumstances that create hormonal changes may increase the risk of ovarian cancer.

Number of Ovulations. Risk of ovarian cancer is directly related to the number of times a woman ovulates, which is indicated by the total number of menstrual periods she has had. A lower number of ovulations occur when the menstrual periods are shut off (as in pregnancy), so the risk of developing ovarian cancer is reduced.

The following women have a lower risk for ovarian cancer:

Women with a history of multiple pregnancies.
Women who took birth control pills (these shut off the menstrual period).
Women who breast-fed. (The body usually does not release eggs while a woman is breast-feeding.)

Some researchers theorize that ovarian cancer develops in women with a higher number of ovulations because of persistent damage to the epithelial cells as the egg passes through during ovulation. Researchers postulate that the recurring cell division needed to heal these tiny wounds to the ovaries, month after month and year after year, creates opportunities for errors in cell reproduction that lead to the formation of cancerous cells. Therefore, the more ovulations, the more risk of ovarian cancer. Ovulation temporarily ceases during pregnancy, breast-feeding, and birth control pill use.

Gonadotropins and Fertility Drugs. Gonadotropins are hormones produced in the pituitary gland that stimulate the ovaries to secrete estrogen and cause the follicles to produce and release eggs.

The pituitary is a gland attached to the base of the brain which secretes hormones that govern the onset of puberty, sexual development and reproductive function.

In a few studies, elevated levels of gonadotropins have been associated with an increased risk for ovarian cancer. These hormones are the basis for many fertility drugs, including human menopausal gonadotropin (Pergonal, Repronal, Metrodin) and clomiphene (Clomid, Serophene). Although there has been concern about an increased risk for ovarian cancers in women, a growing body of evidence is finding no higher risk from the drugs themselves. Instead, evidence suggests that ovarian cancers are most likely caused by factors contributing to the infertility -- not the drugs used to treat it.

Hormone Replacement Therapy. Hormone replacement therapy (HRT) appears to increase the risk for ovarian cancer. A 2007 UK study of nearly 1 million women found that women who used HRT for more than 5 years were 20% more likely to develop and die from ovarian cancer than women who had never taken HRT. Another important study, from the U.S. National Cancer Institute, indicated that 5 or more years of combination HRT (estrogen and progestin) increases the risk of ovarian cancer for women who have not had a hysterectomy.

Family history plays a role in 5 - 10% of women who have ovarian cancer. Certain genes are being investigated and identified that are responsible for some of these cases. Depending on the particular genetic type, the lifetime risk for ovarian cancer in women who carry these genes ranges from 16 - 65%.

BRCA1 and 2 Genes. Inherited mutations in genes known as BRCA1 or BRCA2 are now believed to be responsible for 30 - 50% of breast cancers, ovarian cancers, or both in patients with a strong family history of these cancers.

According to some studies, the risks are as follows:

Studies indicate that about 25 - 40% of women who carry the abnormal BRCA1 gene may develop ovarian cancer.
The risk for women with the BRCA2 gene mutation is generally believed to be lower, about 9 - 15%.

The mutated genes are linked to an even higher risk for developing breast cancer. These mutations are present in only about 0.5% of the U.S. population overall but occur in about 2.5% of all Jewish women of Eastern European (Ashkenazi) descent. These mutations are not restricted to the Ashkenazi population and may occur in women of any ethnicity, including women of Asian and African descent.

Either a mother or father can pass down BRCA mutations to the daughter. These mutations may also occur in 5 - 10% of ovarian cancer patients who have no family history of breast or ovarian cancer. A number of studies have suggested that women with BRCA-mutated ovarian cancers tend to have better survival rates than other women.

A 2005 study in the Journal of the National Cancer Institute indicated that women who have a family history of breast cancer, but no history of BRCA genetic mutations, are not at increased risk for ovarian cancer.

Other Genetic Mutations. Women who carry the hereditary nonpolyposis colorectal cancer (HNPCC) gene have about a 9% chance of developing ovarian cancer.

Risk Factors for Inherited Ovarian Cancer. Women are considered at high risk for ovarian cancer if they have:

A first-degree relative (mother, sister, or daughter) with ovarian cancer at any age. The risk increases with the number of affected first-degree relatives.
A first-degree relative (or two second-degree relatives on the same side) with early onset breast cancer (occurring before age 50).
A family member with both breast and ovarian cancer.
A family history of male breast cancer (which might indicate a BRCA2 mutation).
A family history of hereditary nonpolyposis colorectal cancer.

When a woman describes her family history to her doctor, she should include the history of cancer in women on both the mother's and the father's side. Both are significant.

Screening High-Risk Women. It is now possible to test for genetic mutations in the BRCA1 and BRCA2 genes and for hereditary nonpolyposis colorectal cancer (HNPCC) and Peutz-Jeghers syndrome in high-risk women. Any positive result raises difficult issues:

The presence of a mutation in any of these genes does not predict with absolute certainty that either breast cancer or ovarian cancer will occur. The lifetime risk for BRCA1, for example, is significantly higher (up to 40%) than for BRCA2 (about 10 - 15%).
Surgical preventive strategies, which can involve both mastectomy and removal of the ovaries, do not completely eliminate the risk for cancer, since malignant cells may occur in nearby regions. Removal of the ovaries will reduce ovarian cancer risk, however, and may also reduce breast cancer risk in mutation carriers.

Most ovarian cancers are the result of genetic mutations that are not inherited but occur from environmental or other factors that cause damage to genetic material over time. Such genetic changes are referred to as sporadic (as opposed to inherited). Genetic alterations that have been observed in ovarian cancers involve the p53 tumor suppressor gene, the HER2/neu gene, and the PIC3KA gene.

Some research indicates that ovarian cancer occurs more often in North America and Northern Europe and among middle-to-upper socioeconomic class women from highly industrialized countries. Ovarian cancer is also much more common in Caucasian women than in African-American women. Japan has a low, but rising, number of ovarian cancer cases. One study observed that when Japanese women immigrate to the United States, they and their daughters have an incidence of ovarian cancer that approaches that of Caucasian women, although another study did not support such findings.

Pregnancy. Women who have never had children are more likely to develop ovarian cancer than women who have had children. The more children a woman has had, the lower her risk for ovarian cancer.

Obesity. Obesity may increase the risk of developing more aggressive types of ovarian tumors. A 2006 study indicated that a higher body mass index was associated with poorer survival.

Endometriosis. Women with endometriosis may have some higher risk for ovarian cancer. However, endometriosis is very common and ovarian cancer is not, so the risk is still very low. Some research suggests that ovarian cancer associated with endometriosis may differ from most ovarian cancer cases and, in fact, have a better outlook.

Click the icon to see an image of endometriosis.

Fat Intake. Fats have been under scrutiny for some time for putting some women at higher risk for ovarian cancer. A review study reported an association between a high intake in animal fats and a greater risk. However, other studies on this subject have found no correlation between fat intake and ovarian cancer.

Prevention

No specific lifestyle factors are proven to protect against ovarian cancer, although the following study results suggest some lower or higher risk:

Some studies have suggested a lower rate of ovarian cancer in women who eat a diet rich in vegetables. The American Cancer Society recommends that women eat 5 servings of fruits and vegetables a day, and limit consumption of high-fat red meat.
A 2005 study of more than 61,000 women suggested that tea consumption may reduce the risk of ovarian cancer. Women in the study who drank at least 2 cups of tea a day (mainly black tea) had a lower risk of ovarian cancer than women who did not drink tea.
Exercise, which protects against many diseases and even some cancers, appears to have no effect on ovarian cancer. However, obesity is associated with poorer ovarian cancer survival. Women who are obese also have a higher risk for breast cancer. Regular exercise is a good idea in any case.
Smokers should quit. Although evidence of an association with ovarian cancer is weak, it is always wise to stop smoking.

In general, factors or behaviors that limit stimulation of the ovaries or inhibit ovulation appear to be protective.

Pregnancy. The more times a woman has been pregnant the less likely she is to develop ovarian cancer. One study indicated that ovarian cancer was reduced by 40% with one pregnancy and by an additional 14% with each subsequent pregnancy.

Breast-feeding. Breast-feeding, even for only 1 - 2 months, may also reduce the risk for ovarian cancer by as much as 40%. A longer duration of breast-feeding does not appear to increase its protective benefits.

Oral Contraceptives and Progestin. Studies have suggested that routine use of birth control pills that contain the female hormones estrogen and progestin, even low-dose forms, reduces a woman's risk of ovarian cancer by about 50% when compared to women who have never taken oral contraceptives. The longer a woman takes oral contraceptives the greater the protection and the longer protection lasts after stopping oral contraceptives.

Click the icon to see an illustrated series detailing the birth control pill.

Pregnant women or women with breast cancer should not take birth control pills. Other conditions that may preclude taking oral contraceptives include:

Liver disease
Migraines
Coronary artery disease and any risk factors for heart disease or stroke (particularly smoking, obesity, high blood pressure, blood clotting disorders, or diabetes)

Tubal Ligation. Tubal ligation, a method of sterilization that ties off the fallopian tubes, has been associated with a decreased risk for ovarian cancer in some -- but not all -- studies.

Click the icon to see an image of tubal ligation.

Surgical removal of the ovaries, called oophorectomy, significantly reduces the risk for ovarian cancer. When it is used to specifically prevent ovarian cancer in high-risk women, the procedure is called a prophylactic oophorectomy. Prophylactic oophorectomy is approximately 95% protective against ovarian cancer. It is sometimes recommended for women at high risk for ovarian cancer. These women generally have the BRCA1 or BRCA2 genetic mutation, or have two or more first-degree relatives who have had ovarian cancer.

Bilateral oophorectomy is the removal of both ovaries. Bilateral salpingo-oophorectomy is the removal of both fallopian tubes plus both ovaries. Several recent studies indicate that salpingo-oophorectomy is very effective in reducing risk for ovarian cancer in women who carry the BRCA1 or BRCA2 mutation.

A 2006 Journal of the American Medical Association study reported that bilateral salpingo-oophorectomy reduces ovarian cancer risk by 80% for women with certain mutations in the BRCA1 and BRCA2 genes. A study presented at the 2006 meeting of the American Society of Clinical Oncology (ASCO) indicated that this procedure is most effective for reducing ovarian cancer risk in women with the BRCA1 gene mutation. For women with BRCA2 gene mutation, the procedure was better at reducing the risk for breast cancer.

Even after oophorectomy, women in high-risk groups for ovarian cancer still have a risk for the development of cancer in the peritoneum (the sac inside the abdomen that holds the intestines, uterus, and ovaries).

Premenopausal women should realize that oophorectomy causes immediate menopause, which poses a risk for several health problems, including osteoporosis, heart disease, and reduction in muscle tone. Estrogen replacement can help offset these problems. Women who have a bilateral oophorectomy and do not receive hormone replacement therapy may experience more severe hot flashes than women who enter menopause naturally.

Diagnosis

Up to 95% of women diagnosed with ovarian cancer will survive longer than 5 years if their cancers are treated before they have spread beyond the ovaries. Unfortunately, there are no screening tests for ovarian cancer that are the equivalent to mammography for early detection of breast cancer. Therefore, only about 25% of ovarian cancer cases are diagnosed at such early stages. It is possible to perform genetic screening in high-risk women, but this raises some complex issues.

Every woman should have a regular annual examination with her doctor that includes:

Pelvic examination. Routine exams called bimanual pelvic examinations are a reasonable precaution, although they are not perfect screening methods due to their low sensitivity. This exam can be performed two ways. In the more common method, the doctor inserts two fingers into the vagina while palpating the abdomen with the other hand. The other method, called a bimanual rectovaginal exam, involves the insertion of one finger into the vagina and another into the rectum.

Either exam enables the doctor to assess the size of the ovaries as well as the contour and mobility of the uterus and to feel for masses and growths. The rectovaginal exam may reveal rectal lesions that may otherwise go unnoticed and is particularly important for women over 50. A mass felt on pelvic exam often requires further evaluation by ultrasound and sometimes requires surgery to make a definitive diagnosis.

Pap smear. This test is specifically designed to detect cervical cancer. In very rare instances, however, it may reveal abnormal ovarian cells, which might indicate the presence of an ovarian cancer.

Click the icon to see an image of a pap smear.

Unfortunately, ovarian cancer rarely produces changes that are detectable during a regular checkup.

An estimated 290,000 women are hospitalized each year in the United States because of ovarian growths or lesions. Many more women find out about some ovarian abnormality during their annual Ob/Gyn check up. The vast majority of conditions are noncancerous. They include:

Benign functional ovarian cysts
Abscesses and infection
Fibroids

Click the icon to see an image of a fibroid tumor.

Endometriosis
Polycystic ovaries

Click the icon to see an image of a polycystic ovary.

Ectopic pregnancies

Click the icon to see an image of an ectopic pregnancy.

Meig syndrome (which involves a benign ovarian growth associated with fluid buildup in the abdomen and around the lungs)
Ovarian hyperstimulation syndrome following fertility treatments.

Once a growth is detected, additional tests [below] may help the doctor gauge the risk for it being cancerous.

Ultrasound. Ultrasound is a noninvasive diagnostic tool that can evaluate tumors and masses discovered during the rectovaginal exam:

Typically, a probe is placed in the vagina and emits sound waves (ultrasound). The sound waves bounce off tissues, organs, and masses in the pelvic cavity. These echoes are collected and converted into a picture of the area called a sonogram.

Click the icon to see an image of transvaginal ultrasound.

The ultrasound probe may also be placed on abdominal walls above the ovaries (transabdominal ultrasound), but it does not provide as clear a picture of the ovaries. Healthy tissue, fluid-filled cysts, and solid tumors produce different sound waves.

Ultrasound is not helpful for identifying early-stage ovarian cancer in high-risk women. (Researchers hope that blood tests for protein markers may eventually provide a better method for diagnosing early-stage ovarian cancer.) In addition, ultrasound does not provide enough specific information to reliably determine which abnormal masses are cancerous or noncancerous.

Studies suggest that small so-called simple cysts (fluid-filled without an associated mass) are usually noncancerous, particularly when they appear in premenopausal women whose blood tests for the protein CA-125 are normal. Such women are sometimes given oral contraceptives and observed for a few months to see if the cyst goes away.
Postmenopausal women with small simple cysts and normal CA-125 levels may sometimes be observed for a time if they have no other risk factors or symptoms of ovarian cancer.
In contrast, a "complex" cyst (one that shows a mass or other abnormalities) is often surgically removed, since it has a higher chance of being malignant. Only a small percentage of these cysts turn out to be cancerous. (In one study 6% of complex cysts were actually cancerous.)

Click the icon to see an image of an ovarian cyst.

Other Imaging Techniques. Other imaging techniques are less common for the diagnosis or evaluation of suspected ovarian cancer but may help determine if cancer has spread to other parts of the body:

Computed tomography (CT). Computed tomography records x-ray absorption rates of tissue and bone. These data is converted into clear images on a screen. CT scans help determine if cancer has spread to the lymph nodes, abdominal organs, abdominal fluid, and the liver.

Click the icon to see an image of a CT scan.

Magnetic resonance imaging (MRI). MRI creates multiple cross-sectional images of the pelvis and abdominal organs, which are assembled into three-dimensional images. An MRI is not usually used to diagnose ovarian cancer, but may help determine if cancer has spread to the brain or spinal cord.

Click the icon to see an image of a MRI scan.

Chest x-rays. Find cancer that has spread to the lungs.

Click the icon to see an image of an x-ray machine.

CA-125 is a protein that is secreted by ovarian cancer cells and is elevated in over 80% of patients with ovarian cancer. The CA-125 blood test is not approved for screening in the general population. Oncologists will usually only obtain a blood test for this protein if ovarian cancer is strongly suspected or has been diagnosed. In general, a CA-125 level is considered to be normal if it is less than 35 U/mL (microns per milliliter). The test may also be useful for evaluating tumor growth and predicting survival in patients with recurrent cancer who have been treated with topotecan or paclitaxel-carboplatin chemotherapy regimens.

The test is not useful for diagnosis or early screening, however. In about half of women with very early ovarian cancer, CA-125 levels are not elevated above the normal standard at all. Furthermore, an elevated level can be caused by a number of other conditions including:

Endometriosis (which may be a risk factor for ovarian cancer)
Fibroids
Noncancerous ovarian cysts
Pregnancy
Pelvic inflammatory disease
Liver diseases
Other tumors, such as breast, colon, lung, and pancreatic cancers
Age and menstrual status can also affect the levels of CA-125

Research is under way to find better tests that will detect this cancer in early stages.

Proteomics. A promising new approach relies on a technique called proteomics. Proteomics is the analysis of certain proteins. In this approach, researchers are looking at a unique pattern of proteins produced by ovarian cancer cells. Studies suggest this set of proteins serves as an early biomarker for detecting ovarian cancer. Scientists at the National Cancer Institute (NCI) and Food and Drug Administration (FDA) have developed a blood test to check for the presence of these abnormal proteins. In one study, the proteomics tool identified 100% of patients with ovarian cancer and incorrectly diagnosed cancer in only 3 out of 66 of women who were actually cancer-free. A clinical trial is now under way comparing the proteomics test to the CA-125 test. OvaCheck, another investigational ovarian cancer blood test, is based on principles similar to the NCI and FDA platform, but is being developed independently by a private corporation.

Osteopontin. Scientists are also looking into the possibility that the protein osteopontin may be a biomarker for ovarian cancer. Studies have shown that osteopontin is overexpressed in tumors and serum of women with ovarian cancer.

Other Biomarkers. Researchers have also had preliminary success with a blood test that measures osteopontin along with three additional protein markers in blood: leptin, prolactin, and insulin-like growth factor-II. In early trials, prolactin and osteopontin levels were significantly elevated in women with early ovarian cancer. The other two proteins were greatly reduced. When measured collectively, these four proteins completely distinguished between healthy women and those with early ovarian cancer, according to the results published in the May 2005 journal of the Proceedings of the National Academy of Sciences.

An exploratory surgical procedure called laparotomy generally is required for the definitive diagnosis of ovarian cancer. Laparotomy involves the following steps:

It requires general anesthesia and employs standard surgical techniques to make a vertical, midline incision from the pubic bone to the navel.
Such an incision ensures careful evaluation of the entire abdominal area. After the incision is made, the surgeon assesses the fluid and cells in the abdominal cavity.
During this procedure, cysts or other suspicious areas will be removed and biopsied (tested for cancer).
If the lesion is cancerous, the surgeon continues with a process called surgical staging to find out how far the cancerous tumor has spread and to remove the ovaries and any cancerous tissue.

Investigators are also studying laparoscopy -- instead of more invasive surgery -- for initial surgical evaluation (staging).

Click the icon to see an image of pelvic laparoscopy.

Prognosis

Ovarian cancer ranks behind lung, breast, and colorectal cancer as the fourth most common cause of female cancer death in this country. About 15,280 American women are expected to die from ovarian cancer in 2007.

In general, overall 5-year survival rates (all stages combined) increased from 37% in 1974 to greater than 50% currently. Survival rates vary depending on different factors, including age and the stage at which it is detected.

The survival rate also varies according to the cancer stage:

Five-year survival rates are over 90% if the cancer is still confined to the ovary at diagnosis. However, only 19% of ovarian cancers are found at this stage.
If the cancer has spread to nearby regions in the pelvis, the survival rate drops to 60 - 80%.
If the cancer has spread to sites outside the pelvis, the 5-year survival rates are only 10 - 30%.

Unfortunately, most patients with ovarian cancer are not diagnosed until the disease is advanced. This usually means the cancer has spread to the upper abdomen. In order to establish a prognosis and determine treatment, the doctor needs to know the cell type, stage, and grade of the disease.

About 90% of ovarian epithelial cancers fall into one of four major subtypes based on their origin and shape as viewed under a microscope:

Serous. (This is the most common type.)
Endometrioid. (This is sometimes associated with endometriosis and tends to have a more favorable outlook.)
Mucinous. (The presence of malignant mucinous cells indicates a poorer outlook if the disease is advanced.)
Clear cell. (Clear cell carcinomas are the most difficult to treat even when the malignancy is still confined to the ovary.)

The remaining 10% of common epithelial cancers are referred to as undifferentiated, because their exact cell of origin cannot be determined microscopically. These epithelial ovarian carcinomas tend to grow and spread quickly.

Cancers are staged (I through IV) according to whether they are still localized (remaining in the ovary) or have spread beyond the original site.

Tumors are also graded according to how well or poorly organized they are (their differentiation). Ovarian tumors are graded on a scale of 1, 2, or 3. Grade 1 tends to closely resemble normal tissue and has a better prognosis than grade 3, which indicates very abnormal, poorly defined tissue.

Age. In general, younger women have a better prognosis than older women although stage and grade of tumor also are important to the prognosis.

BRCA Carriers. Some studies have reported that women who carry mutated BRCA genes may have better survival rates than non-carriers. The survival advantages may be due to having a slower course or being more responsive to therapies than sporadic ovarian cancers, although this is controversial.

Angiogenesis. Experimentally, the level of biochemicals stimulating the formation of new blood vessels that support tumor growth (angiogenesis) appears to correlate with prognosis. The more angiogenic factors present in a tumor population, the more new blood vessels will form, encouraging both tumor growth and metastasis.

Overexpression of p53 Mutations. High levels of a defective p53 gene (which regulates cell growth) are associated with a poorer outlook.

Women who survive ovarian cancer have a high risk for psychological stress. Support groups can be very helpful.

Treatment

In general, the course of treatment is determined by the stage of the cancer. Stages range from I to IV based on the cancer's specific characteristics, such as whether it has spread beyond the ovaries.

In stage I, the cancer has not spread. It is confined to one ovary (stage IA) or both ovaries (stage IB). In stages IA and IB, the ovarian capsules are intact, and there are no tumors on the surface. Stage IC can affect one or both ovaries, but the tumors are on the surface, or the capsule is ruptured, or there is evidence of tumor cells in abdominal fluid (ascites). The overall 5-year survival rate for stage IA or IB can be as high as 90%, but the presence of other factors may affect this rate. For example, non-clear-cell well-differentiated cancer cells or borderline tumors have a favorable prognosis. Clear cells or those that are more poorly differentiated have a worse outlook. Stage IC has a poorer outlook than the earlier stages. It is very important that women receive an accurate staging assessment, including a pathologic review conducted by a gynecologic pathologist.

Treatment Options: Treatment for most women with stage IA and IB includes surgical removal of the uterus and both ovaries and fallopian tubes (total hysterectomy and bilateral salpingo-oophorectomy), partial removal of the omentum (the fatty layer that covers and pads organs in the abdomen), and surgical staging of the lymph nodes and other tissues in the pelvis and abdomen. (Carefully selected premenopausal women in Stage I with the lowest-grade tumors in one ovary may sometimes be treated only with the removal of the diseased ovary and tube in order to preserve fertility.) Patients with stage IA or B disease, grade 1 (or sometimes grade 2), usually do not need further therapy after surgery. However, higher risk patients (stage IC, stage I/grade 3) are usually treated with platinum-based chemotherapy to reduce their risk of subsequent relapse.

A 2005 study suggested that adjuvant platinum-based chemotherapy (chemotherapy added to surgical treatment) can improve survival and reduce cancer recurrence. With the considerable adverse effects of chemotherapy, more research is needed to determine which stage 1 patients would benefit most from this adjuvant treatment.

Click the icon to see an illustrated series detailing hysterectomy.

In stage II, the cancer has spread to other areas in the pelvis. It may have advanced to the uterus or fallopian tubes (stage IIA), or other areas within the pelvis (stage IIB), but is still limited to the pelvic area. Stage IIC indicates capsular involvement, rupture, or positive washings (that is, they contain malignant cells). The 5-year survival rate for stage II is about 60 - 80%.

Treatment Options: Surgical management for most women in this stage is total hysterectomy, bilateral salpingo-oophorectomy, and removal of as much cancer in the pelvic area as possible (tumor debulking). Surgical staging should be performed.

After the operation, treatment with chemotherapy is usually necessary in an attempt to eradicate residual cancer and decrease the chance for relapse.

In stage III, one or both of the following are present: (1) The cancer has spread beyond the pelvis to the omentum (the fatty layer that covers and pads organs in the abdomen) and other areas within the abdomen, such as the surface of the liver or intestine. (2) The cancer has spread to the lymph nodes. The average 5-year survival rate for this stage is 20%.

Click the icon to see an image of the lymph system located near the ovaries.

Treatment Options: Surgical management for most women in this stage is total hysterectomy and bilateral salpingo-oophorectomy and removal of as much cancer as possible (tumor debulking).

Following surgery, chemotherapy is usually needed for any remaining cancer cells. Several approaches are under investigation for reducing high rates of recurrence (about 80%). These approaches include the following:

Experimental chemotherapy drugs
Anti-angiogenic therapies
Gene and biological therapies
Intraperitoneally administered high-dose chemotherapy
Neoadjuvant therapy (chemotherapy before surgery)
High-dose chemotherapy
Peripheral blood stem cell transplantation (to date this approach has proven to be very toxic with no convincing improvement in survival)

Stage IV is the most advanced cancer stage. The cancer may have spread to the inside of the liver or spleen. There may be distant spreading of the cancer, such as ovarian cancer cells in the fluid around the lungs. The average 5-year survival rate for this stage is less than 10%.

Treatment Options: Tumor debulking may be performed before chemotherapy.

Although not standard practice in the United States, a surgical procedure called retroperitoneal lymphadenectomy is sometimes performed. This procedure involves removal of aortic and pelvic lymph nodes from the rear of the abdomen. Results from a 2005 randomized controlled trial suggest that while retroperitoneal lymphadenectomy does help reduce cancer progression, it does not prolong survival.

Treatment Options: If ovarian cancer returns, chemotherapy is the mainstay of treatment, although it is not generally curative in the setting of relapsed disease.

If the interval between the last platinum-containing chemotherapy (carboplatin or cisplatin) and relapse is long (greater than 6 months), it is reasonable to attempt a repeat trial of platinum-based chemotherapy, with or without paclitaxel.

If the interval is short, or if these drugs fail to control the tumor, other second-line drugs may be useful in achieving a response. They include topotecan, liposomal doxorubicin, etoposide, docetaxel, gemcitabine, or tamoxifen. There is no evidence that second-line drug combinations are any more effective than single drugs, although they are generally more toxic.

Clinical trials using various investigative approaches are under way. It is not clear if there is a role of a second debulking surgical procedure. A 2004 study published in the New England Journal of Medicine found that additional debulking did not prevent cancer progression or prolong survival.

Surgery

Surgery for ovarian cancer uses laparotomy, a major abdominal operation. It is the primary diagnostic tool for ovarian cancer and also plays a role in treatment. Complete surgical intervention includes the following:

Surgical staging (examining all tissues and organs in the pelvic cavity for accurate assessment of the disease stage).
Debulking (removal of as much of the cancerous tissue as possible). This is an important component of ovarian cancer management and should be performed by a surgeon trained in cancer surgery techniques.

Patients with ovarian cancer should see a qualified gynecologic oncologist (a surgical specialist in female reproductive cancers) and a qualified medical oncologist with special expertise in the chemotherapeutic management of gynecologic cancer. Studies indicate that it is best for patients, especially those with advanced-stage ovarian cancer, to receive care at medical centers that specialize in cancer treatment and surgery.

According to a 2007 study, 1 in 3 patients with ovarian cancer fails to receive recommended surgical treatment. Women over age 70, poor patients, and African-American or Hispanic patients were least likely to receive proper treatment. Women who were not treated by gynecologic oncologists were also less likely to receive optimal surgical care.

Surgical staging includes biopsies of the following:

The undersurface of the diaphragm
The omentum (the fatty layer that covers and pads organs in the abdomen)
Sometimes lymph nodes along the abdominal aorta

An abdominal wash is performed by injecting a salt solution into the abdominal cavity to facilitate microscopic detection of cancerous cells not visible to the naked eye. The surgeon then evaluates the pelvis and abdomen and removes suspected cancer tissue. The entire affected ovary is usually removed (oophorectomy) during surgical staging if the surgeon believes it might be cancerous. The tissue is sent to a laboratory for an immediate evaluation called a frozen section diagnosis. The doctor will also examine the bowel and bladder for cancer invasion.

If the tumor is in an early stage on one ovary and a young woman wants to retain her ability to have children, the surgeon may be able to remove only the affected ovary and perform surgical staging. Chemotherapy follows in selected patients. Studies indicate that in carefully selected young patients, many can expect normal fertility afterward. However, most women with ovarian cancer are not candidates for this procedure.

The goal of surgery is to remove as much of the tumor as possible (called debulking or cytoreductive surgery) for improving symptoms and increasing the effectiveness of chemotherapy. The surgery itself is typically performed as follows:

In premenopausal women in later stages, and in all postmenopausal women, the surgeon usually removes the uterus (a hysterectomy) and both ovaries and fallopian tubes (a bilateral salpingo-oophorectomy).
In addition, the surgeon usually removes the omentum (omentectomy), any growths on the diaphragm and intestine, and possibly certain lymph nodes (lymphadenectomy).

If surgical staging reveals that the cancer has invaded the bowel, a portion of the intestine may have to be removed as well.

Postoperative Care. If possible, a patient should ask a family member or friend to help out for the first few days at home. The following are some of the precautions and tips for postoperative care:

For 1 - 2 days after surgery, the patient is given medications to prevent nausea and painkillers to relieve pain at the incision site.
As soon as the doctor recommends it, usually within a day of the operation, the patient should get up and walk in order to help prevent pneumonia, reduce the risk of blood-clot formation, and to hasten recovery.
Walking and slow, deep breathing exercises may help to relieve gas pains, which can cause major distress for the first few days.
Coughing can cause pain, which may be reduced by holding a pillow over a surgical abdominal wound or by crossing the legs after vaginal surgery.
Patients are advised not to lift heavy objects (including small children), not to douche or take baths, and not to climb stairs or drive for several weeks.
For the first few days after surgery, many women weep frequently and unexpectedly. These mood swings may be due to depression from the loss of reproductive capabilities and form abrupt changes in hormones, particularly if the ovaries have been removed.

The patient should talk to their doctor about when they can start exercise programs that are more intense than walking. The abdominal muscles are important for supporting the upper body, and recovering strength may take a long time. Even after the wound has healed, the patient may experience an on-going feeling of overall weakness, which can be demoralizing, particularly in women used to physical health. Some women do not feel completely well for as long as a year. Others may recover in only a few weeks.

Complications Following the Procedure. Minor complications after hysterectomy are very common:

Women may develop minor and treatable urinary tract infections.
There is usually light vaginal bleeding and pain after the operation, which can be well-controlled with pain medications.

More serious complications are uncommon but patients should be aware of their symptoms and call the doctor immediately if they occur:

Infection occurs in 10 - 15% of patients, with the risk being higher with abdominal than with vaginal surgery. Symptoms might include continuing or increasingly severe pain, fever, heavy discharge, or bleeding. Antibiotics given at the time of surgery help to reduce this risk. Other risk factors for infection include obesity, a longer than normal operative time, and low socioeconomic status.
There is a slight risk for small blood clots, usually in veins of the legs (thrombophlebitis). A sudden swelling or discoloration in the leg can indicate this condition and requires immediate medical attention.

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (iliofemoral veins), preventing normal return of blood from the leg to the heart.

Other serious and even life-threatening complications, though rare, include pulmonary embolism (blood clots that travel to the lung), abscesses, perforation of the bowel, fistulas (a passage that bores from an organ to the skin or to another organ), or dehiscence (the opening of the surgical wound).

Treating Menopausal Symptoms and Premature Menopause after Hysterectomy. After hysterectomy, premenopausal women usually have hot flashes, a symptom of menopause. Symptoms come on abruptly and may be more intense than those of natural menopause. Symptoms include hot flashes, vaginal dryness and irritation, and insomnia. A significant number of women gain weight.

The most important complications that occur in women who have had their ovaries removed are due to estrogen loss, which places women at risk for osteoporosis (loss of bone density) and a possible increase in risks for heart disease. Women have typically taken hormone replacement therapy (HRT) after surgery if their ovaries have been removed. There have been concerns however about health risks, including the risk for breast cancer and stroke, that have now limited its use. Risks in premenopausal women who have had a hysterectomy have not yet been clarified. Several nonhormonal drugs, however, can help protect both bones and heart.

After chemotherapy is completed, surgeons used to perform an exploratory procedure called second-look laparotomy. Although this procedure is the most sensitive way of detecting residual cancer that remains after chemotherapy, it has no proven impact on patient survival. Its use is restricted to patients being treated in clinical trials.

Bowel obstruction is common in ovarian cancer. Surgery can be very helpful for selected patients with this problem.

Medications

Following surgery, patients (other than those with early-stage, low-grade disease) usually have chemotherapy. Unlike surgery and radiation, which treat the cancerous tumor and the area surrounding it, drug therapy destroys rapidly dividing cells throughout the body, so it is as systemic therapy.

Ovarian cancers are very sensitive to chemotherapy and often respond well initially. Unfortunately, in most cases, ovarian cancer recurs. With treatment advances, however, more than half of women now survive 5 years or longer. Doctors are now approaching this disease as a chronic and potentially long-term illness that requires the following:

Identifying the disease recurrence as soon as possible
Administering treatments that are as effective as possible without causing suffering
Partnering with the patient in determining her own best course

Standard Chemotherapy. The standard initial chemotherapy uses a combination of:

A platinum-based drug, such as carboplatin (Paraplatin) or cisplatin (Platinol). Carboplatin is preferred over cisplatin in the combination. Carboplatin works as well as cisplatin but is less toxic and can be administered in a more convenient, outpatient regimen.
A taxane, such as paclitaxel (Taxol) or docetaxel (Taxotere). Currently paclitaxel is the drug most often used as initial therapy in combination with a platinum drug. Docetaxel, however, is less toxic to the nervous system (but has more adverse effects on blood cell production). Taxotere is now commonly substituted for Taxol.

Paclitaxel-carboplatin chemotherapy will reduce tumor size in about 70% of women. Older women (over age 60) may benefit as much as younger ones from this regimen.

Other drugs that may prove to be useful first-line treatments are gemcitabine (Gemzar) and doxorubicin (Doxil). A third drug, topotecan (Hycamtin), is not helpful for first-line treatment for advanced ovarian cancer, according to recent studies. In an important 2006 study, topotecan following paclitaxel-carboplatin therapy did not help prolong survival, and it caused many serious side effects, including anemia and infections.

Chemotherapy Drugs Studied for Relapsed or Refractory Cancer. Unfortunately, some ovarian tumors are resistant to platinum drugs. Even in patients who respond, the disease eventually becomes resistant to the first-line drugs, and the cancer returns. Various approaches for increasing responsiveness to these drugs are being investigated. Investigators are studying two approaches for preventing relapse after remission:

Developing more effective drug combination regimens to increase initial response rates and duration of the response.
Developing maintenance drugs to prevent or delay relapse.

Once cancer recurs or continues to progress, several second-line chemotherapies are available or under investigation. The following lists some drugs that are being used, usually as single drugs, for relapsed or refractory cancers:

Nucleoside analogs, including gemcitabine (Gemzar). In 2006, gemcitabine was approved as a treatment for recurrent ovarian cancer. It is used in combination with carboplatin for women with advanced ovarian cancer that has relapsed at least 6 months after initial therapy.
Paclitaxel or carboplatin alone or in combination. A landmark study published in the July 2003 Journal of Clinical Oncology, found that additional cycles of paclitaxel significantly delayed disease progression in women with advanced ovarian cancer.
Pegylated liposomal doxorubicin (Doxil) is a form of standard doxorubicin (Adriamycin) that remains in the bloodstream longer, tends to spare the bone marrow, and moves selectively through the tumor. It is showing promise in clinical trials and also may have fewer toxic effects than standard doxorubicin and other drugs used for ovarian cancer. Studies show that peglyated liposomal doxorubicin is very well tolerated, with a total response rate of about 20 - 30% in patients with recurrent cancer. This compares favorably with other drugs, such as topotecan, carboplatin, and taxol.
Topoisomerase I inhibitors, including topotecan (Hycamtin) and irinotecan (Campto).
Topoisomerase II alpha inhibitors, including etoposide (VePesid).
Alkaloids, including vinorelbine (Navelbine).
Hormonal drugs: tamoxifen (Nolvadex) or anastrozole (Arimidex).
Valspodar and capecitabine (Xeloda) are oral drugs that may help improve response to other drugs, although data are preliminary.

In addition to studying individual drugs in different combinations, investigators are looking for the optimal sequence, dosages and timing of administering them. In general, the typical regimen is as follows:

Paclitaxel and carboplatin are administered in an outpatient clinic within several weeks of the surgery.
Each treatment takes about 4 - 5 hours to complete.
It is repeated every 3 weeks for a total of six times. (Each 3-week interval is known as a cycle of chemotherapy.)

Such chemotherapy is usually administered intravenously (by vein). However, an important 2006 study in the New England Journal of Medicine found that patients with Stage III ovarian cancer who received intraperitoneal chemotherapy had a significant survival advantage compared with patients who received standard intravenous chemotherapy. (Intraperitoneal chemotherapy involves administering the drugs directly into the abdominal cavity.) Patients in the intraperitoneal group did have more severe side effects than those who had intravenous chemotherapy. Researchers are continuing to investigate ways to reduce these side effects. Another 2006 study noted that intraperitoneal chemotherapy requires careful catheter insertion and maintenance, and that doctors need to be well trained to perform this procedure.

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Some may be long-lasting. In one study of ovarian cancer survivors, 20% had long-term treatment side effects, such as gynecologic and abdominal problems. Even so, most enjoyed a high quality of life that was comparable to other cancer survivors and peers without a history of cancer.

Common side effects include:

Nausea and vomiting. Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve these side effects in nearly all patients given moderate drugs and most patients who take more powerful drugs.
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Depression

Serious short- and long-term complications can also occur and may vary depending on the specific drugs used. The following list includes some of these complications and a few of their treatments:

Anemia. Erythropoietin stimulates red blood cell production and can help reduce or prevent this side effect. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp stays in the blood longer than epoetin alfa, so fewer injections are needed.
Increased chance for infection from severe reduction in white blood cells (neutropenia). The addition of a drug called granulocyte colony-stimulating factor (filgrastim and lenograstim) is very helpful in reducing the risk for severe infection in selected patients.
Liver and kidney damage.
Abnormal bleeding (thrombocytopenia).
Allergic reaction, particularly to platinum-based drugs.
Rarely, secondary cancers such as leukemia.
Between a quarter and a third of women report problems in concentration, motor function, and memory. These problems may be long-term and may be due to reductions in estrogen levels after treatments.
Cumulative doses of anthracyclines can damage heart muscles over time and increase the risk for heart failure. An encapsulated form doxorubicin (Myocet, Doxil) may reduce the risk for toxic effects on the heart.
Taxanes can cause a drop in white blood cells and possible problems in the heart and central nervous system. Allergic reactions can occur. Talking a corticosteroid before taxane administration can help prevent such reactions. Taxane therapy may also cause severe joint and muscle pain in some patients, which is relievable with corticosteroids.

Physical Exam and CA-125 Blood Test. During treatment, the effectiveness of the chemotherapy is evaluated primarily with a physical examination and the CA-125 blood test. Falling CA-125 levels indicate effective treatment and persistently elevated levels indicate resistance to the chemotherapy.

Second Look Laparotomy. Second-look laparotomy is sometimes considered after completion of chemotherapy for patients who are participating in clinical trials.

Comparative Computed Tomography Scans. Another method for evaluating the success of chemotherapy is to compare computed tomography (CT) scans of the pelvis and abdomen before and after chemotherapy to check the size of any residual tumors that persisted after the original surgery. CT scanning is not always required, however.

Positron Emission Tomography ). Positron emission tomography (PET) scans have no proven role in the management of patients with ovarian cancer. More study is needed to determine their utility in diagnosing relapsed disease.

Any patient with ovarian cancer is a candidate for clinical trials. In addition to testing high-dose or combinations of chemotherapy, drugs with unique actions are being investigated.

Anti-angiogenesis drugs. Angiogenesis, the formation of new blood vessels that feed the growth of a cancerous tumor, is a critical process in the spread of ovarian cancer. Drugs that block this process are under investigation for ovarian cancer. Some of these drugs target vascular endothelial growth factor (VEGF), a protein involved in tumor cell growth. Results of a phase II study, presented at the 2007 meeting of the American Society of Clinical Oncology, indicated that the anti-angiogenesis drug aflibercept (VEGF-TRAP) may benefit patients with epithelial ovarian cancer who are resistant to platinum-based chemotherapy. Such drugs include thalidomide, gefinitib (Iressa), and carboxyamido-triazole (CAI).

Aromatase inhibitors. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many body tissues. Aromatase inhibitors are used for treatment of estrogen-sensitive breast cancer. These drugs include anastrozole (Arimidex) and letrozole (Femara). Studies indicate that they may provide an alternative to chemotherapy for types of ovarian cancers that are responsive to anti-estrogen hormonal therapy.

Multiple signal transduction regulators. Phenoxodiol is an multiple signla transduction regulator that is being developed as a broad-spectrum anti-cancer drug. It is currently being evaluated in phase III clinical trials, in combination with other drugs, such as carboplatin, for its ability to shrink tumors or stop tumor growth in women with ovarian or fallopian cancer who have failed other forms of chemotherapy.

HER Dimerization Inihibitors. Pertuzumab (Omnitarg) is the first of a new class of drugs called HER dimerization inhibitors. It is designed to inhibit tumor growth for tumors that express the HER2 receptor protein. Pertuzumab is currently in phase II trials in combination with gemcitabine for women with platinum-resistant ovarian, peritoneal, or fallopian cancer.

Immunotherapy. Several therapies under investigation use the body's immune response to attack ovarian cancer cells. Experimental immunotherapies include vaccines designed to treat -- not prevent -- cancer. Some of these vaccines use specially designed antibodies (called monoclonal antibodies, or MAbs) to boost the immune responses against tumor-associated factors, such as CA125 or HER-2/neu. Vaccine therapy is still in early-stage clinical research and is being studied in combination with various chemotherapy drugs.

Epothilones. Epothilones are a new class of anti-cancer drugs that are similar to taxanes (paclitaxel) but are more potent. One of these drugs, ixabepilone (BMS-247550), is being studied for ovarian cancer.

Radiation Therapy

Radiation therapy is not typically used in ovarian cancer. This is because radiation would need to be given to the entire abdomen and pelvis, increasing its toxicity. Radiation is sometimes useful to treat isolated areas of tumor that are causing pain and are no longer responsive to chemotherapy.

Resources

www.cancer.gov -- National Cancer Institute
www.cancer.org -- American Cancer Society
www.aacr.org -- American Association for Cancer Research
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.ovarian.org -- National Ovarian Cancer Coalition
www.ovariancancer.org -- Ovarian Cancer National Alliance
www.sgo.org -- Society of Gynecologic Oncologists
www.wcn.org -- Women's Cancer Network
www.ovariancancer.com -- The Gilda Radner Familial Ovarian Cancer Registry
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Beral V; Million Women Study Collaborators; Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007 May 19;369(9574):1703-10.

Bristow RE, Santillan A, Diaz-Montes TP, Gardner GJ, Giuntoli RL 2nd, Meisner BC, et al. Centralization of care for patients with advanced-stage ovarian cancer: a cost-effectiveness analysis. Cancer. 2007 Apr 15;109(:1513-22.

Goff BA, Mandel LS, Drescher CW, Urban N, Gough S, Schurman KM, et al. Development of an ovarian cancer symptom index: possibilities for earlier detection. Cancer. 2007 Jan 15;109(2):221-7.

Goff BA, Matthews BJ, Larson EH, Andrilla CH, Wynn M, Lishner DM, et al. Predictors of comprehensive surgical treatment in patients with ovarian cancer. Cancer. 2007 May 15;109(10):2031-42.

Lacey JV Jr, Brinton LA, Leitzmann MF, Mouw T, Hollenbeck A, Schatzkin A, et al. Menopausal hormone therapy and ovarian cancer risk in the National Institutes of Health-AARP Diet and Health Study Cohort. J Natl Cancer Inst. 2006 Oct 4;98(19):1397-405.

[No authors listed] An experiment in earlier detection of ovarian cancer. Lancet. 2007 Jun 23;369(9579):2051.

Smyth JF, Gourley C, Walker G, MacKean MJ, Stevenson A, Williams AR, et al. Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. Clin Cancer Res. 2007 Jun 15;13(12):3617-22.

Review Date:
10/16/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Colon and rectal cancers

FitSugar — Wed, 08 Oct 2008 17:35:05 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Dietary Factors
Prevention
Diagnosis
Staging
Prognosis
Surgery
Medications
Radiation Treatment
Follow-up Testing
Treatment for Metastasized ...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

In September 2006, the Food and Drug Administration approved panitumumab (Vectibix) for the treatment of patients with colorectal cancer that has spread to other parts of the body following chemotherapy. Like cetuximab (Ertibux), panitumumab targets the epidermal growth factor receptor (EGFR) on cancer cells. Panitumumab is the first new colorectal cancer drug approved since 2004. The FDA granted accelerated approval to panitumumab based on a clinical trial of patients with metastatic cancer. The average time to disease progression or death was 96 days in patients treated with panitumumab compared to 60 days in patients who received standard care.

Diet and Colorectal Cancer Recurrence

Evidence indicates that diet plays a role in colorectal cancer prevention. Now, a 2007 study in the Journal of the American Medical Association (JAMA) suggests that dietary factors also affect the risk of cancer recurrence. Patients with stage III colorectal cancer who ate lots of red meat, refined grains, and sweets had a higher risk of cancer recurrence and death than patients whose diets were high in fruits and vegetables, poultry, and fish.

Folic Acid No Good for Prevention?

Many experts have long believed that folic acid supplements may help protect against colorectal cancer. But according to a 2007 JAMA study, high-dose folic acid supplements may not prevent colorectal cancer and may actually increase the risk for adenomatous polyp formation. Adenomatous polyps are benign colorectal tumors that can potentially become cancerous. In the study, patients who took folic acid supplements had a greater risk of developing new, more numerous, and larger adenomatous polyps than patients who did not take the supplements.

NSAIDS Not Recommended for Colorectal Cancer Prevention

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent colorectal cancer in people who are at average risk for this disease. Several recent studies have indicated that aspirin, and NSAIDs such as celecoxib (Celebrex), can help prevent colorectal cancer. But the USPSTF notes that the risks of these drugs outweigh the benefits. Long-term daily use of NSAIDs increases the risk for gastrointestinal bleeding, kidney function problems, and heart attack and stroke.

Introduction

Cancers of the colon and rectum, often referred to collectively as colorectal cancer, are life-threatening tumors that develop in the large intestine.

More than 80% of colorectal tumors evolve from adenomatous polyps. These gland-like growths develop on the mucous membrane that lines the large intestine. They are usually either:

Tubular polyps, which protrude mushroom-like
Villous adenomas, which are flat and spreading and are more apt to become malignant (cancerous)

Polyps are very common and almost always benign. Their numbers increase with age. Polyps are found in about 25% of people by age 50, and 50% of people by age 75. Fewer than 1% of polyps under 1 centimeter (slightly less than half an inch) become cancerous. About 10% of larger polyps become cancerous within 10 years, and about 25% of these larger polyps become cancerous after 20 years. Certain inherited polyps can become cancerous more rapidly.

Digestion takes place in the gastrointestinal (GI) tract, essentially a long tube that extends from the mouth to the anus. It is a complex organ system that first carries food from the mouth down the esophagus to the stomach. Food then travels through the small and large intestines before being excreted through the rectum and out the anus.

The esophagus, stomach, large and small intestine -- aided by the liver, gallbladder, and pancreas -- convert the nutritive components of food into energy and break down the non-nutritive components into waste to be excreted.

The esophagus is a narrow muscular tube, about 9 1/2 inches long that begins below the tongue and ends at the stomach.

In the stomach, acids and stomach motion break food down into particles small enough so that the small intestine can absorb nutrients.

Click the icon to see an image of stomach anatomy.

The small intestine, despite its name, is the longest part of the gastrointestinal tract, extending for about 20 feet. Food passes from the stomach through its three parts: first the duodenum, then the jejunum, and finally the ileum. Most of the digestive process occurs in the small intestine.

Click the icon to see an image of small intestine anatomy.

Undigested material, such as plant fiber, is passed next to the large intestine, mostly in liquid form. The large intestine is wider than the small intestine but only about 6 feet long. It is the final portion of the digestive tract and includes the cecum, the appendix, the colon, and the rectum, which extends to the anus.

Cecum and Appendix. The cecum and the appendix are located in the lower-right quadrant of the abdomen.

Colon. The colon absorbs excess water and salts into the blood. The remaining waste matter is converted to feces through bacterial action. The colon is divided into four major sections.

Click the icon to see an image of large intestine anatomy.

The first section, the ascending colon, extends upward from the cecum on the right side of the abdomen.
The second section, the transverse colon, crosses the upper abdomen to the left side.
The third section extends downward on the left side of the abdomen toward the pelvis and is called the descending colon.
The final section is the sigmoid colon.

Rectum and Anus. Feces are stored in the descending and sigmoid colon until they are passed through the rectum and anus. The rectum extends through the pelvis from the end of the sigmoid colon to the anus.

Causes

In most cases of colon or rectal cancers, the cause or causes are unknown. Defects in genes that normally protect against cancer play the major role in causing polyp cells to continuously spread and become cancerous. Some of these cases are caused by inherited genetic defects, and such patients usually have family histories of colorectal cancer. Most of the genetic mutations involved in colon cancers, however, appear to arise spontaneously (no strong family history) rather than being inherited. In such cases, environmental or other factors trigger genetic changes in the intestine that lead to cancer.

About 6% of cases of colon cancer are due to inherited factors.

APC Gene and Familial Adenomatous Polyposis (FAP). When the adenomatous polyposis coli (APC) gene is normal, it helps suppress tumor growth. In its defective form, it permits high levels of the protein beta-catenin to accumulate, which accelerates cell growth leading to polyps. Various genetic mutations that affect the APC gene directly or indirectly have been identified:

Familial adenomatous polyposis (FAP) is a rare and serious disorder in which the patient inherits an adenomatous polyposis coli (APC) mutation from either parent. It occurs in about 1 in 8,000 people. During early adulthood, hundreds to thousands of polyps grow in the colon. FAP causes less than 1% of all cases of colorectal cancer, but if untreated, virtually everyone who inherits this condition develops cancer before the age of 40. Many of the deaths attributed to FAP can be prevented with early and aggressive surgical treatment.
Non-inherited mutations of the APC gene have been detected in nearly all patients with spontaneous colon cancers.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC). Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, accounts for at least half of colorectal cancers that run in families. (However, only 3% or less of all colorectal cancers are due to this problem). About 50 - 80% of people who inherit the abnormal gene will develop colon cancer. HNPCC tends to develop in the right side of the colon, often in young individuals. (Left-sided cancers can still occur as well.)

People who inherit HNPCC and other defects are prone to other cancers, including uterine and ovarian cancers, as well as cancers of the small intestine and kidney system (very rare). HNPCC is highly associated with genes containing an abnormality called microsatellite instability (MSI), which is a sign of defective DNA repair. Testing tumors for MSI in people with newly diagnosed colon cancer who also have a family history of the disease may prove to be an effective method for identifying patients with hereditary nonpolyposis colorectal cancer. Tests are being developed that can detect the actual HNPCC genetic abnormality (mutation) that was inherited from a father or mother. The two most commonly affected genes are MSH2 and MLH1.

Cyclooxygenases and Prostaglandins. Cyclooxygenase 1 and 2 (COX-1 and COX-2) are enzymes involved in the production of prostaglandins, substances produced by the body that cause inflammation, widen and narrow blood vessels, control muscle contractions, and inhibit hormones that regulate fat metabolism. COX-2, but not COX-1, appears to play a role in the development and spread of colorectal tumors. COX-2 increases the levels of prostaglandin E2 (PGE2), which, in turn, stimulates factors that inhibit apoptosis, the natural process whereby all cells, including cancerous ones, self-destruct. It also activates interleukin-6 (IL-6), a factor in the immune system that is associated with cancer cell invasion.

C-Reactive Protein (CRP). CRP is another indicator of inflammation. In a 2004 study published in the Journal of the American Medical Association, elevated CRP levels predicted the development of colon -- but not rectal -- cancer.

Bile Acid Salts. Deoxycholic acid, which is found in the fat-digesting bile salts released by the gallbladder, appears to have carcinogenic properties. Its effects are now believed to play a role in some cases of colon cancer. Levels of the acid can rise as a result of high-fat diets or certain diseases.

Growth Factors. Chronically higher circulating levels of growth factors, including insulin-like growth factor, have been associated with colorectal cancer.

Inflammatory bowel diseases include Crohn's disease and ulcerative colitis. These chronic disorders cause persistent injuries in the intestinal tract that can, in some cases, produce cancerous changes.

Symptoms

It is possible to have colon or rectal cancer without symptoms. Many patients are free of symptoms until their tumors are quite advanced.

Weight loss and changes in bowel movements are general symptoms for colon cancer, but these symptoms also occur in many other diseases.

Blood in the stools is a common sign of many intestinal cancers. It may appear red if it is fresh or black if it is old. It should be reported to a doctor immediately, even though it is often caused by conditions other than cancer, including:

Hemorrhoids
Minor tears around the rectal or anal areas
Diverticulosis

In addition, stool can change color by:

Eating certain red foods, such as beets or red licorice (red)
Taking iron supplements and medications that have bismuth subsalicylate, most commonly Pepto-Bismol (black)

Nevertheless, blood in the stools is an abnormal finding that should never be ignored. Always report it to your doctor for further advice.

Symptoms of colorectal cancer vary widely depending on the location of the cancer within the large intestine.

Tumors in the Cecum and Ascending Colon (Right Colon). The waste matter in the first portion of the colon is in liquid or semi-liquid form. Tumors that develop here do not change bowel habits or stool formation, but they may cause intermittent or chronic bleeding. Although the stools look normal, patients may develop symptoms of anemia from iron deficiency. Such symptoms include weakness, fatigue, heart palpitations, shortness of breath, and exercise intolerance.

Tumors in the Transverse Colon. As waste material passes across the upper quadrants of the abdomen (the transverse colon), the intestine absorbs water, and the waste matter becomes more solid. In addition to bleeding, tumors here may cause cramps, gas, partial or complete obstruction, and even perforation of the bowel. Anemia can also occur.

Tumors in the Descending Colon and Rectum (Left Colon). When tumors partially block the lower intestine, thin, pencil-shaped stools may form. Bowel habits can change. Tumors in the rectum and lowest part of the intestine can cause pain and a feeling of fullness. Defecation may be painful, or patients may feel the urge to defecate but nothing happens. Bleeding from these locations may be brisk and bright red or maroon, but cancer is often detected before symptoms of chronic anemia develop.

Risk Factors

Colorectal cancer is the third most common cancer in the U.S., with Americans facing a lifetime chance of 5.5 - 6% for this cancer. In 2007, colorectal cancer was expected to cause 153,760 new cases and 52,180 deaths in the United States. About 73% of cancers occur in the colon and 27% in the rectum.

The lifetime risk of cancer of the colon or rectum is 5.9% for men and 5.5% for women.

Colorectal cancer risk increases with age. More than 90% of these cancers occur in people over age 50. The rate of colorectal cancer in patients under 20 years is less than 1 in 100,000 per year. At age 50 about 1 in 2,000 people per year will develop colorectal cancer. After age 65, this rate increases to almost 3 in 1,000.

African-Americans have the highest risk of being diagnosed with, and dying from, colorectal cancer. Among Caucasians, Jews of Eastern European (Ashkenazi) descent have an elevated rate of colorectal cancer. Asian Americans/Pacific Islanders, Hispanics/Latinos, and American Indians/Alaska Natives have a lower risk than Caucasians.

About 20 - 25% of colorectal cancers occur among people with a family history of the disease. (Seventy-five percent of cases are due to other causes.) People who have more than one first-degree relative (sibling or parent) with the disease are especially at high risk. The risk is even higher if the relative was diagnosed with colorectal cancer before the age of 60.

About 5 - 10% of patients with colorectal cancer have an inherited genetic abnormality that causes the disease. Genetic mutations associated with colorectal cancer include familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer.

The risks for colon cancer are far higher in industrialized nations than less developed countries. A Western lifestyle, being sedentary, smoking, and having excess weight have all been associated with increased risk for colorectal cancer. (However, about 75% of cases occur without a known predisposing factor.)

Dietary Factors. Eating a lot of red meat increases the risk for colorectal cancer. Other types of animal protein (low-fat dairy products, fish, poultry) may decrease the risk of developing polyps and colorectal cancer. Studies on fruits, vegetables, and fiber are mixed. Some evidence suggests that diets very low in fruits and vegetables may increase the risk. In any case, eating a variety of fruits and vegetables should be part of a healthy diet.

A 2007 study in the Journal of the American Medical Association suggested that diet may play a role in colorectal cancer recurrence, as well as prevention. The study evaluated patients with stage III colon cancer who had been treated with surgery and chemotherapy. Patients who ate diets high in red and processed meats, refined grains, and sweets had a higher risk of cancer recurrence and poorer survival than patients whose diets were high in fruits and vegetables, poultry, and fish.

Alcohol and Smoking. Alcohol use and smoking increase the risk for colorectal cancer. Patients who smoke and drink may also be diagnosed with colorectal cancer at a younger age than non-drinkers and non-smokers. Several studies suggest that women who smoke are at especially high risk of developing colorectal cancer.

Obesity. There is a demonstrated link between body mass and colon cancer risk for both men and women. The Centers for Disease Control and Prevention has reported that the risk of colon cancer rises as body mass index increases. Obesity has been associated biologically with higher circulating levels of insulin and a hormone called insulin-like growth factor. Chronically high levels of these substances may increase colorectal cancer risk.

Physical Inactivity. More than 50 studies from around the world suggest that physical activity helps prevent colon cancer. In contrast, exercise does not protect against rectal cancer.

Crohn's disease and ulcerative colitis are chronic afflictions of the large intestine known as inflammatory bowel diseases (IBD). Both have been linked to increased risk for colorectal cancer. (Patients with ulcerative colitis have a higher risk than those with Crohn's disease.) Family histories are helpful in determining risk associated with inflammatory bowel disease. Some studies suggest the following:

Patients with IBD who have a family history of colorectal cancer face up to a five-fold risk of colon cancer themselves.
Individuals without IBD who have relatives who suffered from both IBD and colorectal cancer may face a higher risk for developing colorectal cancer themselves.
Individuals without IBD but with a family history of IBD and no colon cancer most likely face no higher risk for cancer themselves.

Crohn's disease, also called regional enteritis, is a chronic inflammation of the intestines that is usually confined to the terminal portion of the small intestine, the ileum. Ulcerative colitis is a similar inflammation of the colon, or large intestine. These and other inflammatory bowel diseases have been linked with an increased risk of colorectal cancer.

Polyps. Polyps are tissue growths, usually benign, that develop in the color or rectum, most often in patients over 50 years of age. When pathologists examine polyps removed from the colon, they classify them as either hyperplastic or adenomatous. Both types are benign, but some adenomas will become malignant. As a preventive measure, polyps should be removed (polypectomy).

Ureterosigmoidostomy. People who have had ureterosigmoidostomy, a surgical procedure to correct a birth defect in the bladder or to treat some bladder cancers, may develop tumors near the site of the defect, which is chronically exposed to urine and feces. Such patients have a 5 - 10% chance of developing colon cancer 15 - 30 years after the operation.

Diabetes. Many studies have identified an association between type 2 diabetes and colon cancer. Both diseases share common risk factors of obesity and physical inactivity, but diabetes itself is a risk factor for colorectal cancer. Both men and women who have diabetes are at risk.

Heart Disease. Coronary artery disease (CAD) increases the risk for colorectal cancer. Both CAD and colorectal cancer share important risk factors, including smoking, high fat diet, sedentary lifestyle, and obesity.

Dietary Factors

Some, but not all, studies have suggested that a high intake of fruits and vegetables can lower the risk for colorectal cancer. One study, for example, reported that these foods do not prevent polyps from forming but may help prevent them from becoming cancerous.

Phytochemicals. Many studies have demonstrated the cancer-fighting effects of plant chemicals called phytochemicals. Fruits and vegetables that contain phytochemicals can often be identified by colors:

Dark green (broccoli, spinach, kale, collard greens, mustard greens). These vegetables contain chemicals called isothiocyanates, which have been associated with a lower risk for cancer in general.
Red (red pepper, tomatoes, watermelon, raspberries, pink grapefruit). Lycopene is a chemical found in these foods that may have strong cancer-protective properties. Cooking tomatoes appears to increase their benefits.
Yellow-orange (carrots, pumpkin, sweet potatoes, oranges, tangerines). The colors in these foods are due to carotenoids. Carotenoids have been associated with health protection, although they may not have much effect on colon cancer itself.
Blue-black (many berries). Dark berries appear to have potent antioxidant chemicals that may be protective against cancer.

Organosulfurs are important food chemicals that are part of the allium family. Studies have reported health benefits from foods containing them. These compounds are found in garlic, leeks, onions, chives, scallions, and shallots. A review of 300 studies concluded that people who eat raw or cooked garlic regularly experience about two-thirds the risk of colorectal cancer as people who eat little or none. Another analysis, however, found the available evidence about garlic to be inconclusive. Garlic supplements, in any case, do not appear to be protective.

Fiber. Studies have been mixed on whether fiber (found in fruits, vegetables, and whole grains) protects the colon from cancer. For example, three major studies in 2002 and 2003 reported no difference in the development of colorectal polyps or cancer recurrence with high intake of fiber. On the other hand, results of the 2003 European Prospective Investigation into Cancer and Nutrition (EPIC) -- the largest study ever conducted on the role of diet in the development of cancer -- suggested that fiber is protective regardless of its source. However, in the study, the greatest benefits were observed for the left side of the colon and the least for the rectum. In any case, fiber, which is only found in plant products, may be beneficial for the heart and have other health advantages.

The role of fats in inflammatory bowel disease is complex and not fully known. A 2006 study from the Women’s Health Initiative found that a low-fat diet did not help reduce the risk for colorectal cancer. However, the study did not distinguish between types of fat.

Monounsaturated fats (olive, peanut, canola oils; avocados, nuts) and omega-3 polyunsaturated fats (fish, flaxseed oil, walnuts) are the healthiest types of fats.
Saturated fats (red meat, butter, high-fat dairy products) and trans-fats (hydrogenated fat found in snack foods, fried foods, commercial baked goods) are unhealthy types of fats.

Dietary guidelines recommend that adults limit the total fat in their diet to 25 - 35% of total daily calories. Saturated fat intake should be less than 7%, and trans fats less than 1%, of total daily calories. (Patients with heart disease or diabetes may need to limit unhealthy fat in their diet even further.) Most fats should come from polyunsaturated and monounsaturated fat sources.

[See In-Depth Report #43: Heart healthy diet; and #42: Diabetes diet.]

Evidence strongly suggests that red meat raises the risk for colon cancer development, and perhaps also recurrence. Red meat contains dietary iron, which has been associated with a higher risk for colon cancer.

High-temperature cooking (grilling, broiling, or pan-frying) has been specifically associated with increased risk for colon polyps and colon cancer. Overcooking meat increases the amount of carcinogens called heterocyclic amines, which has been associated with cancerous changes.

Milk, Lactose, and Probiotics. In one study, adults who drank the most milk had the lowest risk for colon cancer. A 2004 study published in the Journal of the National Cancer Institute supported this conclusion. In this review of 10 epidemiologic studies that included more than 500,000 people, those who consumed more milk and calcium had a lower risk of developing colorectal cancer. Milk contains not only calcium but also other compounds, such as lactose, that may help protect against colon cancer.

Yogurt specifically has been associated with a lower risk for colon cancer if it contains live active bacterial cultures, such as Lactobacillus acidophilus, that are called probiotics. These "friendly bacteria" appear to protect the colon from cancerous changes. (Acidophilus and other probiotic capsules are also available in health food stores.)

Calcium. Calcium, which is found in dairy products, is associated with colon cancer protection. Many studies have shown a possible protective effect from either high-calcium diets or calcium supplements. However, a 2006 study from the Women’s Health Initiative found that calcium and vitamin D supplements do not reduce women’s colorectal cancer risk. Many doctors still recommend that postmenopausal women take these supplements for bone health.

Obesity has been associated with colon cancer. In some studies of people under 67 years old, the amounts of fat and protein were less important than the total number of calories consumed: the higher the energy intake, the greater the risk for developing colon cancer. In older adults, high calorie intake did not make any significant difference. Other studies have indicated that eating too much sugar may increase the risk for colon cancer.

Studies conducted in several countries have found that drinking four or more cups of coffee a day is associated with a lower risk for colorectal cancer. Green tea may have also beneficial properties, but more research is needed in both of these areas.

Folate and B Vitamins. For years, many doctors have believed that the B vitamin folate (called folic acid) may help protect against colorectal cancer, particularly for people who are genetically predisposed to this disease. Folate is found in beans, citrus fruits, and green vegetables, but some studies have indicated that the greatest protective benefits come from taking supplements.

However, an important study published in 2007 in the Journal of the American Medical Association challenged this assumption. The study suggested that high-dose folic acid supplements do not prevent colorectal cancer, and may actually increase the risk for developing certain types of colorectal tumors. The study evaluated over 1,000 men and women who had a recent history of non-cancerous colorectal polyps. (Adenomatous polyps, also called colorectal ademomas, are the most common type of polyp found in colorectal cancer screenings.) The results indicated that patients who took 1 mg/day of folic acid supplements were more likely to develop new adenomatous polyps than patients who did not take supplements. Patients in the folic acid supplement group were also more likely to have advanced adenomas and more numerous adenomas.

Adenomatous polyps are benign tumors, but they can potentially develop into cancerous tumors. Researchers are continuing to investigate the role that folic acid plays in colorectal cancer risk and prevention. It is possible that folic acid may help prevent the initial appearance of adenomatous polyps, but increase the risk for additional polyp formation once they have begun to occur.

Antioxidant Supplements. Antioxidants are chemicals that help eliminate harmful particles called oxygen-free radicals that have been associated with cancerous changes. Some studies have associated supplements of the antioxidants selenium and vitamins A, C, D, and E with lower colon cancer risk, but most studies have found no protective effect.

Prevention

Studies indicate that daily exercise is one of the best ways to reduce the risk of colorectal cancer. The more vigorous the activity, the greater the benefit, but even moderate exercise (walking, stair-climbing) can help reduce colorectal cancer risk. The American Cancer Society (ACS) recommends that people engage in at least moderate exercise for 30 minutes or more at least 5 days a week. The ACS also notes that 45 minutes or more of moderate-to-vigorous activity at least 5 days a week may help further reduce cancer risk.

Some studies also suggest that regular exercise may be beneficial for patients who have been diagnosed with colorectal cancer. Two 2006 studies indicated that exercise may reduce the risk of colorectal cancer recurrence and death for patients with stage I - III cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are very common pain relievers that are available over-the-counter and by prescription. They include aspirin, ibuprofen (Motrin), naproxen (Aleve), and the COX-2 inhibitor celecoxib (Celebrex). Several studies have reported that NSAIDs help reduce the risk of colorectal cancer. However, regular use of NSAIDs, even in low doses, can increase the risk of gastrointestinal bleeding and stomach ulcers. Long-term use of NSAIDs can also increase the risk for heart attack and stroke, especially in people who have a history of heart disease. Several 2006 and 2007 studies in the New England Journal of Medicine reported that celecoxib prevented precancerous polyps, but the drug more than doubled patients’ risk for heart attack and other cardiovascular events.

A 2005 Nurse’s Health Study found that aspirin, but not other NSAIDs, does provide protection against colorectal cancer. However, the risk was only reduced for women who took 2 aspirin a day for more than 10 years. In addition, this dose level greatly increases the risk for gastrointestinal bleeding. Furthermore, a 2007 study in the New England Journal of Medicine suggested that aspirin’s protective effects may only apply to some types of colorectal cancer tumors. Another 2007 study, published in the Lancet, indicated that long-term daily use of aspirin can protect against polyps and colorectal cancer, but experts agree that aspirin’s risks do not outweigh its benefits for most people. (Some people who are at high risk for developing colorectal cancer may benefit from aspirin therapy.)

In March 2007, the U.S. Preventive Services Task Force (USPSTF) recommended against the routine use of aspirin and other NSAIDs to prevent colorectal cancer in people at average risk for this disease. (This recommendation does not apply to people who have a family history of colorectal cancer or who are at high risk for developing colorectal cancer due to other risk factors.) Long-term use of NSAIDs can increase the risk for gastrointestinal bleeding, kidney function problems, and heart problems. Aspirin can also increase the risk for hemorrhagic stroke. Due to these risks, the American Cancer Society and other professional associations also recommend against the use of NSAIDs or other types of medications for colorectal cancer prevention.

Medications containing 5-aminosalicylate (5-ASA) are sometimes given to patients with ulcerative colitis to help control inflammation. These drugs, which include sulfasalazine and mesalamine, are chemically related to aspirin. A 2005 review of clinical trials found that patients with ulcerative colitis who used 5-ASA were 49% less likely to develop colorectal cancer than patients who did not use these drugs

Some studies have suggested that cholesterol-lowering statin drugs may help reduce colorectal cancer risk. A 2006 study in the Journal of the National Cancer Institute did not find any protective benefit for statins.

Estrogen has been associated with a lower risk for colon cancer, perhaps because of specific enzymes that prevent cell proliferation. Drugs containing estrogen, then, may help high-risk women:

There is some evidence that hormone replacement therapy (HRT) reduces the risk of colon cancer in postmenopausal women. It carries other risks, however, including a higher risk for breast and uterine cancer and blood clots. A 2004 New England Journal of Medicine study found that while short-term use of estrogen plus progestin reduced the risk of developing colon cancer, combination HRT users who were diagnosed with the disease had more advanced forms of the cancer. Older women who are at higher risk for colon cancer might discuss risks and benefits of HRT with their doctor.
Oral contraceptives may reduce younger women's risk of colon cancer. Duration of use does not seem to be associated with decreased risk, but protection appears stronger for women who have more recently used oral contraceptives.

Diagnosis

Colon and rectal cancers are diagnosed using the screening tests discussed below. These tests can detect precancerous polyps and colorectal cancers at stages early enough for complete removal and cure.

Unfortunately, only 30 - 40% of adults over 50 years old (mostly in the upper socioeconomic group) have regular screening tests that could detect a cancer early enough for curative treatment. A survey reported that many people are not screened because they are too embarrassed. Those who had already had the tests were willing to have them again if they saved one additional day of their lives.

There is some debate about what is the best screening method. Current screening guidelines offer several different options for patients. Doctors agree that not enough people are screened and that these tests, if adopted with the same regularity as such screening tests as Pap smears, would save many lives. It is especially important for anyone at increased risk or with symptoms, such as rectal bleeding or ulcerative colitis, to have testing at an earlier age.

There is also debate about when people should stop being screened. A 2006 study in the Journal of the American Medical Association indicated that screening provides little benefit for elderly people, especially because colorectal cancers grow very slowly. The researchers suggest that doctors should carefully consider the risks versus benefits of screening patients age 80 and older.

Individuals should discuss with their doctors the risks and benefits of all screening procedures. Some controversy exists over how often people without risk factors for cancer should be screened and which detection method should be used for them.

Guidelines for Adults Age 50 and Over with Average Risk. The following are the five screening options recommended for people age 50 and over who have no symptoms and no family history of colon cancer:

Fecal occult blood test (FOBT) or fecal immunochemical test (FIT) every year
Flexible sigmoidoscopy every 5 years
FOBT or FIT every year plus sigmoidoscopy every 5 years
Double-contrast barium enema every 5 years
Colonoscopy every 10 years

Choosing between Colonoscopy and Sigmoidoscopy. The choice between colonoscopy and sigmoidoscopy for routine screening for older adults with average risk is an area of intense debate. The issues are as follows:

Sigmoidoscopy is less costly, less invasive, quicker, and safer than colonoscopy. Although it allows inspection of only the left side of the colon, any abnormal findings from sigmoidoscopy trigger a full colonoscopy. Therefore, experts estimate that sigmoidoscopy can detect 80% of all significant problems.
Colonoscopy is more sensitive than any other current screening method for detecting colon cancer. It can find 75 - 90% of colorectal cancers. If the goal were to reduce the number of cancer cases, regardless of cost, colonoscopy would be the preferred approach. Colonoscopy, however, is more expensive than sigmoidoscopy and has a slightly higher risk for complications (bowel tears or bleeding when a polyp is removed).

There are 3 basic tests for colon cancer: a stool test (to check for blood), sigmoidoscopy (inspection of the lower colon), and colonoscopy (inspection of the entire colon). All 3 are effective in catching cancers in the early stages, when treatment is most beneficial.

Screening, particularly with colonoscopy, in increased- and high-risk populations can save lives. The most important risk factors are a family history of colorectal cancer and personal history of colorectal cancer, polyps, or chronic inflammatory bowel disease. People with these risk factors should be screened before age 50 and may need more frequent screenings.

Guidelines for Increased-Risk Groups. Anyone with first-degree relatives diagnosed with colon cancer younger than 60, or with two relatives who have been diagnosed with colon cancer at any age, should consider beginning the standard screening regimen with a colonoscopy every 5 years, beginning at age 40 or 10 years before the youngest case in the family (whichever is earlier).

Men of African descent are also considered to be at increased risk for colon cancer and should discuss similar screening guidelines with their doctors.

Guidelines for High-Risk Groups. The following guidelines may be useful for specific high-risk groups.

People who have the mutated hereditary nonpolyposis colorectal cancer gene (MSH2 or MLH-). Frequent colonoscopy (for instance, every 1 - 2 years) beginning in their early 20s. (Regular screening for other cancers, such as uterine cancer, is also reasonable.)
People who have the mutated familial adenomatous polyposis (FAP) gene. Frequent screening with endoscopy (flexible sigmoidoscopy or colonoscopy) beginning in early puberty. Genetic testing is now recommended for family members of people with known FAP.
People with predisposing intestinal problems, such as widespread and active ulcerative colitis or Crohn's disease. Annual screening with colonoscopy with biopsies of suspicious areas.

Guidelines for Follow-Up After Detection of Precancerous Polyps. Patients who have had a previous examination in which polyps were detected (and removed) should have a repeat colonoscopy 1 - 3 years later, depending on the size, number, and type of polyps removed.

The digital rectal examination is used to detect tumors in the rectum, lower intestine, and prostate gland. The doctor inserts a lubricated-gloved finger into the patient's rectum and feels for lumps or other abnormalities. The exam is quick and painless but embarrassing for some. Fewer than 10% of colon cancers develop within the region that can be evaluated by a DRE, so it is not useful as a sole screening test.

Blood in bowel movements is not always visible, in which case it is called occult (hidden) blood. Fecal occult blood tests (FOBTs) are used to detect this hidden blood. The most common FOBT method is called the guaiac-based test. The patient is asked to supply up to six stool specimens in a specially prepared package. A small quantity of feces is smeared on specially treated paper, which reacts to hydrogen peroxide. If blood is present, the paper turns blue.

Accuracy. FOBTs can miss more than 75% of advanced cancers. Nevertheless, large studies have indicated that this simple test, performed annually, saves lives and may reduce the risk of dying from colon cancer by 15 - 33%. The following factors may affect its accuracy:

The levels of iron in the blood can affect results. Patients should not take iron supplements or eat red meats several days before the test.
Certain raw fruits and vegetables that contain the chemical peroxidase (cauliflower, horseradish, radishes, melons, and turnips) can cause a positive test reaction even if no blood is present.
Aspirin and NSAIDs are anticoagulants that can cause minor bleeding. They should not be taken for a week before the test. However, a 2005 study suggested that the prescription anticoagulant warfarin does not affect FOBT results.
Vitamin C and foods rich in this vitamin may cause a false negative reaction and should be avoided a few days before the test.
Bleeding from other causes, such as menstruation, hemorrhoids, gingivitis, or urinary infections, can produce blood in the stools and affect results.

Even if none of these conditions is present, a test that shows hidden blood does not necessarily mean that cancer is present. About 20 - 30% of people with occult blood have noncancerous polyps or other conditions, such as gastritis, and only 5 - 10% actually have cancer. Any abnormal result, however, requires further testing, such as colonoscopy.

Lack of Compliance. Compliance is a major problem. Patients are asked to perform the tests at home and send the test cards to the laboratory. Only 35 - 50% of patients actually follow through. Occult-blood tests that give results at home are available but are extremely inaccurate. In one large study, these tests failed to detect advanced cancer in about 62% of cases, although they may detect some early cancers.

If a digital rectal exam (DRE) or fecal occult blood test (FOBT) shows signs of trouble, several methods to visualize the colon are available. They include colonoscopy, sigmoidoscopy, and double-contrast barium enema. They have the following similarities and differences:

Sigmoidoscopy can only view the rectum and the left side of the colon, while colonoscopy and barium enemas allow a view of the entire large intestine.
Both flexible sigmoidoscopy and colonoscopy involve snaking a fiber optic tube through regions of the rectum and colon to view the walls of the intestine. The tube contains a tiny camera that transmits the image to a video screen. The use of an ultrasound (sound wave) scanner is proving to enhance viewing quality. Barium enemas simply use x-rays.
During either sigmoidoscopy or colonoscopy, the doctor is able to remove polyps or other abnormalities revealed by these procedures with surgical instruments inserted through the tube. It is not possible to remove polyps with a barium enema, which is not invasive.

Sigmoidoscopy. Sigmoidoscopy examines the rectum and the lower two feet of the colon. It cannot, however, detect the roughly half of cancers that occur in the right colon. Right-sided cancers are more common in older people.

The procedure uses a flexible fiber optic tube (it is thus referred to as flexible sigmoidoscopy) that contains a tiny camera and surgical instruments.
It lasts about 10 minutes and may be mildly uncomfortable, but it is not painful and is generally very safe. In one study, 70% of patients reported that the procedure was far less unpleasant than they had expected.

This procedure has been found to reduce the risk of fatal cancers in the rectal and sigmoid area by 60%. If polyps are detected, a colonoscopy is then used.

Colonoscopy. Colonoscopy is the most accurate testing method and can reduce cancer incidence by up to 90%. It is clearly indicated for anyone with an increased risk for colorectal cancer, including those with a personal or family history of the disease. As with sigmoidoscopy, a colonoscopy uses a flexible tube, but it is snaked through the entire large intestine.

For about a day before the procedure the patient eats nothing and drinks a laxative solution that cleans out the colon. The taste of the solution is unpleasant, although it has improved in recent years.
The procedure typically uses a sedative that produces a "twilight" sleep and often makes the procedure more comfortable than sigmoidoscopy.
Air may be introduced into the intestine to widen it and allow the tube to navigate curves. A colonoscopy avoids the risk of radiation associated with a barium enema, but it is important to note that even a colonoscopy does not detect all cancers.

Complications are rare, but include the following:

Hyponatremia. Hyponatremia is a low concentration of sodium in the blood. The complication may be caused by the effects of bowel cleaning before the procedure that can result in water retention and reductions in sodium. When severe, it can cause temporary neurological symptoms, such as confusion, lethargy, unsteadiness, and slurred speech. Researchers suggest that sodium concentrations be measured in patients who develop such symptoms after colonoscopy.
Bowel perforation (very low risk, about 2 in 1,000 procedures). The risk for bowel perforation is greater with colonoscopy than flexible sigmoidoscopy.
Bleeding at the site of biopsy or polyp removal.

Overall, colonoscopy is a safe procedure. However, according to a 2006 study in the Annals of Internal Medicine, serious complications occur in about 5 of every 1,000 colonoscopies. Most of these complications occurred when a biopsy or polyp removal was performed. (The risk for complications without biopsy or polyp removal is about 1 in every 1,000 colonoscopies.) This study looked at colonoscopies in general, including those that are done to diagnose the causes of a patient's symptoms. The risk may be lower for colonoscopies performed solely to screen for colorectal cancer.

Barium Enema. The double-contrast barium enema, which uses an x-ray image, is the less expensive alternative for viewing the entire colon. It is not as accurate as colonoscopy, and if any polyps or abnormalities are revealed on x-ray, a colonoscopy is then required to remove suspicious tissue, so it is now recommended much less often than in the past.

The barium enema is a valuable diagnostic tool that helps detect abnormalities in the large intestine (colon). The barium enema, along with colonoscopy, remains the standard in the diagnosis of colon cancer, ulcerative colitis, and other diseases of the colon.

Screening for familial adenomatous polyposis. Genetic screening for familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC) is now available and may be recommended for high-risk patients. The test for FAP detects a mutation in the adenomatous polyposis coli in up to 90% of people who carry it. Testing for HNPCC mutation is somewhat more complex.

Screening for insulin-like growth factor. A gene that regulates insulin-like growth factor (IGF-2) is functional during fetal development and then becomes inactive. Some evidence now suggests that people who have IGF-2 in adulthood have a higher risk for colon cancer. Blood tests for detecting IGF-2, then, may be helpful in identifying patients who should have more intensive screening. Currently, however, this is only used as a research tool.

Stool DNA Testing. A promising technique for colorectal cancer screening is the detection of altered DNA in cancer cells that have shed from the colon and are excreted in the stool. Such tests may prove to detect both inherited and noninherited genetic mutations. This may become a widely used tool in the future. However, larger clinical studies are needed.

Virtual Colonoscopy. A promising experimental technique called virtual colonoscopy allows three-dimensional imaging of the colon without using invasive instruments. As with standard colonoscopy, the patient takes a laxative first to clear out the intestine. The procedure itself involves pumping air into the colon and scanning the intestine using computed tomography (CT). It is very safe and takes about only 10 minutes. The procedure is similar in accuracy to conventional colonoscopy for detection of larger polyps (6 mm or more in diameter) and is also potentially less expensive. Colonoscopy is required, however, if suspicious areas are found, which may occur frequently with the CT procedure, since it erroneously identifies a high number of nonexistent polyps.

A study published in April 2004 in the Journal of the American Medical Association compared results of standard colonoscopy versus virtual colonoscopy in over 600 patients at nine major medical centers. Virtual colonoscopy had much lower rates of successfully finding polyps than standard colonoscopy. Virtual colonoscopy detected polyps of at least 6 mm in 39% of patients and polyps of at least 10 mm in 55% of patients. By contrast, standard colonoscopy detected 99% of polyps of at least 6 mm, and 100% of polyps of at least 10 mm. In addition, accuracy rates varied widely among the different hospitals. The authors advised that until more improvement in training and technique is achieved, virtual colonoscopy "is not yet ready for widespread clinical application."

Magnetic Resonance Colonography. Magnetic resonance colonography (MRC) is another non-invasive technique for visualizing the colon. The patient receives an enema containing a contrast substance, and then magnetic resonance images are taken. MRC is fast, comfortable, and less invasive than colonoscopy. Currently, however, there is a poor detection rate for flat tumors and for polyp tumors less than 10 mm in diameter.

Staging

A diagnosis of cancer will lead to staging and other tests to help determine the outlook and the appropriate treatments.

The large intestine is a long hollow organ lined with mucous membrane (mucosa). Muscle layers wrap around the entire length and help move food material through to the rectum.

Unlike many other cancers, the size of the tumor is not a major factor in determining the outcome of colorectal cancer. Of greater importance is how far the cancer has spread. To determine this, doctors will assign a stage to the tumor. There are several methods for staging. The older system, known as Dukes', categorizes four basic stages: A, B, C, and D. A more recent system refers to these stages as I, II, III, and IV but divides the categories slightly differently. The term "5-year survival" means that patients have lived at least 5 years since diagnosis. Most patients who live 5 years without a recurrence are considered to be cured of their disease.


Stage	Condition	5-Year Survival
A or I	Tumor superficially involves the inner lining of the intestine.	More than 90%
B or II	Tumor has penetrated through the muscle wall of the intestine but has not reached the lymph nodes.	70 - 85%
C or III	Lymph nodes are involved.	65% or below
D or IV	Tumor has spread to other organs (metastasized), usually the liver first.	5 - 9%

Click the icon to see an image of the stages of cancer.

Researchers are continually seeking to identify tumor markers, substances (usually found in blood samples) that will assist in the diagnosis of cancer and in monitoring effects of treatment.

Carcinoembryonic Antigen. High blood levels of a protein called carcinoembryonic antigen (CEA) sometimes indicate the presence of colon cancer. Unfortunately, it is also elevated in other cancers and in some noncancerous conditions. CEA is not effective as a screening tool for healthy people, but might eventually be helpful for patients with cancer.

An advanced diagnostic technique called polymerase chain reaction (PCR) can detect genetic evidence of CEA. One study indicated that when these microscopic footprints of colon cancer are detected in the lymph nodes of patients with Stage II cancer (whose lymph nodes otherwise appear to be not involved with cancer), the outlook is similar to that of patients with Stage III cancer. Patients without this so-called micrometastasis have a very favorable prognosis. Further research is needed, however, before PCR can be used in widespread practice.
In patients with a history of, or active, colon cancer, follow-up measuring of blood CEA levels may be helpful in detecting recurrence of the cancer and effectiveness of treatments.

Defective P53 Gene. The presence of a defective p53 gene is a marker for very poor prognosis in patients with advanced colon cancer. In its normal state, the gene is important for regulation of cell growth. Testing for this abnormality, however, is not widely done because it is not clear how to use this information.

Other Tumor Markers. Other tumor markers under investigation include a protein called GLUT1, cancer antigen 19-9 (CA 19-9), matrix metalloproteinase-9 (MMP-9) RNA, HER-2/neu oncoprotein, transforming growth factor beta-1 (TGF-beta-1), and CD44.

Click the icon to see an image of drawing blood for culture.

A technique known as a sentinel node biopsy is increasingly performed by experienced surgeons in selected patients. This procedure is used to determine if cancer has spread beyond the nodes, possibly reducing the need for complete axillary lymphadenectomies. It involves the following:

The procedure uses an injection of a tiny amount of a tracer, either a radioactively-labeled substance (radioisotope) or a blue dye, into the tumor site.
The tracer or dye then flows via the lymphatic system into the so-called sentinel node. This is the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed.
If they do not show any signs of cancer, it is highly likely that the remainder of the lymph nodes will be cancer free, and further surgery becomes unnecessary.

It is still not known if the sentinel node biopsy has any survival advantages compared to the standard procedures with lymph nodes removal. However, one study indicated that careful and complete removal of potentially cancerous lymph nodes is still very important for improving survival in patients with Stage II and III colorectal cancer.

Whole-body imaging scans that combine positron emission tomography (PET) and computed tomography (CT) may be helpful in accurately staging colorectal cancer, according to preliminary research published in 2006 in the Journal of the American Medical Association.

Prognosis

Survival rates for colorectal cancer have been rising in recent years. The 5-year survival rate is as high as 90% for cancer that has not spread to the lymph nodes (localized cancer). When cancer has spread to lymph nodes and other parts of the body, survival rates drop to 65% and below. Because many cancers are detected at later stages, the overall survival rate is currently about 60%. African-Americans and other minorities tend to have lower survival rates than Caucasians. Studies suggest, however, these higher mortality rates are largely due to less access to optimal health care, including appropriate surgical care and aggressive treatments.

In most cases, age is not a factor in treatment success. Good survival rates are achieved in the elderly as well as in young people. Chances for survival are less in Stage II cancers if the intestine is obstructed or perforated. If cancer has spread to lymph nodes (Stage III), the outlook is better if three or fewer lymph nodes are involved. Treatment can prolong life even when cancer has spread.

Surgery

Surgical removal of the tumor ("resection") along with any affected surrounding tissue is the standard initial treatment for potentially curable colorectal cancers (cancers that have not spread beyond the colon or lymph nodes). Drug and radiation therapy are often used for advanced cancers and are continuously being tested with surgery in different combinations and sequences.

Although choosing a qualified surgeon is critical, choosing a hospital experienced in procedures is also important. The more often colon cancer surgery is performed at a given hospital, the lower the mortality rate at that hospital is likely to be.

Unless cancer is very advanced, most tumors are removed by an operation known as colectomy:

Colectomy involves removing the cancerous part of the colon and nearby lymph nodes.
The surgeon then reconnects the intestine.
If the surgeon cannot reconnect the intestine, usually because of infection or obstruction, the surgeon will perform a colostomy. The need for colostomies is higher after surgery for rectal cancer. In most cases of colon cancer, colostomies are not needed. [See "Colostomy" below.]

Click the icon to see an illustrated series detailing colon cancer treatment.

The Surgical Approach. The standard technique for a colectomy is open, invasive surgery. Laparoscopy, sometimes called “keyhole surgery,” is a less invasive method. Laparoscopy is still considered an investigational technique for treating colon cancer, but it is gaining more acceptance and showing good results in clinical trials.

Open Surgery:

Open surgery uses a wide incision to open the patient's abdomen. The surgeon then performs the procedures with standard surgical instruments. This is the usual method for performing colectomy.

Laparoscopy:

Laparoscopy uses a few small incisions through which the surgeon passes a fiber optic tube (laparoscope) containing a small camera or tiny instruments. It is generally used for early colon cancer (for tumors less than 2 centimeters or for well-defined tumors less than 3 centimeters).
A 2004 New England Journal of Medicine study found that patients who received laparoscopic colectomy had similar rates of surgical complications, cancer recurrence, and survival as those who received traditional open surgery. However, the patients who had laparoscopy recovered faster and did not need as many narcotic painkillers.
Several 2005 studies indicated that laparoscopy works as well as conventional surgery for treatment of colon cancer. However, laparoscopy does not appear to be as effective for rectal cancer.

Click the icon to see an image detailing pelvic laparoscopy.

Click the icon to see an illustrated series detailing a resection of the large intestine.

Other Investigational Measures. Researchers are testing expandable metal tube-like devices called stents to keep the intestine open. Stents may be used before a procedure to allow bowel cleansing or for long-term use to keep open colons that can't be operated on.

A colostomy is performed in order to bypass or remove the lower colon and rectum. The procedure generally involves creating a passage, called a stoma, through the abdominal wall that is connected to the colon. The feces pass through this passage and are eliminated. Patients must learn how to care for the stoma and keep the area sanitary.

A colostomy usually will have one opening (single-barreled), or there may be two loops opening through the skin (double-barreled).

Usually the colostomy is temporary and can be reversed by a second operation after about 3 - 6 months. It the rectum and sphincter muscles in the rectum need to be removed, the colostomy is permanent. Permanent colostomies are more common when the cancerous regions are within 2 - 3 centimeters of the anus. Fortunately, surgical advances and knowledge of the extent of safe margins are reducing the need for permanent colostomies.

Click the icon to see an illustrated series detailing a colostomy procedure.

Managing Permanent Colostomies. In cases where the colostomy is permanent, the patient must wear a colostomy pouch, which sticks to the skin using a special glue. Pouches are available as one- or two-piece systems. The one-piece system is simpler, but the two piece system allows replacement of the pouch without removing the tape.

For best results, the pouch should be emptied when about one-third full. It should be replaced 1 - 2 times a week, depending on signs of leakage (itching or burning of the skin near the stoma). The pouches are odor proof.

Surgical treatments for cancer in the rectum are complex since they involve muscles and tissue that are critical for urinary and sexual function.

Local Excision or Polypectomy for Early Stages. In order to preserve the function of the anal sphincter and prevent the need for colostomy, Stage I and Stage II tumors may be removed by local excision, sometimes followed by chemotherapy and radiation. In this procedure, the tumor is cut out without removal of a major section of rectum. In some cases cancer recurs, but a second operation may be possible. Another treatment for early-stage rectal cancer, called electrocoagulation, destroys tumors using a high frequency electric current. It is being tested in clinical trials.

Radical Resection. In about a third of cases of rectal cancer, the cancer occurs in the lower part of the rectum, where between 70 - 80% of cancers have spread beyond the rectal wall. These patients need a radical resection, in which surrounding structures, including the sphincter muscles that control bowel movements, must often be removed.

The use of chemotherapy and radiation prior to surgery may prevent the need for permanent colostomy in some patients. This is an active area of clinical research, and trials are under way to address this issue. Another technique, called coloanal anastomosis, reconstructs the area to avoid the need for colostomy, and may be appropriate in some patients.

Total Mesorectal Excision. Total mesorectal excision (TME) involves dissection and removal of the entire cancerous area of the rectum along with surrounding fatty regions where the lymph nodes are located (the mesorectum). When successful, TME preserves the sphincter muscle, reducing the need for a permanent colostomy. Increasing use of this procedure is resulting in lower recurrence rates, lower levels of impotence and incontinence, and better overall survival rates compared to other resection techniques. Some experts now recommend it as a first choice for certain patients with locally advanced rectal cancer.

Combining chemotherapy and radiation either before or after TME is yielding promising long-term results and a low risk for local recurrence. There are many questions, however, and it is not clear which approach is better for specific patients.

Side effects of colon surgery include:

Sexual dysfunction. This is of particular concern. In general, colostomy does not usually affect sexual function. However, wide rectal surgery can cause short- or long-term sexual dysfunction. Sildenafil (Viagra) may help men who experience this after surgery.
Irregular bowel movements.
Gas and flatulence. Pouching filters are available to reduce gas. Certain foods produce more gas than others -- usually within 6 - 8 hours after ingestion for colostomy patients. They include beans, oat bran, most fruit, and certain vegetables (cabbage, cauliflower, Brussels sprouts, broccoli, and asparagus). To prevent swallowing air, patients should avoid sipping through straws, chewing gum, and chewing with their mouths open.
Diarrhea.
Bladder complications.
Sense of urinary urgency.
Fecal incontinence. Patients with rectal surgery have a higher risk for bowel dysfunction than those who had a colostomy.
Complications in or around the stoma. These can occur early after surgery to many years after the procedure. They include skin infection or breakdown, hernias, narrowing of the stoma, bleeding, and collapse.

There are no dietary restrictions, although many patients avoid foods that can produce gas. Everyone should drink plenty of fluids and get sufficient fiber.

The potential side effects of sexual and bowel dysfunction for colorectal surgical patients can be devastating, although many patients do very well and live normal productive lives. Positive emotions play a strong role in recovery. Patients who are depressed should discuss with a doctor all aspects of treatment that affect the quality of life, and consider seeking support groups.

Medications

Chemotherapy uses drugs that kill cancer cells throughout the body. There are two situations in which chemotherapy is used:

The adjuvant setting. Adjuvant refers to the use of chemotherapy after surgery in patients with Stage III tumors and selected patients with high-risk Stage II tumors (disease that is potentially curable). The goal of this therapy is to eliminate any cancer cells that surgery may have missed, thereby preventing recurrence and increasing the chance of cure. Patients of all ages, including the elderly, can benefit.
In metastatic disease. In patients with metastatic disease (where the cancer has spread to other parts of the body) the goal of chemotherapy is to shrink tumors, improve symptoms and quality of life, and lengthen life.

In the adjuvant setting, there are some differences in chemotherapy treatments between colon and rectal cancers:

Chemotherapy for Stage II is considered standard care for Stage II rectal cancer but is under debate for colon cancer.
Chemotherapy is standard for patients with Stage III colon cancer. Chemotherapy is also standard for patients with Stage III rectal cancer but is used in combination with radiation.

Chemotherapy for Stage II Colon Cancer. Adjuvant chemotherapy for Stage II colon cancer is controversial. Such patients tend to have a good outcome after surgery, and the positive effects of chemotherapy have been difficult to demonstrate. To date, the survival advantage of adjuvant chemotherapy in this group has been reported to be only in the range of 2%. However, better trials are still needed to confirm or refute the benefits in specific patient groups.

Although not yet known with certainty, some data suggest that certain patients with Stage II cancer may be at higher risk of recurrence and would theoretically benefit from adjuvant therapy. These include patients with cancers that have:

Obstructed the bowel
Perforated the wall of the colon
Adhered to structures outside the intestine

Advanced diagnostic techniques are under investigation for helping to select appropriate candidates for adjuvant therapy. None of these methods, however, are ready to be used routinely to help make treatment decisions. The decision whether to pursue chemotherapy for Stage II disease should be made after careful discussion between the patient and their oncologist, especially after features, such as bowel perforation or obstruction, are taken into account.

Chemotherapy for Stage III Colon Cancer. Since the early 1990s, adjuvant chemotherapy with 5-FU and leucovorin has been the standard of care for Stage III colon cancer. In recent years, the FOLFOX (5-FU, leucovorin, oxaliplatin) regimen has also been used for chemotherapy following surgery. Numerous trials have shown that adjuvant chemotherapy in this setting reduces the absolute risk of death from colon cancer by about one-third and improves survival by 10%. Clinical trials are also investigating combinations of other drugs.

Chemotherapy for Advanced Colorectal Cancer. Chemotherapy is either given directly into the arteries of the liver or intravenously (through a vein) with 5-FU and leucovorin. Oxaliplatin is sometimes added, but recent evidence suggests that the targeted therapy biologic drug bevacizumab may be a better addition. Other alternative chemotherapy choices are capecitabine, or irinotecan combined with cetuximab. Radiation therapy may be used in place of chemotherapy or in combination with it. Studies indicate that chemotherapy offers only a modest improvement in survival, but may help reduce symptoms.

Seven drugs are currently approved for colorectal cancer chemotherapy:

5-fluorouracil (5-FU, Adrucil), which is often given in combination with leucovorin (Wellcovorin). Leucovorin is a vitamin that helps boost the effectiveness of 5-FU.
Capecitabine (Xeloda)
Oxaliplatin (Eloxatin)
Irinotecan (Camptosar)
Bevacizumab (Avastin)
Cetuximab (Erbitux)
Panitumumab (Vectibix)

Capecitabine is a pill form of 5-FU. The other drugs are administered intravenously. Many of these drugs are given in combination with each other. Common chemotherapy combination regimens include:

5-FU / LV (5-FU and leucovorin)
FOLFOX (5-FU with leucovorin and oxaliplatin)
FOLFORI (5-FU with leucovorin and irinotecan)
IFL (Irinotecan, 5-FU, leucovorin)
XELOX (Capecitabine and oxaliplatin)

Side effects occur with all chemotherapeutic drugs. They are more severe with higher doses and increase over the course of treatment. Because cancer cells grow and divide rapidly, anticancer drugs work by killing fast-growing cells. This means that healthy cells that multiply quickly can also be affected. The fast-growing normal cells most likely to be affected are blood cells forming in the bone marrow, and cells in the digestive tract, reproductive system, and hair follicles. Nausea and vomiting is a very common side effect, but drugs such as ondansetron (Zofran) can help provide relief. In general, side effects are nearly always temporary, and medications can help manage them. Most patients are able to continue with normal activities for all but perhaps 1 - 2 days a month.

5-Fluorouracil (5-FU) with Leucovorin. Adjuvant therapy using 5-fluorouracil, either alone or with leucovorin (5-FU/LV), is the standard treatment for patients with high-risk colon cancer (Stage III or select patients with Stage II tumors). Leucovorin, also called folinic acid, is a form of the B vitamin folic acid, which helps increase 5-FU’s effectiveness. Patients are given a series of cycles that usually continue for at least 6 months.

There are many different ways of giving 5-FU, including intravenously over several hours once a week, intravenously daily for 5 consecutive days every month, or as continuous infusion with a portable pump.

The side effects can be quite different, depending on the way 5-FU is given, and women may be more susceptible than men. In one analysis, 53% of women and 40% of men experienced severe side effects, while response rates and survival were similar for both sexes. Many patients, however, tolerate 5-FU with leucovorin well, with manageable side effects. The most common side effects include nausea and vomiting, diarrhea, loss of appetite, hair loss, swelling of hands and feet, rashes, and mouth sores.

Irinotecan. Irinotecan (Camptosar) blocks an enzyme essential for cell division. Irinotecan can be given alone or in combination with 5-FU and leucovorin. This combination therapy (irinotecan plus 5-FU/LV) is also referred to as the "Salz regimen," or IFL. When it was approved in the mid 1990s, irinotecan was the first new drug developed for colon cancer in over 30 years. Studies have shown that irinotecan combined with 5-fluorouracil and leucovorin (5-FU/LV) significantly delays the time at which tumors progress and improves survival in metastatic cancer compared to 5-FU/LV alone. While the survival advantage is small, the combination has become the standard of care for metastatic cancer. Of concern, however, are studies that have reported an increased risk of death from toxic effects with the use of the three-drug combination. These deaths appeared to be related to blood-clotting complications. Doctors should carefully monitor dosages. Diarrhea is a common side effect of irinotecan.

Capecitabine. Capecitabine (Xeloda), an oral form of 5-FU, was approved in 2001 as a treatment for metastatic colorectal cancer. It is the only pill approved for colorectal cancer. A major 2005 study, published in the New England Journal of Medicine, found that capecitabine works as well as the standard 5-FU/LV regimen and causes significantly fewer side effects. The study involved patients with Stage III colon cancer who had undergone surgical removal of the tumor. In 2005, capecitabine was approved for postsurgical treatment of patients with Dukes’ C colon cancer. Capecitabine is also showing promise in combination with radiation therapy for rectal cancers.

Oxaliplatin. Oxaliplatin (Eloxatin) is related to cisplatin, a widely used platinum-based chemotherapy drug. Oxaliplatin is used in combination with 5-FU and leucovorin. (This triple combination therapy is called the FOLFOX regimen.) Oxaliplatin was first approved in 2002 for use in combination with 5-FU and leucovorin as a second-line treatment for cancer that has progressed after initial therapy.

Since 2002, oxaliplatin has received additional approvals as a first-line treatment for advanced colorectal cancer, and as a post-surgical treatment for patients who have undergone tumor resection.

Oxaliplatin can cause pain and tingling sensations in the hands and feet (neuropathy) that is worsened by exposure to cold. Recent research suggests that adding xaliproden (Xaprila) to the FOLFOX regimen may help reduce the frequency of neuropathy without interfering with the benefits of chemotherapy. Xaliproden is a drug used to treat the neurological disease amyotrophic lateral sclerosis (also known as Lou Gehrig's disease).

Bevacizumab. Bevacizumab (Avastin) was approved in February 2004 as a first-line treatment for patients with metastatic colorectal cancer (advanced cancer that has spread in the body). It is used in combination with IFL (irinotecan, 5-FU, leucovorin). Bevacizumab is a genetically engineered monoclonal antibody that targets and inhibits vascular endothelial growth factor (VEGF), a protein that regulates angiogenesis (the development of new blood vessels that feed a tumor's blood supply). It is the first anti-angiogenic therapy approved for the treatment of colorectal cancer.

In a study of 800 patients with metastatic colorectal cancer, bevacizumab administered intravenously along with IFL extended survival by about 5 months longer than IFL alone. Common side effects of bevacizumab include nosebleeds, fatigue, diarrhea, and high blood pressure. Less common side effects include stroke, heart attacks, angina, and formation of holes in the colon and stomach (gastrointestinal perforation).

Cetuximab. Cetuximab (Erbitux) was approved in February 2004 for the treatment of metastatic colorectal cancer. This monoclonal antibody drug targets epidermal growth factor receptor (EGFR), a protein required by cancer cells in order to proliferate. It can be used either in combination with irinotecan or alone for patients who have not responded to irinotecan. Studies of the cetuximab-irinotecan combination suggest it can help in tumor shrinkage. It has a modest effect on survival, prolonging patients’ lives by about an additional month.

Panitumumab. Panitumumab (Vectibix) was approved in September 2006 for treatment of colorectal cancer that has metastasized following standard chemotherapy. Like cetuximab, panitumumab is a monoclonal antibody drug that targets EGFR. In clinical trials, panitumumab helped delay disease progression and prolong survival by about 3 months. About 8% of patients experienced tumor shrinkage. Common side effects of this drug include skin rash, fatigue, abdominal pain, nausea, and diarrhea or constipation. Serious side effects include pulmonary fibrosis, severe skin rash, and skin reactions at the infusion site.

One of the most promising recent developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotype. In the future, diagnostic tests may help doctors identify which patients are more likely to respond successfully to specific drugs.

Biologic therapies use the body's immune system to attack the cancer (immunotherapy). These drugs are derived from biological sources and include vaccines, monoclonal antibodies (MAbs), and gene therapies. Many targeted therapies are classified as biologics. Bevacizumab (Avastin), cetixumab (Erbitux), and panitumumab (Vectibix) are currently the three biologic drugs approved for colorectal cancer treatment, but many other drugs are in development.

Targeted therapies involve many different types of drugs and molecular pathways. These include:

Angiogenesis Inhibitors. Anti-angiogenesis drugs inhibit the formation of new blood vessels that supply tumors with the blood, oxygen, and nutrients vital to tumor growth. Angiogenesis inhibitors, such as the monoclonal antibody bevacizumab (Avastin), target vascular endothelial growth factor (VEGF). Cediranib (Recentin), formerly AZD2171, is a new angiogenesis inhibitor that is in Phase III clinical trials for treatment of colorectal cancer.

Tumor Growth Factor Inhibitors. Tumor growth factors, such as epidermal growth factor, stimulate cell growth. Cetixumab (Erbitux) and panitumumab (Vectibix) are the two currently approved colorectal cancer drugs that target the epidermal growth factor receptor (EGFR). Nimotuzumab (TheraCIM) is currently being studied in combination with irinotecan in Phase III trials.

Tyrosine Kinase Inhibitors. Tyrosine kinase is an enzyme associated with EGFR that is involved with the signaling mechanisms that prompt cell growth. The EGFR/tyrosine kinase inhibitor erlotinib (Tarceva), which is approved for the treatment of pancreatic and lung cancers, is being investigated as an adjuvant treatment for metastatic colorectal cancer. Sunitinib (Sutent), which is approved for renal cell carcinoma, is another tyrosine kinase inhibitor in Phase III trials for colorectal cancer.

Radiation Treatment

Radiation therapy uses x-rays to kill cancer cells that might remain after an operation or to shrink large tumors before an operation so that they can be removed surgically. The object of radiation therapy is to damage the tumor as much as possible without harming surrounding tissues. Radiation may be administered in the following ways:

Externally by an x-ray machine (external beam radiation).
By passing radioactive pellets through thin plastic tubes inserted into the intestine.
By implanting tiny radiation seeds directly into the tumor (brachytherapy).
Computer imaging techniques providing 3-dimensional pictures of the cancerous area are allowing precise targeting of radiation to the tumor.

Postoperative radiation treatment combined with chemotherapy is common practice for patients with rectal cancer in Stages II and III. Such patients are at risk of recurrence both at the site of their original tumor and elsewhere in the body. Although there can be significant long-term side effects, the combination of 5-FU and radiation is still considered standard after surgery.

The standard procedure in the U.S. is to apply radiation after surgery (postoperative). Pre-operative chemotherapy and radiation, however, are sometimes used to preserve sphincter-muscle function and reduce the chance that a patient will need a colostomy. Furthermore, some studies suggest that the use of radiation before surgery reduces the likelihood of recurrences and may slightly prolong survival in some patients with rectal cancer. (It has no additional advantages, however, if the subsequent surgery does not completely remove the cancerous regions.) Studies comparing preoperative and postoperative chemotherapy and radiation are currently under way.

Radiation therapy can also be used during surgery (a procedure called intra-operative radiotherapy). It allows the surgeon to move healthy tissue out of the path of the radiation beam.

Short-term side effects of radiation include:

Diarrhea
Skin irritation around the anus
Incontinence
Fatigue
Bowel movement problems

Longer-term complications may include:

Incontinence
Hip and pelvic fractures
Diarrhea
Increased risk for bowel obstruction

Follow-up Testing

The American Society of Clinical Oncology (ASCO) sets guidelines for follow-up testing to detect recurring cancer after the completion of treatment. The following guidelines are based on ASCO’s 2005 updated recommendations.

Most colorectal cancer recurrences happen within 3 years after surgery. American Society of Clinical Oncology recommends that a colorectal cancer patient sees their doctor for a physical examination every 3 - 6 months for the first 3 years, every 6 months for the fourth and fifth years, and at the doctor's and patient's discretion during subsequent years.

Patients should have a colonoscopy 3 years after surgery. If the results are normal, patients should then receive a colonoscopy every 5 years. Some patients with hereditary types of colorectal cancer may need more frequent screenings.

A flexible sigmoidoscopy is recommended every 6 months for 5 years for patients with Stage II or III rectal cancer who did not receive radiation therapy.

Carcinoembryonic antigen (CEA) levels should be measured every 3 months after surgery for 3 years in patients with Stage II or III cancer. High CEA levels in the blood may indicate that the cancer has spread to other parts of the body.

Patients at high risk for cancer recurrence should receive an annual computerized tomography (CT) scan for the first 3 years after treatment. The CT scan can help determine if cancer has spread to the lungs or liver. Patients who have had rectal cancer, and did not have radiation therapy, should receive a pelvic CT scan. The scan is not recommended for most lower-risk patients with Stage I or II colorectal cancer.

American Society of Clinical Oncology does not recommend other follow-up blood tests such as complete blood count, liver function tests, fecal occult blood tests. There appears to be no additional benefit for these tests.

Treatment for Metastasized Colorectal Cancer

The liver is the most frequent site for colorectal cancers to spread (metastasized). Here, treatments may slow the spread of cancer and even prolong survival. Cure is very rare.

When cancer has spread, surgery to remove or bypass obstructions in the intestine may be performed. In these circumstances, surgery is considered palliative in that it may improve symptoms but will not lead to cure. In rare cases, metastatic colon cancer may be cured with surgical removal of tumors in areas to which the cancer has spread, such as the liver, ovaries, and lung. The liver is the most common site of spread. Only selected patients may be eligible for such surgery, but in these patients, 5-year survival has been 25% or higher.

Chemotherapy may help improve symptoms and possibly prolong survival in metastasized colorectal cancers. Several investigational drugs are being tested. Doctors are also testing chemotherapy administered directly into the liver -- a treatment called hepatic arterial infusion (HAI). A 2006 study found that hepatic arterial infusion improves survival and quality of life for patients whose cancer has spread to the liver. The study indicated that HAI works better for these patients than chemotherapy delivered intravenously.

Other investigative techniques used to destroy liver tumors include:

Cryosurgery. This approach freezes the tumor or surrounding tissue.
Embolization. Embolization employs a catheter to deliver substances into the liver that block blood vessels and therefore starve the tumor. Chemotherapy is often administered during this procedure.
Radiation.

For end-stage cancer, hospice care is a compassionate option.

Resources

www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.oncolink.org -- OncoLink cancer information
www.asco.org -- American Society of Clinical Oncology
www.plwc.org -- People Living with Cancer
www.nccn.org -- National Comprehensive Cancer Network
www.cancer.gov/clinicaltrials -- Find clinical trials

References

Chan AT, Ogino S, Fuchs CS. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N Engl J Med. 2007 May 24;356(21):2131-42.

Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS, et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA. 2007 Jun 6;297(21):2351-9.

Flossmann E, Rothwell PM; British Doctors Aspirin Trial and the UK-TIA AspirinTrial. Effect of aspirin on long-term risk of colorectal cancer: consistent evidencefrom randomised and observational studies. Lancet. 2007 May 12;369(9573):1603-13.

Kerr DJ, Dunn JA, Langman MJ, Smith JL, Midgley RS, Stanley A, et al. Rofecoxib and cardiovascular adverse events in adjuvant treatment of colorectal cancer. N Engl J Med. 2007 Jul 26;357(4):360-9.

Levin TR, Zhao W, Conell C, Seeff LC, Manninen DL, Shapiro JA, Schulman J. Complications of colonoscopy in an integrated health care delivery system. Ann Intern Med. 2006 Dec 19;145(12):880-6.

Meyerhardt JA, Niedzwiecki D, Hollis D, Saltz LB, Hu FB, Mayer RJ, et al. Association of dietary patterns with cancer recurrence and survival in patients with stage III colon cancer. JAMA. 2007 Aug 15;298(7):754-64.

U.S. Preventive Services Task Force. Routine aspirin or nonsteroidal anti-inflammatory drugs for the primary prevention of colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2007 Mar 6;146(5):361-4.

Veit-Haibach P, Kuehle CA, Beyer T, Stergar H, Kuehl H, Schmidt J, et al. Diagnostic accuracy of colorectal cancer staging with whole-body PET/CT colonography. JAMA. 2006 Dec 6;296(21):2590-600.

Review Date:
9/8/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Menopause

FitSugar — Wed, 08 Oct 2008 17:34:57 -0700

In This Report

Highlights
Introduction
Complications
Symptoms
Lifestyle Changes
Medications
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Black Cohosh Doesn’t Help Hot Flashes

The herbal remedy black cohosh is no better than placebo for treating hot flashes and night sweats, according to a 2006 study in the Annals of Internal Medicine.
Most complementary and alternative medicines are ineffective for relieving menopausal symptoms, according to a 2006 review in the Archives of Internal Medicine.

Hormone Replacement Therapy (HRT)

Short-term use of HRT remains an option for recently menopausal women who have a low risk for stroke, according to a 2007 statement from the North American Menopause Society (NAMS). However, NAMS recommends that women who are at risk for heart disease or breast cancer should consider other approaches for managing hot flashes.
For women who want to discontinue HRT, gradually tapering off the medication or stopping it abruptly appears to make little difference in the recurrence of symptoms, suggests a 2006 study. A gradual approach may delay the reappearance of symptoms, but does not prevent them from returning.

HRT and Heart Disease: Timing Counts

Women who begin HRT within 10 years of menopause have a much lower risk for heart disease and heart attack than women who start HRT later on, indicates a 2007 study in the Journal of the American Medical Association. Experts suggest that HRT is relatively safe for younger women (under age 60) but should not be used by older women. HRT should never be used for prevention of heart disease, and HRT increases the risk for stroke regardless of a woman’s age or when she begins taking it.

HRT and Cancer

A dramatic fall in breast cancer rates has accompanied the decline in HRT use, according to a 2007 study in the New England Journal of Medicine.
Women who use HRT for more than 5 years have a 20% greater risk of developing and dying from ovarian cancer than women who have never used HRT, indicates a 2007 Lancet study of nearly 1 million women.

Introduction

The ovaries contain 200,000 - 400,000 follicles, tiny sacks that contain the materials needed to produce mature eggs, or ova. The ovaries produce two major female hormones: estrogen and progesterone.

The uterus is a hollow muscular organ located in the female pelvis between the bladder and rectum. The ovaries produce the eggs that travel through the fallopian tubes. Once the egg has left the ovary it can be fertilized and implant itself in the lining of the uterus. The main function of the uterus is to nourish the developing fetus prior to birth.

Estrogen. Estrogens have an effect on about 300 different tissues throughout a woman's body:

They are essential for the reproductive process and for the development of the female organs.
Estrogens determine the characteristic female distribution of body fat on the hips and thighs, which develops during adolescence.
They also are involved in tissues in the central nervous system (including the brain), the bones, the liver, and the urinary tract.

Estrogen has different forms:

The most potent form is estradiol.
The other important, but less powerful, estrogens are estrone and estriol.

Most of the estrogens in the body are produced by the ovaries, but they can also be formed by other tissues, such as body fat, skin, and muscle.

Progesterone. Progesterone, the other major female hormone, is necessary for thickening and preparing the uterine lining for the fertilized egg.

As a woman ages, her supply of eggs declines. Menopause occurs naturally after the woman's supply of follicles has been depleted and menstruation ends completely. (Menopause may also be induced if the ovaries are surgically removed.)

Perimenopause. Menopause does not occur suddenly. A period called perimenopause usually begins a few years before the last menstrual cycle. Some experts believe there are three stages in the transition:

Early Stage. The beginning of perimenopause can begin in some women in their 30s, but most often it starts between ages 40 - 44. It is marked by changes in menstrual flow and in the length of the cycle. There may be sudden surges in estrogen.
Middle Stage. In the middle cycle, periods become irregular but they are not skipped.
Late Stage. In the late stages, women begin missing the periods until they finally stop. About 6 months before menopause estrogen levels drop significantly. The fall in estrogen triggers the typical symptoms of vaginal dryness and hot flashes (which can last from half a year to more than 5 years after onset of menopause).

Menopause. At the point at which menopause occurs, the following hormonal changes occur:

Ovarian secretion of estrogen and progesterone ends.
Once the ovaries have stopped producing estrogens, however, they still continue to produce small amounts of the male hormone testosterone, which can be converted to estrogen (estradiol) in body fat.
In addition, the adrenal gland continues to produce androstenedione (a male hormone), which is converted to estrone and estradiol in the body fat.

Click the icon to see an image of the adrenal glands.

The total estrogen produced after menopause, however, is far less than that produced during a woman's reproductive years.

The average age of women at menopause today is 51.4 years although it can occur as early as age 40 to as late as the early 60s. Women now have a life expectancy of more than 80 years. Currently, women can expect to live some 30 or 40 years of their life in the postmenopausal state.

Menopause is not a disease. However, many conditions are associated with estrogen depletion, including heart disease, osteoporosis, and other complications. Fortunately, effective treatments are available for these conditions.

In a number of studies, most women have reported menopause as a positive experience and have welcomed it with relief and as a sign of a new stage in life.

Complications

After a woman reaches menopause, her average life expectancy is 30 - 40 years. During those years, however, she faces certain health risks due to lower levels of estrogen that cause accelerated bone loss and an increase in LDL cholesterol (the so-called bad cholesterol). Her risks for serious disorders are estimated at 46% for heart disease, 20% for stroke, and 15% for hip fracture. In addition, about 8% of people over 75 have dementia, with postmenopausal women having 1.4 - 3 times the risk for Alzheimer's disease compared to men.

Heart disease is the number one killer of women. In 2003, more than 480,000 women died from diseases of the heart and circulation (cardiovascular diseases). Although young women have a much lower risk for cardiovascular disease than young men, after menopause women catch up. After age 51, women’s risk of dying from heart disease is very close to that of men. Estrogen loss is believed to play a major role in this increased risk.

Some studies indicate that women who reach menopause at an early age are at increased risk of heart disease. However, recent research suggests that the reverse may also be true. A 2006 study suggested that women who have heart disease risk factors (smoking, high total cholesterol levels, high blood pressure) during premenopause may enter menopause earlier than women with healthier heart profiles. [See In-Depth Report #3: Coronary artery disease.]

Estrogen has the following effects:

Harmful Effects on Cholesterol and Other Lipids (Fats in the Blood). About 2 years before menopause, as estrogen levels begin to decline, the levels of the harmful low-density lipoprotein (LDL) cholesterol begin to rise, and the advantageous high-density lipoprotein (HDL) levels decrease.
Positive Effect on Blood Flow. Estrogen has significant effects on smoothing, relaxing, and opening blood vessels, thereby increasing blood flow and reducing pressure.
Antioxidant Actions. Estrogen is also an antioxidant. That is, it helps clean up particles called oxygen-free radicals that are released by natural chemical processes in the body, which can cause significant damage, including harm to the arteries.
Mixed Effects on Blood Pressure. The effects of estrogen on blood pressure are not clear. Oral contraceptives, for instance, which contain estrogen, appear to increase pressure slightly.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

Mixed Effects on Blood Clotting. Estrogen affects many blood-clotting factors in the liver: It reduces blood viscosity (stickiness) and may enhance fibrinolysis, the natural process for breaking down blood clots. Unfortunately, estrogen also has other actions that increase the risk for blood clots. Women who take hormone replacement therapy are at risk for thromboembolism -- blood clots that block a vessel.

Click the icon to see an image of thromboembolism.

This action may explain the higher rates of adverse heart events now observed in women with heart disease who take HRT.

Osteoporosis is a disease of the skeleton in which bones become brittle and prone to fracture. In other words, the bone loses density. At age 65, about 30% of women have osteoporosis, and nearly all of them are unaware of their condition. After age 80, up to 70% of women develop osteoporosis. Osteoporosis is a major risk factor for fracture in the spine and hip. The lifetime risk of spinal fracture in women is about 1 in 3 and that for hip fracture is 1 in 6. Furthermore, between 10 - 20% of women who experience a hip fracture die within a year and about 25% require nursing home treatment.

Click the icon to see an image of osteoporosis.

Experts are still puzzled by the extreme speed-up of bone breakdown (resorption) after menopause. Estrogen may have an impact on bone density in various ways:

Estrogen's most important effect on osteoporosis appears to be prevention of bone break down (resorption). Some research suggests that estrogen may control the lifespan of osteoclasts, the cells responsible for bone breakdown.
Part of estrogen's beneficial actions may involve maintaining normal levels of vitamin D, an important nutrient in bone protection.

Risk factors for osteoporosis include:

Being tall and thin
Being Caucasian
Smoking
Taking thyroid hormone
Being sedentary
Early menopause or surgical menopause (removal of ovaries)

Women at risk for osteoporosis should have a bone density test to measure their bone mass and then make a decision about treatment after consulting their doctor. [See In-Depth Report #18:Osteoporosis.]

Depression may occur as a woman transitions into menopause (perimenopause), even among women with no history of clinical depression. Hormonal changes and declines in estrogen levels are probably involved in this process. Research suggests that a depressive disorder is 2.5 times more likely to develop during perimenopause than premenopause. Women who transition to menopause at a younger age are at increased risk of a first episode of depression.

Symptoms of clinical depression include:

Loss of interest or pleasure in activities once enjoyed
Persistent (longer than 2 weeks) sad mood
Decreased energy
Sleep problems (insomnia or oversleeping)
Feelings of guilt, worthlessness, and hopelessness
Difficulty concentrating

Some of these symptoms may overlap with other symptoms that typically accompany perimenopause. Women who experience these symptoms should talk to their doctor. Depression is treatable. [See In-Depth Report #8: Depression.] For many women, depression eases once they reach menopause.

Estrogen, the primary female hormone, appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Estrogen's effects on the brain include:

Laboratory studies suggested that estrogen may help block production of beta-amyloid, the source of the sticky plaques found in Alzheimer's brains.
Estrogen may trigger the temporary growth of nerve pathways in the memory portion of the brain.
Estrogen may stimulate production of the neurotransmitters acetylcholine and serotonin, which are depleted in Alzheimer's patients.
Estrogen also appears to smooth, relax, and open blood vessels, which may help blood flow in the brain.
Estrogen is an antioxidant. That is, it helps clean up free-oxygen radicals, the unstable particles thought to play a role in Alzheimer's.
Studies have been mixed on the association between natural estrogen levels and mental functioning in older women.

Estrogen therapy has been associated with reduced gum bleeding and with decreased bone loss around the teeth, and women who take estrogen are less likely to lose their teeth. Thus, the same principle that helps prevent bone loss in osteoporosis is also at work in preventing bone loss in the mouth.

Estrogen, progesterone, or both appear to protect against cataracts.

Click the icon to see an image of a cataract.

Studies also indicate that estrogen helps prevent glaucoma and macular degeneration.

Click the icon to see an image of glaucoma.

Click the icon to see an image of macular degeneration.

The drop in body estrogen levels brought on by menopause may contribute to both urinary stress and urge incontinence.

Women are at increased risk for recurrent urinary tract infections after menopause. Research suggests that estrogen may prevent infection by increasing the number of lactobacilli, a microorganism that fights infection by preventing bacteria from adhering to vaginal cells.

Estrogen may help prevent slackness and dryness in the skin and reduce wrinkles.

Menopause is associated with more sleeping problems, including inability to fall asleep and nighttime wakefulness.

Symptoms

The most prominent symptoms of the transition to menopause include:

Hot flashes and night sweats. Women often experience hot flashes as an intense build-up in body heat, followed by sweating and chills. Some women report accompanying anxiety as the sensation builds. In most cases, hot flashes resolve within 2 years of menopause, although in some women they may persist for years. Women who have a hysterectomy (surgical removal of the uterus) are less likely to experience hot flashes than women who have a natural menopause. However, women who have surgical removal of both ovaries, and who do not receive hormone replacement therapy, may have more severe hot flashes than women who enter menopause naturally.
Heart pounding or racing can occur, with or without hot flashes.
Difficulty sleeping. Insomnia is common during perimenopause. It may be caused by the hot flashes or it may be an independent symptom of hormonal changes. A 2006 study indicated that severe hot flashes are frequently associated with chronic insomnia.
Mood changes. Mood changes are most likely to be a combination of sleeplessness, hormonal swings, and psychological factors as a woman undergoes this intense passage in her life. Once a woman has reached a menopausal state, however, depression is no more common than before, and women with a history of premenstrual depression often experience significant mood improvement.
Sexuality. Sexual responsiveness tends to decline in most women after menopause, although other aspects of sexual function, including interest, frequency, and vaginal dryness vary. It is useful to remember that the symptoms of menopause eventually go away.
Forgetfulness. This appears to be one of the few symptoms that are common across most cultural and ethnic groups.
Urine leakage.
Vaginal dryness.
Joint stiffness.

Women from different ethnic and or cultural groups report different menopausal symptoms. For example, in one study hot flashes occurred in about 30% of Caucasians and 45% of African-Americans. Hispanic women tended to complain of urine leakage, vaginal dryness, and heart pounding. Japanese and Chinese women experienced far fewer menopausal symptoms, except for forgetfulness. All groups complained about this symptom.

Lifestyle Changes

Simple changes in lifestyle and diet can help control menopausal symptoms such as hot flashes. Avoid hot flash triggers like spicy foods, hot beverages, caffeine, and alcohol. Dress in layers so that clothes can be removed when a hot flash occurs. For vaginal dryness, moisturizers, and non-estrogen lubricants, such as KY Jelly, Replens, and Astroglide are available.

When women reach menopause, they are at increased risk for heart disease. A heart-healthy diet is an important way to control cholesterol and blood pressure levels. [See In-Depth Report #42: Heart-healthy diet.]

In 2007, the American Heart Association (AHA) issued revised diet and lifestyle recommendations. The current guidelines recommend:

Balancing calorie intake and physical activity to achieve or maintain a healthy body weight. (Controlling weight, quitting smoking, and exercising regularly are essential companions of any diet program. Try to get at least 30 minutes, and preferably 60 – 90 minutes, of daily exercise.)
Consuming a diet rich in a variety of vegetables and fruits. Vegetables and fruits that are deeply colored (spinach, carrots, peaches, berries) are especially recommended as they have the highest micronutrient content.
Choosing whole-grain, high-fiber foods. These include fruits, vegetables, and legumes (beans). Good whole grain choices include whole wheat, oats/oatmeal, rye, barley, brown rice, buckwheat, bulgur, millet, and quinoa.
Eating fish, especially oily fish, at least twice a week (about 8 ounces/week). Oily fish such as salmon, mackerel, and sardines are rich in the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Consumption of these fatty acids is linked to a reduced risk of sudden death and death from coronary artery disease. Women with existing heart disease may also consider taking a daily dietary supplement of 850 – 1,000 mg of EPA and DHA.
Limiting daily intake of saturated fat (found mostly in animal products) to less than 7% of total calories, trans fat (found in hydrogenated fats, commercially baked products, and many fast foods) to less than 1% of total calories, and cholesterol (found in eggs, dairy products, meat, poultry, fish, shellfish) to less than 300 mg per day. Choose lean meats and vegetable alternatives (such as soy). Select fat-free and low-fat dairy products. Grill, bake, or broil fish, meat, and skinless poultry.
Using little or no salt in your foods. Reducing salt can lower blood pressure and decrease the risk of heart disease and heart failure.
Cutting down on beverages and foods that contain added sugars (corn syrups, sucrose, glucose, fructose, maltrose, dextrose, concentrated fruit juice, honey).
If you consume alcohol, do so in moderation. The AHA recommends limiting alcohol to no more than 1 drink per day for women.
The AHA does not recommend antioxidant supplements (such as vitamin E, C, or beta carotene) or folic acid supplements for prevention of heart disease.

Soy is an excellent food. It is rich in both soluble and insoluble fiber, omega-3 fatty acids, and provides all essential proteins. Soy proteins have more vitamins and minerals than meat or dairy proteins. They also contain polyunsaturated fats, which are better than the saturated fat found in meat. The best sources of soy protein are soy products (tofu, soy milk, soybeans).

For many years, soy was promoted as a food that could help lower cholesterol and improve heart disease risk factors. But an important 2006 review of studies found that soy protein and isoflavone supplement pills do not really have any effects on cholesterol or heart disease prevention. The AHA still recommends soy foods, but not supplements, as a healthy food choice. The benefits of soy on menopausal symptoms are mixed, according to research (see below in Alternative Therapies). A 2006 study reported that increased soy intake does not help reduce the frequency or severity of hot flashes and night sweats.

Soy is high in estrogen-like plant chemicals called isoflavones, which may improve bone health in older women. A 2005 review of 15 clinical trials found that, although the results were mixed, isoflavones appeared to decrease bone loss, especially in younger postmenopausal women. Soy food products, such as tofu, that also contain calcium may be particularly beneficial.

A combination of calcium and vitamin D is important for helping to prevent bone loss. [See In-Depth Report #18: Osteoporosis.]

Calcium. Women should be sure they have sufficient calcium and vitamin D in their diet by consuming low-fat dairy products or calcium-enriched orange juice. Calcium supplements may be another option for some women. For calcium supplements, calcium citrate (Citracal) is better absorbed than calcium carbonate (Tums, Os-Cal) and other types of calcium compounds. Calcium citrate was the first calcium supplement reported to preserve bone density after menopause.

Click the icon to see an image of the benefits of calcium.

The standard recommended calcium dose for adults age 50 years and older is 1,000 – 1,500 mg per day, depending on risk factors. High doses (over 2,500 mg per day) of calcium supplements may increase the risk for kidney stones. (Because many commercial foods are now fortified with calcium, this upper limit may be easier to reach than people think.)

Click the icon to see an image of calcium sources.

For years, doctors have recommended that women take supplements of calcium plus vitamin D to help maintain bone density and reduce the risk for fractures. However, a 2006 New England Journal of Medicine study raised some questions about this approach. In the Women’s Health Initiative study, women were randomly assigned to receive either 1,000 mg of calcium carbonate plus 400 IU of vitamin D a day or placebo. The results indicated that daily calcium and vitamin D supplements:

Improve hip bone density slightly (by 1%)
Prevent hip fracture, but only for women who consistently take the supplements. (Another 2006 study supported this finding.)
Do not prevent spine or other types of fractures
Produce a slight increase in the risk of kidney stones

The medical community has differing views on how to interpret these findings. Some doctors recommend that women over age 60 should still consider taking calcium and vitamin D for bone health. Other doctors feel that due to the risks of kidney stones, supplements are beneficial only for women (especially those over age 70) who do not get enough calcium in their diets. Ask your doctor whether you should take calcium supplements.

Vitamin D. Vitamin D is necessary for the absorption of calcium in the stomach and gastrointestinal tract and is the essential companion to calcium in maintaining strong bones. Some studies suggest that vitamin D protects against osteoporosis only in combination with calcium.

Vitamin D is manufactured in the skin using energy from the ultraviolet rays in sunlight. It can also be obtained from dietary supplements. As a person ages, vitamin D levels decline. Levels also fall during winter months and when people have inadequate sunlight. Pollution may also contribute to less sunlight and declining vitamin D levels.

Click the icon to see an image of vitamin D sources.

Daily dosage guidelines vary. General recommendations include:

400 IU for people age 50 - 60
600 IU for those over age 70 who do not have sufficient exposure to sunlight. (Some evidence suggests that higher doses of vitamin D -- up to 800 IU per day -- may help prevent fractures in people with osteoporosis.)
800 – 1,000 IU for adults over age 50 (the amount recommended by the National Osteoporosis Foundation)

Drinking milk fortified with vitamin D and sunlight exposure supply most people's need for vitamin D. (One cup of whole milk provides about 100 IU of vitamin D.) Oily fish (sardines especially, as well as salmon, fresh tuna, and mackerel) are also important dietary sources of vitamin D. Wild salmon has a much higher vitamin D content than farmed salmon.

Effect on the Heart. One drink a day in women who are not at risk for alcohol abuse may be beneficial for the heart. Red wine in particular contains a substance called resveratrol, which is classified as a phytoestrogen and has estrogen-like effects.

Effect on Bones. Alcohol has different effects on bones depending on how much is consumed. A 2004 study found that moderate wine consumption was linked to improved bone mineral density in postmenopausal women. Alcohol, in moderate amounts, may increase estrogen levels. Excessive drinking, however, has been associated with brittle bones.

Effect on Breast Cancer. Women who drink face an increased risk for breast cancer, but the risk associated with mild-to-moderate drinking is small.

Many women need to increase physical activity and reduce caloric intake before and after menopause. Weight gain is common during these years, and it can be sudden and distressing, particularly when habitual exercise and eating patterns are no longer effective in controlling weight. Gaining weight around the abdomen (the so-called apple shape) is a specific risk factor for heart disease and diabetes and many other health problems. A 2007 study suggested that calcium and vitamin D supplements may help prevent weight gain in postmenopausal women. The benefit was greatest for women who had not been getting enough daily calcium in their diets.

Click the icon to see an image of different types of weight gain.

For protection against all aging diseases, women, whether or not they are taking hormone replacement therapy, should pursue a lifestyle that includes a balanced aerobic and weight resistance exercise program appropriate to their age and medical conditions. Brisk walking, stair climbing, hiking, dancing, and tai chi are all helpful. Several studies report that exercise can help control hot flashes. A healthy diet plus regular, consistent exercise can also help ward off the weight gain associated with menopause. Weight-bearing exercises are specifically helpful for protecting against bone loss. Women should strive for at least 30 minutes of exercise each day (for weight loss, 60 – 90 minutes is preferred). While more exercise is better, any exercise is helpful. A 2007 study showed that postmenopausal sedentary women who exercised only 75 minutes a week experienced improvement in fitness levels.

If a woman smokes, she should quit. Smoking is linked to a decline in estrogen levels. Women who smoke experience menopause about 2 years earlier than nonsmokers. Smoking doubles a woman’s odds of developing coronary heart disease and is a major risk factor for osteoporosis.

Aspirin. The American Heart Association recommends daily low-dose aspirin for all women age 65 years and older who can safely take aspirin. High-risk women may require 75 – 325 mg per day; lower-risk women may benefit from 81 mg a day or 100 mg every other day.

There are many unproven methods for relieving menopausal symptoms, some more effective than others. Acupuncture, meditation, and relaxation techniques are all harmless ways to reduce the stress of menopause, and some people report great benefit from these practices.

Acupuncture, hypnosis, and biofeedback are all alternative ways to control pain. Acupuncture involves the insertion of tiny sterile needles, slightly thicker than a human hair, at specific points on the body.

Women often try herbal or so-called natural remedies to treat menopausal symptoms. There have been numerous studies conducted on various herbal products and other complementary and alterative therapies. These studies have not found that these approaches have any benefit. Some can have adverse side effects.

Many studies have researched plant estrogens (phytoestrogens), which are generally categorized as isoflavones (found in soy and red clover) and lignans (found in whole wheat and flaxseed). No evidence to date indicates that phytoestrogen supplements provide any benefit for hot flashes or other menopausal symptoms. Nevertheless, foods containing them may be healthful.

Supplements containing specific isoflavones found in soy -- typically the estrogen-like compounds genistein and daidzein -- do not appear to provide any benefits compared to the whole soy protein. Taking them separately may, in fact, cause harm, including a possible increase in estrogen-related cancers.

The following herbs are sometimes use for menopausal symptoms and carry certain risks:

Black cohosh (Cimicifuga racemosa), also known as squaw root, is the herbal remedy most studied for menopausal symptoms. Although it contains a plant estrogen, this substance does not act like an estrogen in the human body. Studies have shown mixed results in preventing hot flashes. A rigorous 2006 study found that black cohosh worked no better than placebo for treating hot flashes and night sweats. While it may be ineffective, black cohosh appears to be safe. Headaches and gastrointestinal problems are common side effects.
Dong quai (Angelica sinensis) does not appear helpful for hot flashes or other menopausal symptoms. Do not use dong quai with blood-thinning drugs, such as warfarin, because it may cause bleeding complications.
Ginseng (Panax ginseng) may help menopausal symptoms of depression and sleep problems, but it has no effect on hot flashes.
Kava (Piper methysticum) may relieve anxiety but it does not help hot flashes. This herb is generally considered unsafe, due to several reports of liver failure and death, especially in people with liver disease.
Wild yam (Dioscorea villosa) is an herb sometimes used for menstrual problems as well as menopausal symptoms. It contains a plant progesterone. However, like black cohosh, there is no evidence that the human body can convert this substance into a hormone. Patients should be aware that some commercial herbal wild yam products contain prescription progesterones.
Dehydroepiandrosterone (DHEA) is a weak male hormone secreted by the adrenal gland. It is available as a dietary supplement. DHEA has no benefit for hot flashes and may increase the risk of breast cancer.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like with drugs, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Patients should check with their doctors before using any herbal remedies or dietary supplements.

Medications

Doctors used to believe that HRT could help reduce the risk of heart disease and other health risks in addition to treating menopausal symptoms. The results of an important study, called the Women's Health Initiative (WHI), led doctors to revise their recommendations regarding HRT.

The WHI, started in 1991, enrolled 161,809 women between the ages of 50 - 79 in 40 different medical centers. Part of the study was intended to examine the health benefits and risks of hormone replacement therapy, including the risks of breast cancer, heart attacks, strokes, and blood clots.

In 2002, one component of the WHI, which studied the use of estrogen and progestin in women who had a uterus, was stopped early because the health risks exceeded the health benefits. The main reason for stopping the estrogen-progestin study was a 26% increase in breast cancer. This combination therapy study also showed an increased risk for heart attack, stroke, blood clots, and dementia. There was a reduced risk for colorectal cancer and bone fractures, but these benefits did not outweigh the considerable risks.

In 2004, a second component of the WHI, which studied estrogen-only therapy in women who no longer have a uterus, was stopped early. This was primarily because of an increase in the risk for strokes and blood clots. The study also found the estrogen-only therapy had no effect on heart attack or colorectal cancer risk. An update in 2006 suggested that estrogen-only therapy does not increase breast cancer risk over the short term (average 7 years) but may increase risk when taken for a longer time (15 years or more). Another WHI update, from 2007, indicated that estrogen-only therapy can help reduce calcium deposits in the coronary arteries (a sign of heart disease) for women in their 50s who have had a hysterectomy. However, women who have a uterus cannot take estrogen-only HRT because it increases the risk for uterine cancer. Combination estrogen-progestin HRT does not have the same benefits for cholesterol reduction as estrogen-only HRT.

While the WHI studies indicate that HRT should not be prescribed for prevention of chronic diseases, many doctors still accept its use for short-term treatment of moderate-to-severe hot flashes and other menopausal symptoms, and in women undergoing premature menopause for medical or other reasons. Current guidelines recommend using the lowest possible dose for the shortest duration of time. A 2007 position statement from the North American Menopause Society (NAMS) supports short-term use of HRT for treatment of hot flashes and other vasomotor symptoms in recently menopausal women who have a low risk for stroke. However, NAMS recommends that women who are at risk for heart disease or breast cancer should avoid hormone therapy and try other options to manage symptoms.

When a woman stops taking HRT, perimenopausal symptoms may recur. There is some debate about whether it is better to abruptly stop the medication or to taper it off gradually. A 2006 study suggested that gradual discontinuation of HRT delays -- but does not prevent -- the reappearance of symptoms. However, when a woman reaches full menopause, symptoms will eventually go away.

Hormones Used in HRT. Hormone replacement therapy uses either estrogen alone (known as ET or unopposed estrogen) or in combination with forms of progesterone (known as combined hormone therapy or EPT). Progesterone is referred to by one of several names:

Progesterone is the name for the natural hormone.
Progestin is the term for any hormone, natural or synthetic, that causes progesterone effects.
Progestogen is any hormone that has effects similar to progesterone.

Both ET and EPT are available in many forms, including oral tablets, skin patches, and vaginal and skin applications. A new form approved by the FDA in 2004 is a topical estrogen gel that is applied to the arm.

HRT is mainly recommended for relieving menopausal symptoms, including hot flashes, night sweats, vaginal dryness, sleep problems, and mild depression. HRT does not prevent certain other problems associated with menopausal changes, such as thinning hair.

Oral hormonal medications and skin patches are equally effective in reducing hot flashes, mild depression, and sleep problems. Progestins may sometimes be prescribed alone for hot flashes and other acute menopausal symptoms, though they can cause side effects, such as mood swings, bloating, and breast tenderness. Estrogen creams, rings, or vaginal tablets restore vaginal elasticity and lubrication and improve sexual pleasure.

HRT may be useful for some women at high risk for osteoporosis, although other drugs, such as bisphosphonates, should be considered first. It increases bone density and also appears to improve balance and protects against falling. Studies also report reductions in fractures (especially hip fractures) among women taking HRT, but the benefits may not outweigh the risks of HRT. It appears that the beneficial effects wear off soon after therapy is stopped. Estrogen must be taken life long for maximum protection against osteoporosis, which then increases the risk for adverse health effects.

Heart Disease. HRT does not prevent heart disease and can increase the risk for heart disease and heart attack, especially in older women. An important 2007 Women’s Health Initiative study in the Journal of the American Medical Association indicated that this risk is time and age dependent. The study found that women who began HRT within 10 years of menopause had less risk of heart disease than women who begin HRT later on. This study suggests that HRT may be safest for women younger than age 60, and should be avoided by women older than age 60. Any woman who is considering HRT should be sure to have her blood pressure and cholesterol levels evaluated.

Another 2007 study, published in the New England Journal of Medicine (NEJM), also indicated that timing is important. The NEJM study found that that estrogen-only HRT may help reduce calcium deposits in coronary arteries in younger women (age 50 - 59) who have had a hysterectomy. (Because of the increased risk for uterine cancer, estrogen-only HRT is only appropriate for women who no longer have a uterus. Women who have a uterus need to take estrogen-progestin HRT. And, estrogen can increase the risk for heart attack in women who have advanced heart disease.) Although the NEJM study found some heart benefits for estrogen-only HRT for younger women, experts still advise that HRT should be used for only a few years. Any woman who is considering HRT should be sure to have her blood pressure and cholesterol levels evaluated.

Stroke. HRT increases the risk of stroke, regardless of years since menopause. In addition, HRT appears to worsen the outlook for women who have had a stroke.

Mental Decline. Observational studies had suggested that hormone replacement therapy (HRT) helped prevent mental decline and even Alzheimer's disease after menopause. Other studies have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. A 2004 review of the Women’s Health Initiative Memory Study found that combined HRT did not reduce the risk of cognitive impairment, and actually increased the risk of dementia among women ages 65 and over.

Thromboembolism. HRT is associated with a higher risk for thromboembolism, in which blood clots form in deep veins. This places women at risk for pulmonary embolism, in which the blood clot travels to the lungs.

Click the icon to see an image of a pulmonary embolism.

Breast Cancer. Because breast tissue growth is highly sensitive to estrogens, the more a woman is exposed to estrogen over her lifetime, the higher the risk for breast cancer. A number of studies have reported a higher risk for breast cancer in postmenopausal women taking HRT that contains both estrogen and progestin. A combination of estrogen and testosterone also increases breast cancer risk. A 2005 study suggested that HRT with no or low progestin is safer than standard estrogen-progestin combination therapy.

Several 2006 studies of women who had a hysterectomy indicated that estrogen alone does not increase overall breast cancer risk when the drug is used for 7 years or less. However, women who take the drug for 15 years or more do have an increased risk. Women who are at low risk for breast cancer tend to have fewer breast cancers with estrogen alone, while women at higher risk tend to have more breast cancers. In addition, estrogen therapy may cause abnormal mammogram results. Breast tissue density increases with HRT, which makes mammograms more difficult to read and leads to more breast biopsies. Women who take estrogen HRT should be aware that they need frequent mammogram screenings.

As further evidence of the association between HRT and breast cancer, a 2007 New England Journal of Medicine study noted that breast cancer rates have fallen as HRT use has declined.

Endometrial (Uterine) Cancers. Estrogen overstimulates the tissue lining the uterus (the endometrium) and causes uncontrolled cell growth, a condition known as hyperplasia, which is a strong risk factor for cancer. Taking unopposed estrogen replacement therapy (ERT) increases the risk of endometrial cancer at least five-fold. Adding progestin to HRT appears to pose no risk for this cancer. However, a 2007 study indicated that short-term treatment (3 years) with ERT is associated with a relatively low risk of endometrial cancer. Women who take ERT should anticipate uterine bleeding, especially if they are obese, and may need endometrial biopsies and other gynecologic tests.

Ovarian Cancer. HRT appears to increase the risk for ovarian cancer. A 2007 UK study of nearly 1 million women found that women who used HRT for more than 5 years were 20% more likely to develop and die from ovarian cancer than women who had never taken HRT.

Gallstones. HRT is associated with a higher risk for gallstones.

Despite its risks, hormone replacement therapy appears to be the best treatment for hot flashes. Nonhormonal treatments for hot flashes and other menopausal symptoms include:

Antidepressants. The antidepressants known as selective serotonin-reuptake inhibitors (SSRIs) are sometimes used for managing mood changes and hot flashes. They include fluoxetine (Prozac), sertraline (Zoloft), venlafaxine (Effexor), and paroxetine (Paxil, Asimia). A 2006 review of nonhormonal therapies, found that paroxetine in particular may help hot flashes. However, paroxetine, like other antidepressants, can cause headache, anxiety, and sexual problems. A 2007 study suggested that the antidepressant citalopram (Celexa), given alone or with HRT, may help treat hot flashes.

An investigational antidepressant, desvenlafaxine (Pristiq), is also being studied for treatment of hot flashes, night sweats, and perimenopausal sleep problems. Research presented at the 2007 meeting of the American College of Obstetricians and Gynecologists indicated that desvenlaxafine, which is related to venlaxafine, showed promise in improving symptoms.

Gabapentin.Several small studies suggest that gabapentin (Neurontin), a drug used for seizures and nerve pain, may relieve hot flashes. Gabapentin may cause drowsiness, dizziness, fatigue, and swelling of the hands and feet.

Clonidine. Clonidine (Catapres) is a drug used to treat high blood pressure. Studies show it may help manage hot flashes. Side effects include dizziness, drowsiness, dry mouth, and constipation

Testosterone. Some doctors prescribe combinations of estrogen and small amounts of the male hormone testosterone to improve sexual function and increase bone density. Side effects of testosterone include increased body hair, acne, fluid retention, anxiety, and depression. Testosterone also adversely affects cholesterol and lipid levels. A 2006 study indicated that combined estrogen and testosterone can increase the risk of breast cancer.


HRT Form	Brand Name	Active Ingredient	Side Effects
Oral Estrogens	Premarin	Natural conjugated estrogen, which is a mixture of estrogens derived from the urine of pregnant mares	Bleeding after withdrawal. It is a primary reason why many women stop treatment, although usually lighter or shorter compared to before menopause. If it is distressing, patient should consider continuous estrogen and progestin therapy. Irregular bleeding. This should be checked with the doctor for possible problems. Nausea and vomiting. If it occurs, usually does so only during the first 3 months and is minimal. Rarely with low doses. Headaches. Cramps. Risk for blood clots.
	Cenestin	Synthetic conjugated estrogen, which is a mixture of estrogens derived from compounds found in yams and soy
	Estratab, Menest	Plant-derived estrogens, called esterified estrogens. Usually made from modified soy
	Estrace (oral)	Estradiol, the most potent natural estrogen
	Ogen, Ortho-Est	Estropipate, a version of estrone, which is a weaker form of estrogen
	Estrovis	Quinetrol, a synthetic estrogen
	Estinyl	Synthetic form estradiol, the most potent estrogen

Oral Progestins	Provera, Amen, Curretab, Cycrin	Medroxyprogesterone, a synthetic progestin	Breast tenderness. Usually subsides in 3 - 4 months and can be relieved with over-the-counter painkillers and possibly by decreasing caffeine intake and adding vitamin E. Headache. Fluid build-up. Bloating. Fatigue, unusual tiredness, weakness. Depression, irritability, or other mood changes.
	Norlutin, Aygestin, Norlutate	Norethindrone and norethindrone acetate, synthetic progestins
		Norgestrel

Oral Combinations of Estrogen and Progestin	Prempro, Premphase	Conjugated estrogens plus medroxyprogesterone	May have some of the side effects of both estrogen and progestin. Continuous regimens eliminate menstrual bleeding in more than half of women. Investigators are studying the use of higher progestin doses or a lower estrogen doses and comparing combinations for further reduction of bleeding risk.
	Activelle, Femhrt	Estradiol and norethindrone or norethindrone acetate
	Ortho-Prefest	Estradiol and norgestimate
	Angeliq	Estradiol and drospirenone

Skin Patch Administration of HRT	Estraderm, Alora, Climara, Vivelle, FemPatch, Evorel	Estradiol	Skin irritation where the patch is applied most common. Hormonal side effects associated with formulation of patch.
Skin Patch Administration of HRT	CombiPath	Estradiol plus norethindrone (a progestin)

Vaginal Creams for dryness and irritation	Estrace (cream)	Estradiol (potent estrogen)	Hormonal side effects associated with estrogen or progestins, depending on formulation.
	Ogen (cream)	Estropipate (weaker estrogen.)
	Premarin (cream)	Conjugated natural estrogens
	Ortho-dienestrol (cream)	Dienestrol (synthetic estrogen)
	Crinone (cream)	A natural progesterone
Other forms of vaginal administration	Vagifem (vaginal tablet)
	Estring (vagina Ring)	Estradiol
	Other forms: injections, nasal sprays, and as pellets inserted under the skin twice a year.
Topical Gel	EstroGel	Estradiol	Hormonal side effects associated with estrogen.

Resources

www.menopause.org -- North American Menopause Society
www.acog.com -- American College of Obstetricians and Gynecologists
www.nia.nih.gov -- National Institute on Aging
www.nhlbi.nih.gov/whi/recommend.htm -- Women's Health Initiative Study
www.nih.gov/PHTindex.htm -- National Institutes of Health -- Menopausal Hormone Therapy Information
http://nccam.nih.gov/health/menopauseandcam -- National Center for Complementary and Alternative Medicine

References

Beral V; Million Women Study Collaborators; Bull D, Green J, Reeves G. Ovarian cancer and hormone replacement therapy in the Million Women Study. Lancet. 2007 May 19;369(9574):1703-10.

Caan B, Neuhouser M, Aragaki A, Lewis CB, Jackson R, Leboff MS, et al. Calcium plus vitamin d supplementation and the risk of postmenopausal weight gain. Arch Intern Med. 2007 May 14;167(9):893-902.

Church TS, Earnest CP, Skinner JS, Blair SN. Effects of different doses of physical activity on cardiorespiratory fitness among sedentary, overweight or obese postmenopausal women with elevated blood pressure: a randomized controlled trial. JAMA. 2007 May 16;297(19):2081-91.

Haimov-Kochman R, Barak-Glantz E, Arbel R, Leefsma M, Brzezinski A, Milwidsky A, et al. Gradual discontinuation of hormone therapy does not prevent the reappearance of climacteric symptoms: a randomized prospective study. Menopause. 2006 May-Jun;13(3):370-6.

Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006 Feb 16;354(7):669-83.

Kalay AE, Demir B, Haberal A, Kalay M, Kandemir O. Efficacy of citalopram on climacteric symptoms. Menopause. 2007 Mar-Apr;14(2):223-9.

Manson JE, Allison MA, Rossouw JE, Carr JJ, Langer RD, Hsia J, et al. Estrogen therapy and coronary-artery calcification. N Engl J Med. 2007 Jun 21;356(25):2591-602.

Mosca L, Banka CL, Benjamin EJ, Berra K, Bushnell C, Dolor RJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007 Mar 20;115(11):1481-501.

Nedrow A, Miller J, Walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopause-related symptoms: a systematic evidence review. Arch Intern Med. 2006 Jul 24;166(14):1453-65.

Newton KM, Reed SD, LaCroix AZ, Grothaus LC, Ehrlich K, Guiltinan J. Treatment of vasomotor symptoms of menopause with black cohosh, multibotanicals, soy, hormone therapy, or placebo: a randomized trial. Ann Intern Med. 2006 Dec 19;145(12):869-79.

North American Menopause Society. The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause. 2007 May-Jun;14(3 Pt 1):355-69.

Ohayon MM. Severe hot flashes are associated with chronic insomnia. Arch Intern Med. 2006 Jun 26;166(12):1262-8.

Ravdin PM, Cronin KA, Howlader N, Berg CD, Chlebowski RT, Feuer EJ, et al. The decrease in breast-cancer incidence in 2003 in the United States. N Engl J Med. 2007 Apr 19;356(16):1670-4.

Rossouw JE, Prentice RL, Manson JE, Wu L, Barad D, Barnabei VM, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007 Apr 4;297(13):1465-77.

Steiner AZ, Xiang M, Mack WJ, Shoupe D, Felix JC, Lobo RA, et al. Unopposed estradiol therapy in postmenopausal women: results from two randomized trials. Obstet Gynecol. 2007 Mar;109(3):581-7.

Tamimi RM, Hankinson SE, Chen WY, Rosner B, Colditz GA. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med. 2006 Jul 24;166(14):1483-9.

Review Date:
6/25/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Brain tumors - primary

FitSugar — Wed, 08 Oct 2008 17:35:12 -0700

In This Report

Highlights
Introduction
Symptoms
Risk Factors
Causes
Prognosis
Diagnosis
Common Brain Tumors
Treatment
Surgery
Radiotherapy
Chemotherapy
Other Treatments
Treatment of Complications...
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Radiation Therapy Complications

Radiation therapy in children with cancer increases the risk of new brain and spinal cord tumors, suggests a study in the Journal of the National Cancer Institute. The risk appears to increase along with the radiation dosage. Children who receive radiotherapy before age 5 are especially at risk for second primary tumors.
Survivors of childhood brain tumors who received cranial radiotherapy as part of their treatment are at risk for later having a stroke, indicates a study in the Journal of Clinical Oncology. The average length of time from brain tumor diagnosis to post-treatment stroke was 14 years.

Radiation Therapy for Elderly Patients

Radiotherapy provides modest improvement in survival for elderly patients (age 70 years and older) with glioblastoma, with no detriment to quality of life or cognition function, according to a 2007 study in the Journal of the American Medical Association.

Temozolomide (Temodar)

The chemotherapy drug temozolomide (Temodar) has become an important and effective treatment for patients newly diagnosed with glioblastoma. However, not all patients respond equally well to this drug. A 2007 study in the journal Neurology suggests that a patient’s genotype may explain differences in response. Though genetic testing, researchers found that temozolomide works best in people who are missing a particular gene.

Investigational Treatments

Vorinostat (Zolinza), a cancer drug used for T-cell lymphoma, may help patients with recurrent glioblastoma multiforme, according to research presented at the 2007 annual meeting of the American Society of Clinical Oncology.
Bevacizumab (Avastin), a targeted therapy drug used for lung and colorectal cancers, may help prolong survival in patients with advanced glioma, indicates a 2007 study in Clinical Cancer Research. Another anti-angiogenesis drug, cediranib (Recentin), may help make glioblastomas more responsive to chemotherapy and radiotherapy, according to recent interim trial results.
Vitespen (Oncophage), an experimental vaccine for glioma, is showing promise in early clinical trials, suggests research presented at the 2007 meeting of the American Association of Neurological Surgeons.

Introduction

Brain tumors are composed of cells that exhibit unrestrained growth in the brain.

The major areas of the brain have one or more specific functions.

They can be benign (noncancerous, meaning that they do not spread elsewhere or invade surrounding tissue) or malignant (cancerous).

Cancerous brain tumors are further classified as either primary or secondary tumors. Primary tumors start in the brain, whereas secondary tumors spread to the brain from another site such as the breast or lung. (In this report, the term "brain tumor" will refer mainly to primary malignant tumors, unless otherwise specified.)

Benign tumors represent half of all primary brain tumors. Their cells look relatively normal, grow slowly, and do not spread (metastasize) to other sites in the body. Benign tumors can still be serious and even life-threatening if they are in vital areas in the brain where they exert pressure on sensitive nerve tissue or if they increase pressure within the brain. While some benign brain tumors may pose a health risk, including risk of disability and death, most are usually successfully treated with techniques such as surgery.

Click the icon to see an image of a primary brain tumor.

A secondary (metastatic) brain tumor occurs when cancer cells spread to the brain from a primary cancer in another part of the body. Secondary tumors are about three times more common than primary tumors of the brain. Usually, multiple tumors develop. Solitary metastasized brain cancers may occur but are less common. Most often, cancers that spread to the brain to cause secondary brain tumors originate in the lung, breast, kidney, or from melanomas in the skin.

A primary malignant brain tumor is one that originates in the brain itself. Although primary brain tumors often shed cancerous cells to other sites in the central nervous system (the brain or spine), they rarely spread to other parts of the body.

Brain tumors are generally named and classified according to the following:

The normal brain cells from which they originate, or
The location in which the cancer develops

The biologic diversity of these tumors, however, makes classification difficult, and some experts believe that more specific categories are needed.

About half of all primary brain tumors are known collectively as gliomas. They are cancerous forms of glial cells, the building-block cells of the connective, or supportive, tissue in the central nervous system. There are several glial cells types from which gliomas form. Their names are:

Astrocytomas are primary brain tumors derived from astrocytes, which are star-shaped glial cells. Normal astrocytes provide nutrients, support, and insulation for nerve cells and are one of the primary neurologic cells in the body. The malignant astrocytomas called glioblastomas account for 23% of brain tumors and are the most common ones.
Oligodendrogliomas develop from oligodendrocyte glial cells, which form the protective coatings around nerve cells. Although oligodendrogliomas were thought to represent about 5% of all gliomas, more recent evidence suggests they may comprise about 20% of gliomas. Pure oligodendrogliomas, however, are rare. In most cases they occur in mixed gliomas.
Ependymomas are derived from ependymal cells, which line the ventricles (fluid-filled cavities) in the lower part of the brain and the central canal of the spinal cord. They constitute about 6% of all primary tumors in the central nervous system. About 30% of these tumors occur in the spinal cord.
Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

It should be noted that gliomas may also contain cancer cells derived from brain cells other than glial cells.

Some brain tumors are categorized by their location in the brain. Such tumors often contain gliomas but are also frequently a mixture of different cell types.

Meningiomas. Meningiomas are usually benign tumors that develop in the membranes that cover the brain and spinal cord (the meninges).

Click the icon to see an image of the meninges.

They are not technically classified as brain tumors, but they have similar symptoms and develop within the brain. So in practical terms, they are considered brain tumors. In fact, meningiomas comprise 20% of all primary brain tumors. They occur more often in women than in men. Most grow very slowly, and the majority of people who have them never know they are present. Malignant forms called anaplastic meningiomas and hemangiopericytomas are less common and are difficult to remove surgically.

Cerebral Astrocytomas. Gliomas that develop inside the brain often occur in the cerebral hemispheres (the right and left sides of the brain). In such cases, they are referred to as cerebral astrocytomas. Gliomas sometimes occur in another part of the brain, called the cerebellum. The cerebellum is responsible for balance and coordination. In such cases, the term cerebellar astrocytoma is used.

Click the icon to see an image of the function of the left cerebral hemisphere.

Click the icon to see an image of the function of the right cerebral hemisphere.

Brain Stem Gliomas. Brain stem gliomas develop in the lowest portion of the brain. The brain stem connects the cerebrum (the higher centers of the brain) to the spinal cord. The brain stem is thought to be the primitive brain because it controls the most basic functions.

Click the icon to see an image of the function of the brainstem.

The brain stem consists of three primary parts:

The medulla regulates breathing, swallowing, blood pressure, and heart rate.
The pons links the cerebellum to the cerebrum.
The midbrain helps control vision and hearing.

Click the icon to see an image of the structures of the brain.

Medulloblastomas. Medulloblastomas are always located in the cerebellum, which is at the base and toward the back of the brain. They represent about 3% of all brain tumors.

Click the icon to see an image of the function of the cerebellum.

Pituitary Tumors. Pituitary tumors comprise about 10% of primary brain tumors and are often benign, slow-growing masses in the pituitary gland.

Click the icon to see an image of the pituitary gland.

Other Brain Tumor Locations. Optic nerve gliomas occur in the optic nerve, which is located behind the eye. Acoustic neuromas make up 7.5% of brain tumors.

Click the icon to see an image of the optic nerve.

Symptoms

Brain tumors produce a variety of symptoms, ranging from headache to stroke. They are great mimics of other neurologic disorders. Symptoms occur if the tumor directly damages the nerves in the brain or central nervous system or if its growth imposes pressure on the brain. Some gliomas develop gradually, and symptoms may be subtle for a long time, making an early diagnosis difficult.

Headache is probably the most common symptom of a brain tumor. It should be strongly emphasized, however, that everyone has headaches, and they rarely represent an underlying brain tumor. Headaches caused by brain tumors may vary depending on the location, and many different features.

Steady and worse upon waking in the morning and clears up within a few hours
Persistent non-migraine headache that occurs while sleeping and is also accompanied by at least one other symptom (such as vomiting or confusion)
May or may not be throbbing, depending on location of the tumor
Accompanied by double vision, weakness, or numbness
May worsen with coughing or exercise or with a change in body position
Sometimes accompanied by neck pain

Gastrointestinal symptoms, including nausea, are also common. Nausea and vomiting, in fact, often occur in children with brain tumors and in all people with brain stem cell tumors.

Seizures occur in between 15 - 95% of patients, depending on the location of the tumor.

Tumors are more likely to be localized and affect one area of the brain. In such cases they can cause partial seizures. In this case, a person does not lose consciousness but may experience confusion, jerking movements, tingling, or odd mental and emotional events.
Generalized seizures, which can cause loss of consciousness, are less common, since they are caused by disturbances of nerve cells in diffuse areas of the brain.

Sometimes the only symptoms are mental changes, which may include the following:

Memory loss
Impaired concentration
Problems with speech and reasoning
Increased sleep

Gradual loss of movement or sensation in an arm or leg
Unsteadiness
Unexpected visual disturbance (especially if it is associated with headache), including vision loss (usually of peripheral vision) in one or both eyes or double vision
Hearing loss with or without dizziness
Speech difficulty

Specific symptom syndromes may help identify the tumor. The following are some examples.

Symptoms of Brain Stem Gliomas. Sudden onset of symptoms that include vomiting (usually just after waking), a clumsy walk, muscle weakness on one side of the face, difficulty in swallowing, slurred or nasal speech, as well as impaired hearing or vision.

Symptoms of Glioblastoma Multiforme. Rapid onset and worsening of symptoms that include headaches, seizures, memory loss, and changes in behavior.

The below symptoms indicate an emergency condition and require immediate medical attention:

Pupil dilation
A fixed gaze
Paralysis on one or both sides of the body
Blindness or defective vision in one eye

Risk Factors

Nearly 360,000 people in the U.S. are living with brain cancer. Men are at higher risk than women for most brain tumors. Primary malignant brain tumors are still uncommon and represent only 1.3% of all cancers diagnosed in the United States and 2.4% of all deaths due to cancer.

Primary brain cancers are rare, occurring in slightly more than 11 people per 100,000 per year. There has been some evidence of a growing incidence of brain cancer among the elderly since the 1980s. The increase, however, is most likely due to the rise in incidence of non-Hodgkin's lymphomas -- which can occur in the brain. When this malignancy is eliminated, any increase in other tumors is not significant.

The average age of diagnosis for brain tumors is 57, and about 90% of primary brain tumors occur in adults. These tumors can develop at all ages, usually peaking in two age groups.

In adults, ages 55 - 65
In children, ages 3 - 12

Risk Factors in Children. Tumors in the central nervous system are now the most common primary cancers in children, but they are still rare. An estimated 3,110 benign or malignant brain tumors are expected to be diagnosed in children each year. Brain tumors in children are more likely to occur in the cerebellum, the midbrain, or the optic nerve.

The incidence has increased over the past years, but there is some evidence that this increase is only due to better diagnostic procedures. The mortality rate has actually decreased. Researchers have attempted to uncover risk factors for childhood brain cancer. There may be some association between a higher risk and the following conditions:

Children treated with radiation to the head for leukemia and who have a specific genetic defect may face a high risk for brain cancer. (It should be noted that for children without this defect, the risk is very small.)
Having parents with specific cancers. (According to one study, having parents with nervous system cancers, colon cancer, or cancer in the salivary glands increased the risk of specific brain tumors in their children.)

Click the icon to see an illustrated series detailing colon cancer surgery.

The risk for primary brain tumors in Caucasians is higher -- as much as twofold depending on type -- than in African-Americans.

Radiation Exposure. People who receive radiation therapy to the head during cancer treatment have an increased risk of developing brain tumors 10 - 15 years later. Workers in the nuclear industry are also at increased risk.

There is no evidence that electromagnetic field exposure from power lines or household appliances poses any risk. Several recent epidemiological studies, including a 2006 study in the British Medical Journal, found that cell phones, cordless phones, and wireless devices are also safe and do not increase the risk for gliomas.

Chemical and Metals in Brain Tumors. High exposure to numerous metals and chemicals have been associated with brain tumors:

Industrial chemicals, including vinyl chloride and petroleum products
Lead, arsenic, or mercury exposure
Exposure to pesticides. A major study of pesticides is underway, but results are not in yet. A 2003 study indicated that parental exposure to pesticides or herbicides did not appear to be important in increasing risk for brain cancer in their children.

Brain cancer is uncommon, and, over the course of their lifetime, many people are exposed to these chemicals, many of which are very common. To date, there has been no clear evidence that implicates any specific industrial chemical or metal.

One study reported a higher risk for brain cancers in patients who had undergone organ transplantations. Researchers believed that the drugs used to suppress the immune response after the procedures may increase the risk.

One study reported lower risks for brain cancers in individuals with allergies and autoimmune diseases (such as type 1 diabetes). Autoimmune diseases were also associated with a lower risk for meningiomas. The cause of this possible association remains unknown.

Studies have also found an association between lower risk for gliomas and a history of infection with varicella zoster, the virus that causes chicken pox and shingles.

Click the icon to see an image of the chicken pox.

Causes

Only 5 - 10% of primary brain tumors are associated with genetic disorders. These inherited conditions and associated genes include:

Von Recklinghausen disease, also called neurofibromatosis 1 (NF1 gene) and neurofibromatosis 2 (NF2 gene)
Turcot's syndrome (APC gene)
Gorlin syndrome, also called basal cell naevus syndrome (PTCH gene)
Tuberous sclerosis (TSC1 and TSC2 genes)
Li-Fraumeni syndrome (TP53 gene)

Certain types of brain tumors are specifically linked with these genetic conditions. For example, neurofibromatosis 1 is associated with about 15% of cases of pilocytic astrocytomas, the most common type of childhood glioma. Neurofibromatosis results from defects in the tumor suppressor genes NF1 and NF2. Li-Fraumeni syndrome results from mutations in the tumor suppressor gene TP53. These mutations affect the production of tumor suppressor protein p53.

Tumor suppressor genes regulate cell division and help repair DNA damage. When mutations that affect protein encoding occur, unregulated cell division and growth can lead to the development of a tumor. Tumor suppressor genes are sometimes described as being in a tug-of-war with cancer-causing genes called oncogenes. Oncogenes derive from mutations or overexpressions of proto-oncogenes. Proto-oncogenes encode for proteins that regulate cell growth and differentiation. When proto-oncogenes become oncogenes, normal cells start to grow uncontrollably. Cancer can occur when tumor suppressor genes are turned off, or when oncogenes are turned on.

Many different oncogenes are involved in cancer. Growth factors are a particularly important type of oncogene associated with brain tumors. Growth factors attach to receptors (connectors) that stimulate cell growth. Epidermal growth factor receptor (EGFR) has been shown to play a role in high-grade brain tumors such as glioblastoma multiforme. In 2007, scientists identified insulin-like growth factor binding protein (IGFBP2) with an oncogene that may be associated with the development of astrocytoma and oligodendroglioma.

Knowing the molecular origin of a brain tumor may help determine the treatment course, both for standard chemotherapy and "targeted therapy" biologic drugs. For example, patients with tumors marked by high EGFR proliferation may benefit from treatment with the EGFR kinase inhibitor drugs gefitinib (Iressa) or erlotinib (Tarceva).

Most genetic abnormalities that cause brain tumors are not inherited but occur as a result of environmental or other factors that affect genetic materials (DNA) in the cells. Researchers are studying various environmental factors (viruses, hormones, chemicals, radiation) that may trigger the genetic disruptions that lead to brain tumors in susceptible individuals. They are also working to identify the specific genes that are affected by these environmental triggers. For example, in a 2007 study, scientists proposed that genetic susceptibility may explain why some people develop meningioma, a rare type of brain tumor, following exposure to ionizing radiation. Future investigations will hopefully identify the specific genes involved and help determine which people would potentially be most at risk.

Prognosis

About 13,100 people die from cancerous brain tumors each year. Recent advances in surgical and radiation treatments have significantly extended average survival times and can reduce the size and progression of malignant gliomas. In general, survival rates are highest in younger people and lowest in the elderly.


Age	Survival Rates
0 - 19 years	63.1%
20 - 44 years	50.4%
45 - 64 years	14.2%
Over 65	4.9%
Data From: 2002 - 2003 Primary Brain Tumors in the United States Statistical Report. Fact Sheet (1973- 1999 data). Brain Tumor Registry of the United States www.cbtrus.org/factsheet/factsheet.html.

In general, studies are reporting that patients who survive the first 2 years after a diagnosis of a brain tumor have at least a 70% chance of surviving for at least 5 years. The best recent progress has been made for:

Medulloblastomas in both children and adults. Long-term survival rates are now about 60% in children after treatment for medulloblastomas, the most common malignant brain tumor in this age group. (New treatments, however, may significantly improve these rates.)
Nonmalignant astrocytomas and oligodendrogliomas in adults.

Unfortunately, the majority of primary brain tumors, notably anaplastic astrocytomas and glioblastoma multiforme, are only rarely curable.

The specific effects of tumors on the brain can cause seizures, mental changes, and mood, personality, and emotional changes. Such effects can be devastating to the patient and the caregivers. Numerous treatments are available that help alleviate these complications, and patients and family members should discuss these with their doctors.

Diagnosis

A neurological exam is usually the first test given when a patient complains of symptoms that suggest a brain tumor. The exam includes checking eye movements, hearing, sensation, muscle movement, sense of smell, and balance and coordination. The doctor will also test mental state and memory.

X-rays of the skull were once standard diagnostic tools but are now performed only when more advanced procedures are not available. Advanced imaging techniques have dramatically improved the diagnosis of brain tumors in recent years.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) is the gold standard for diagnosing a brain tumor. It does not use radiation and provides pictures from various angles that can enable doctors to construct a three-dimensional image of the tumor. It gives a clear picture of tumors near bones, smaller tumors, brainstem tumors, and low-grade tumors. MRI is also useful during surgery to show tumor bulk, for accurately mapping the brain and for detecting response to therapy.

An MRI (magnetic resonance imaging) of the brain creates a detailed image of the complex structures in the brain. An MRI creates a three-dimensional picture of the brain, which allows doctors to more precisely locate problems such as tumors or aneurysms.

A variant called magnetic resonance spectroscopy (MRS) is capable of providing information on the activity of the brain using magnetic resonance imaging. MRS is proving to be accurate for distinguishing dead (necrotic) tissue caused by previous radiation treatments from recurring tumor cells in the brain, a difficult diagnostic issue.

Computed Tomography. Computed tomography (CT) uses a sophisticated x-ray machine and a computer to create a detailed picture of the body's tissues and structures. It is not as accurate as an MRI and does not detect about half of low-grade gliomas. It is useful in certain situations, however. Often, doctors will inject the patient with an iodine dye, called contrast material, to make it easier to see abnormal tissues. A CT scan helps locate the tumor and can sometimes help determine its type. It can also help detect swelling, bleeding, and associated conditions. In addition, computed tomography is used to check the effectiveness of treatments and watch for tumor recurrence.

Click the icon to see an image of a CT scan of the brain.

Positron Emission Tomography. Positron emission tomography (PET) provides a picture of the brain's activity rather than its structure by tracking substances that have been labeled with a radioactive tracer. As with magnetic resonance spectroscopy (MRS), it is also able to distinguish between recurrent tumor cells from dead cells or scar tissue, although MRS is more widely available. PET is not routinely used for diagnosis, but it may supplement MRIs to help determine tumor grade after a diagnosis. Data from PET may also help improve the accuracy of newer radiosurgery techniques.

Other Imaging Techniques. Numerous other advanced imaging techniques may be used for specific purposes, if available or under investigation.

Single photon emission tomography (SPECT) is similar to PET but is not as effective in distinguishing tumor cells from destroyed tissue after treatments.
Magnetoencephalography (MEG) scans measure the magnetic fields created by nerve cells as they produce electrical currents.
Cerebral angiography involves x-rays of blood vessels in the brain. A long, thin tube (catheter) is threaded through blood vessels from a distant site to the brain, and a radiopaque substance (a substance that is impenetrable to x-rays) is injected through it. The role of angiography in glioma is usually limited to planning surgical removal of a tumor suspected of having a large blood supply.
Radionuclide brain scintigraphy uses a radioactive substance that is administered and absorbed by capillaries in the tumor, which are then viewed using imaging techniques.
Digital holography, a new technique that provides full three-dimensional mapping, is under investigation.

A lumbar puncture is used to obtain a sample of spinal fluid, which is examined for the presence of tumor cells. A computed tomography (CT) scan or magnetic resonance imaging (MRI) should generally be performed before a lumbar procedure to be sure that the procedure will be safe.

Click the icon to see an image of a lumbar puncture.

A biopsy is a surgical procedure in which a small sample of tissue is taken from the suspected tumor and examined under a microscope for malignancy. The results of the biopsy also provide information on the cancer cell type.

In some cases, such as brain stem gliomas, a biopsy might be too hazardous because removing any healthy tissue from this area can affect vital functions. In such cases, diagnosis must rely on less invasive and possibly less accurate measures. Of promise is the stereotactic technique (also called stereotaxy), which uses computers to provide three-dimensional views of very small areas. This may allow precise biopsies of cancer cells without affecting healthy brain tissue. Expertise in this technique is extremely important, however, and the technique is not widely available.

The survival rates in people with brain tumors depend on many different variables:

Whether the tumor is malignant or benign
Cancer cell type and location (location affects whether the tumor can be removed surgically or not)
The tendency to spread and the growth rate (tumor grade)
Patient's age
Patient's ability to function
Duration of symptoms

The outlook is poorer in the very youngest and very oldest patients, although younger patients who survive 2 years after diagnosis have a much better outlook than older patients.

Grading Tumors. Malignant primary brain tumors are classified according to tumor grade. Grade I is the least cancerous, and Grades IV and V are the most dangerous. Grading a tumor attempts to predict its tendency to spread and its growth rate. It is based on the appearance of the tumor cells as seen under a microscope.

Lower-grade (I and II) tumor cells are well defined and almost normal-shaped. (Some primary low-grade brain tumors are curable by surgery alone, and some are curable by surgery and radiotherapy. Low-grade tumors tend to have the most favorable survival rates and high-grade the least. However, this is not always the case. For example, some low-grade II gliomas are at very high risk for progression.)
Higher-grade (III and IV) tumor cells are abnormally shaped and are more diffuse, which indicates more aggressive behavior. (High-grade brain tumors usually require surgery, radiotherapy, chemotherapy, and possibly investigational treatments.)
In tumors that contain a mixture of different-grade cells, the tumor is graded using the highest-grade cells in the mixture, even when there are very few of them.

Biologic Markers. Elevated levels of certain cancer-associated molecules or compounds may be correlated with prognosis. For example, evidence of genetically mutated p53 indicates a poorer prognosis in younger patients with glioblastoma multiforme.

Elevations of epidermal growth factors (EGF) or vascular endothelial growth factors (VEGF) suggest aggressive tumors. High levels of the receptor for EGF (EGFR), in fact, are found in 70% of glioblastoma specimens.

Genetic Profiles of Cancer Cells. Analyses that identify genetic types may soon help clinicians determine if patients with specific brain tumor cells might respond better to one treatment than another. For example, specific genetic profiles of oligodendrogliomas can help predict how patients respond to nitrosourea alkylating drugs such as carmustine. Genetic variation tests are also being used to determine how patients may respond to epidermal growth factor receptor (EGFR) kinase inhibitors, such as erlotinib (Tarceva) and gefitinib (Iressa).

A genetic profile can also help give doctors a better idea of a patient’s prognosis and survival. In a 2006 study of patients with anaplastic oligodendroglioma, the status of specific chromosomal deletions within tumors was a better predictor of survival than which kind of treatment patients received. In fact, the researchers suggested that gliomas be classified according to chromosomal deletion status, and recommended that chromosomal testing be a regular part of diagnosis and treatment decisions.

Common Brain Tumors


GENERAL DESCRIPTION OF ASTROCYTOMAS: Derived from star-shaped glial cells called astrocytes.

Low-Grade (Usually I) Astrocytomas. Pilocytic gliomas.	Pilocytic gliomas occur mostly in children. Tumors are well differentiated. Cells are relatively normal and rarely metastasize. They grow relatively slowly. Pilocytic astrocytomas have the highest 5-year survival rates (greater than 70%). However, even well differentiated astrocytomas are life threatening if they are inaccessible.	Cancer may sometimes be completely removed through surgery, particularly if it occurs in the cerebellum. For recurrence or residual tumors, reoperation, radiotherapy, or chemotherapy may be given, depending on the circumstances. Repeat surgery for cerebellar astrocytoma is often very successful. For those who fail radiotherapy and chemotherapy, investigative drugs are used.
Low-Grade (II) Astrocytomas. Fibrillary, protoplasmic, and protoplasmic astrocytomas. Some pleomorphic xanthoastrocytomas.	Tumors are well differentiated. Cells are relatively normal and less malignant than those in higher grades. They grow relatively slowly but can spread. Survival rates average 5 years, but people can survive for a decade or more. Pleomorphic xanthoastrocytomas have a relatively favorable prognosis, but can recur and demonstrate aggressive clinical behavior. Low-grade astrocytomas generally occur in young adulthood, with a peak incidence in 30s and 40s.	Surgery, if possible, plus radiotherapy. Surgery alone in certain children, if possible. Trials on postoperative radiotherapy include the following: radiotherapy with or without chemotherapy; low-versus-high radiotherapy doses (studies suggest results are the same and high-dose causes more side effects); deferring radiotherapy until tumor progresses and symptoms occur. (A major study confirmed earlier ones that suggest that this approach has the same 5-year survival benefits -- about 65% -- as immediate postoperative radiotherapy.)
Malignant (High-grade III and IV) Astrocytomas. Anaplastic astrocytoma (gemistocytic and some pleomorphic xanthoastrocytomas). Usually mid-grade (III).	Tumors grow more rapidly than lower grades and infiltrate other nearby healthy cells. Not well-differentiated. Five-year survival rates are about 30%. Recurrence is common.	Treatment same for all high-grade malignant astrocytomas. Surgery, with removal of as much of tumor as possible followed by radiotherapy, with or without chemotherapy. The addition of chemotherapy, particularly being able to take more than 6 cycles, appears to improve survival rates. Carmustine (BCNU) most effective drug at this time. Other drugs and treatment sequences are under investigation. For example, temozolomide is showing promise for many patients, including the elderly. Topotecan may also be useful with other drugs or with radiation. For recurring gliomas, surgery with placement of wafers that release carmustine (Gliadel wafers) is the only proven beneficial therapy to date. Combinations, such as procarbazine and carmustine, provide benefits for recurrent anaplastic astrocytomas. Single drugs may be less toxic and as helpful for other recurrent gliomas. Temozolomide has been approved in Europe for high-grade recurrent gliomas and is proving to be beneficial. Other trials include the following: drugs that block small molecules involved in tumor growth; radioimmunotherapy using monoclonal antibodies; advanced radiotherapy techniques; intraarterial chemotherapy.
High-grade (IV and V). Glioblastoma (notably glioblastoma multiforme or GBM).	Very rapidly growing tumors that spread quickly. Represents about 25% of all primary brain tumors. Most common in older adults (over age 55) and affect more men than women. Recurrences are common in patients who achieve long-term survival.


GENERAL DESCRIPTION OF EPENDYMOMAS: Derived from cells that line the ventricles (fluid-filled brain cavities) and spinal cord central canal. Do not usually spread into normal brain tissue. Can block exits for cerebrospinal fluid and cause hydrocephalus. They constitute about 4% of all central nervous system tumors in adults and 10% of these tumors in children. About 30% of ependymomas develop in the spinal column.

Low-grade (I). Myxopapillary ependymoma (found in the spine). Subependymoma (found in one of the ventricles).	No or very slow growth. In addition to grade, risk is also based on location of the tumor. Tumors on the spinal cord are more accessible than those in the fourth ventricle or in the middle of the lower back portion of the brain.	Can often be removed and cured with surgery, particularly those on spinal cord. Radiation may be needed. Chemotherapy (avoid radiation, if possible) in children under age 6).
Low-grade (II). Papillary, cellular, and clear cell ependymomas.	Slow growth. Usually affect adults.	Surgery alone or followed by radiotherapy. For those who fail radiotherapy, possible use of nitrosourea-based chemotherapies or investigative drugs.
Grade III. Anaplastic ependymomas.	Spreads to the spinal fluid.	Surgery followed by radiotherapy to brain and spinal cord. Possible shunt.
Grade IV. Primitive neuroecto-dermal tumor (PNET). Composed of malignant forms of early, undeveloped nerve cells called neuroblasts. (This malignancy is also referred to as neuroblastoma.)	Very rare, but more common in children. Primitive nerve cells that grow very rapidly. Usually occur in cerebellum.	Surgery followed by radiotherapy to brain and spinal cord. Chemotherapy in young children. Investigative high-dose chemotherapy with stem cell rescue for children with relapsed cancer.


DESCRIPTION OF OLIGODENDROGLIOMAS: They develop from oligodendrocyte glial cells. These cells form the protective coatings around nerve cells. Pure cell types are rare. Most often occur in mixed gliomas. Categorized as either low- or high-grade. Most are low-grade II.

Low-grade: Low grade difficult to tell from astrocytomas, although they are usually calcified. Very likely to bleed. Usually spread along nerve pathways of the brain and spine and rarely outside this area. In spite of difficulty in removing surgically, in some patients survival can be 30 - 40 years. Usually have better prognosis than astrocytomas of equal grade. Occur mostly in middle-aged adults, although there is also a small peak of incidence in children.	Treatment usually delayed until progression causes symptoms. Surgery to remove whole tumor. Radiotherapy often follows in all adults over age 40 or in anyone in which tumor cannot be completely removed. Solid evidence is lacking on this approach, however, and there is some debate on its benefits. Trials using chemotherapy after radiation are promising. Two-thirds of patients respond to PCV (combination of procarbazine, lomustine and vincristine.) Sustained remissions averaging 16 years often achieved. Pure oligodendrogliomas respond better than mixed gliomas. Temozolomide is showing promise as second-line treatment. Others under investigation. Trials of additional chemotherapy for less well-differentiated tumors or for residual tumors after surgery.
High-grade. Anaplastic oligodendrogliomas.	Immediate treatment. Surgery to remove the whole tumor, if possible. Radiation typically follows surgery. Chemotherapy treatments either before or with radiation. Standard drugs are limited. Experts recommend trying investigative drugs. Temozolomide and retinoic acid may be useful. Possible additional drugs include melphalan, thiotepa, carboplatin, cisplatin, and etoposide. (Numerous biologic markers may help identify specific oligodendrogliomas that will respond better or worse to specific treatments.)


GENERAL DESCRIPTION OF MIXED GLIOMAS: Mixed gliomas contain a mixture of malignant gliomas. About half of these tumors contain cancerous oligodendrocytes and astrocytes.

Grade determined by the highest-grade cell present in the tumor.	Same as for oligodendroglioma.



Meningiomas	They are found in the membranes around the brain and spinal column. They are usually benign and rarely invasive. In such cases, long-term outlook is very favorable. (Malignant forms, anaplastic meningiomas, and hemangiopericytomas are uncommon and occur in about 2% of cases.)	Usually watchful waiting. Aggressive surgery the treatment of choice, if possible, although 20% recur after 10 years. Malignant forms and those at the base of the skull difficult to impossible to remove surgically. Stereotactic radiosurgery or fractionated external beam radiotherapy showing promising results for some patients.
Cerebellar astrocytomas (located in cerebellum)	Located in the cerebellum. Usually low-grade, but depends on cell type. If surgical removal is complete, up to 90% survival rates. More common in children than adults.	Surgery primary treatment. Radiotherapy if removal is incomplete.
Brain Stem Gliomas	About 60 - 70% of brain stem tumors are diffuse, which are likely to spread and have a rapid onset of symptoms. Focal tumors tend to be solid or cyst-like. They generally develop gradually. Occurs in both children and young adults.	Radiation is usual treatment. Tumors in this area are rarely removed surgically since the nerve tissue in this area is responsible for vital life functions. Slow-growing tumors may only require watchful waiting. Trials using advanced radiotherapy techniques, gene therapy, immunotherapy, and other experimental drugs.
Medulloblastomas	Occurs in cerebellum (the lower portion of the brain), brainstem, and spinal cord. Usually fast-growing aggressive cells. Most common brain tumors in children and young people, causing between 15 - 20% of brain tumors. With aggressive therapy, in children 5-year survival rates between 60 - 80%. In patients who survive for 2 years after diagnosis, long-term survival rate is nearly 80%.	Treatment is usually surgery and radiotherapy followed by chemotherapy. A 2005 study found that a combination chemotherapy regimen may replace radiation for very young children. A 2006 study suggested that radiation and chemotherapy doses should be adjusted based on disease severity.
Optic Tract Gliomas	Spread along the optic nerve. Usually slow growing. Most often in children under age 10. Children with these tumors often have vision and hormonal problems.	Usually surgery if one eye is involved. Possible chemotherapy or radiation.

Treatment

The approach for treating brain tumors is to reduce the tumor as much as possible using surgery, radiation treatment (also called radiotherapy), chemotherapy, or investigative procedures. Such treatments are used alone or, more commonly, in combinations. With some very slow-growing cancers, such as those that occur in the midbrain or optic nerve pathway, patients may be closely observed and not treated until the tumor shows signs of growth. The intensity, combination, and sequence of these treatments depends on the glioma subtype, its size and location, and patient age, health status, and medical history.

Recent advances in surgical and radiation treatments have significantly extended average survival times compared to those of standard therapy. Investigative treatments, such as monoclonal antibodies, are also showing promise. Patients or their caretakers should discuss all options thoroughly with a specialist in brain cancer. Different specialists may be needed to help manage symptoms.

Because of the low-cure rates of most malignant brain tumors, support for the patients and their families is a critical component of treatment and management. In response to one survey of patients with gliomas, experts made several recommendations to help both patients and caregivers:

Any physical impairment that could benefit from home equipment or physical therapy should be identified and treated.
Patients should discuss emotional as well as physical issues with their doctors. Depression, for instance, can be medically treated. Caregivers should also seek help for the inevitable stress, depression, and tension arising from their difficult role.
Relaxation techniques, meditation, and spiritual resources can be extremely helpful. Support groups are beneficial, but experts recommend separate groups for patients and their families.

Surgery

Surgery is usually the first step in treating most brain tumors. In some cases, however, such as most brain stem gliomas, it may be too dangerous to perform surgery. The object of most brain tumor surgeries is to remove or reduce as much of its bulk as possible. By reducing the size, other therapies, particularly radiotherapy, can be more effective. (Although there have been significant advances in brain surgeries, some experts argue that in high-grade gliomas extensive surgery may not improve survival rates at all and patients are best served by radiation therapy.)

The standard procedure is called craniotomy.

The neurosurgeon removes a piece of skull bone to expose the area of brain over the tumor.
The tumor is located and then removed.

Click the icon to see an illustrated series detailing craniotomy surgery.

There are various surgical options for breaking down and removing the tumor. They include:

Standard surgical procedures
Laser microsurgery (which produces great heat and vaporizes tumor cells)
Ultrasonic aspiration (which uses ultrasound to break the glioma tumor into small pieces, which are then suctioned out)

Relatively benign, grade I gliomas may be treated only by surgery. Some controversy exists over whether surgery for low-grade astrocytomas improves survival, although insufficient research has been conducted to prove its benefits for these gliomas. Most malignant tumors require additional treatments, including repeat surgery.

The surgeon's skill in removing the tumor as completely as possible is critical to survival. No one should be shy about asking the surgeon the number of similar procedures they have performed. (Asking for complication rates may not be useful, since a very experienced surgeon might operate on many high-risk patients.)

In most cancers outside the brain, surgical removal of a tumor usually involves taking out surrounding healthy tissue to be sure all cancer cells are gone. In the brain, however, removing healthy nearby nerve tissue can be as disastrous for the patient as the cancer itself. Special techniques have been developed to allow maximum removal of tumors while protecting healthy brain cells.

Stereotaxy. Stereotaxy has become a useful adjunct to both surgery (stereotactic surgery) and radiotherapy (stereotactic radiotherapy).

Cortical Localization. Cortical localization, or stimulation, uses a probe that passes a tiny electrical current to delicately stimulate a specific area of the brain. This produces a visible response of the body part (such as a twitch in a leg), which the stimulated region of the brain controls. The surgeon then knows to avoid those areas during the operation.

Image-Guided Surgery. Image guided surgery uses a three-dimensional picture of the patient's brain derived from computed tomography (CT) or magnetic resonance imaging (MRI) scans. An advanced technique called high-field interventional MR imaging (iMRI) is particularly accurate in identifying the tumor, but it is not widely available. The image, with various views of the brain, is displayed on a monitor in the operating room. During surgery, as the surgeon's instrument touches a part of the brain, a camera sends the image to a computer, which calculates the position of the surgical tool and displays it in its proper location on the 3-D image. The surgeon then can look at the monitor and see what structures to avoid.

Magnetic-Tipped Catheters. Neurosurgeons are investigating a technique in which external magnetic fields direct a magnet-tipped flexible catheter to the tumor site through a path that avoids harming certain important areas of the brain.

Heparin. Heparin, a blood-thinning drug, should be given at the time of surgery to help prevent blood clots.

Radiotherapy

Radiotherapy plays a central role in the treatment of most brain tumors, whether benign or malignant.

Radiotherapy after Surgery. Even when it appears that the entire tumor has been surgically removed, microscopic cancer cells often remain in the surrounding brain tissue. Radiation targets the residual tumor with the goal of reducing its size or stopping its progression. If the entire tumor cannot be removed safely, postoperative radiotherapy is often recommended. Even some benign gliomas may require radiation, since they may be life-threatening if their growth is not controlled.

Radiotherapy When Surgery Is not Appropriate. Radiotherapy may be used instead of surgery for inaccessible tumors or for tumors that have properties that are particularly responsive to radiotherapy.

Radiotherapy and Chemotherapy (Radiochemotherapy). Combining chemotherapy with radiotherapy is beneficial in some patients with high-grade tumors.

Various radiation treatments are now available.

Conventional radiotherapy uses external beams aimed directly at the tumor and is usually recommended for large or infiltrating tumors. It begins about a week after surgery and continues 5 days per week for 6 weeks. Older adults tend to have a more limited response to external-beam radiation therapy than younger people. According to a 2007 study in the New England Journal of Medicine, radiotherapy leads to a modest improvement in survival in elderly patients (70 years or older) with glioblastoma, and causes few negative impacts on quality of life or cognition.

For tumors that are highly localized, the radiation therapist has a choice of other radiation treatments:

Brachytherapy (also called interstitial radiation) uses radioactive "seeds" implanted directly in the tumor site. It is used as a booster to external beam radiation for patients with malignant astrocytoma. Brachytherapy appears to prolong survival in some aggressive gliomas. It may also be a safe and effective treatment for some children.
Intensity-modulated radiation therapy (IMRT) uses high-dose radiation beams that conform to the three-dimensional shape of the tumor.
Hyperfractionated radiation uses many small radiation doses to deliver a high total dosage of radiation.
A balloon catheter (GliaSite) that delivers radiation to the tumor cavity after surgery is showing promise.

Stereotactic radiosurgery has been developed to allow highly targeted radiation to be delivered directly to the small tumors while avoiding healthy brain tissue. The term radiosurgery is used because the destruction is so precise that it acts almost like a surgical knife. Some studies suggest that stereotactic radiosurgery improves survival, even in patients with the highly aggressive glioblastoma multiforme brain cancer. The procedure is being tested to boost standard radiotherapy.

Benefits of Stereotaxy. There are numerous benefits for stereotaxy:

Stereotaxy allows precisely focused, high-dose beams to be delivered to gliomas less than 1.25 inch in diameter.
Investigators have found that stereotactic radiosurgery can help them reach small tumors located deep in the brain that were previously considered inoperable.
Sometimes with stereotaxy only a single treatment may be needed.
Unlike traditional radiotherapy, stereotactic radiotherapy can be repeated, so it is useful for recurrent tumors when a patient has already received standard radiation treatments.
Combining stereotaxy with techniques that gauge speech and other mental functions in patients who are awake during the procedure can allow removal of brain tissue with a lower risk for complications in areas that affect such functioning.

The Planning Procedure. Stereotactic radiosurgery usually begins with a series of steps designed to plan the radiation target:

First, the patient is given a local anesthetic. In the standard operation, the patient's head must be totally immobilized by screwing a device known as a stereotactic frame into the patient's skull. (The frame procedure is effective only on brain tumors that have regular margins.) The frame is removed as soon as the whole procedure has been completed (about 3 - 4 hours).
A three-dimensional map, usually using magnetic resonance imaging (MRI) scans, is made of the patient's brain.
A computer program calculates dosage levels and specific areas for radiation targeting.

Advanced imaging techniques are now allowing frameless stereotaxy, which eliminates the frame and may be effective on more tumors. For example, high-field interventional MR imaging (iMRI) uses a guidance system based on cruise-missile technology to calculate the slightest variations in movements of the head and the location of the tumor relative to these movements. These calculations are then used to target the radiation beams directly on the tumor, even if the patient's head is moving slightly.

Delivery of Radiation Beams. Once the preliminary planning stage has been completed, treatment begins. Several advanced machines, such as the gamma knife, adapted linear accelerator (LINAC), and cyclotron, are being used with stereotaxy and can deliver very focused beams of radiation. Actual treatment takes 10 minutes to 1 hour.

The gamma knife uses gamma rays that are sent from multiple points to converge at a single point on the tumor. Although each gamma-ray beam is very low dosage, when the beams converge, the intensity and destructive power is very high. The gamma knife is limited to very small tumors and so is generally useful as a booster after standard radiation, surgery, chemotherapy, or combinations.
The linear accelerator (LINAC) produces photons (positively-charged atomic particles) in patterns that are matched to the tumor shape. The patient is positioned on a bed that can be moved to allow flexible positioning. It allows treatment over multiple sessions of small doses (fractionated stereotactic radiotherapy), instead of a single session. This means that larger tumors can be treated.
The cyclotron is basically an atom smasher, which produces protons that can be directed toward the tumor. As part of this procedure, some researchers are using boron neutron capture therapy (BNCT). BNCT employs intravenous administration of a boron compound, which is picked up more selectively by tumor cells than by normal brain tissue. The cyclotron delivers a single dose of radiation that triggers the release of high-energy particles from the boron to destroy nearby tumor cells. The cyclotron is available only in a very few locations, and there have been few trials to date.

Researchers are studying drugs that may be used along with radiation to increase the effectiveness of the treatment.

Radioprotectors. Drugs such as amifosistine (Ethyol) may protect healthy cells during radiation.

Radiosensitizers. Drugs such as fluorouracil (5-FU) and cisplatin (Platinol) may help make cancerous cells more sensitive to radiation.

Common Side Effects. Side effects of radiotherapy may vary depending on the tumor type and radiation treatment. Side effects may include hair loss, fatigue, and nausea and vomiting. Skin irritation and sensitivity may develop in the areas being treated. To prevent further irritation, avoid scratching or rubbing, avoid direct sunlight and heating pads, and do not attempt to treat the symptoms yourself. (Ask your doctor or radiation therapist for advice.) Brain swelling (edema) is another common radiotherapy side effect, which can sometimes cause an increase in brain tumor symptoms. Edema can be treated with steroids.

Tissue Injury. Radiation necrosis (total destruction of nearby healthy tissue) occurs in about 25% of patients treated with intensive radiation. Radiation necrosis can cause brain swelling and reduction in mental functions. The condition is treated with steroids. If steroids prove ineffective, surgery may be required to remove the damaged tissue.

New Tumors. Radiation therapy for childhood cancer is the most important risk factor for developing new brain and spinal column tumors, according to a 2006 study. The risk appears greatest for children who received radiation therapy before age 5. Researchers found that the risk of second primary tumors increased in relation to the radiation dose used to treat the first cancer.

Stroke. Survivors of childhood brain tumors who were treated with high doses of cranial radiation (especially doses greater than 50Gy) may be at increased risk of having a stroke later in life. In a study of nearly 2,000 brain tumor survivors, the average length of time from cancer diagnosis to stroke was 14 years.

Chemotherapy

Chemotherapy involves the use of drugs to kill or alter cancer cells. Chemotherapy is not an effective initial treatment for low-grade brain tumors, mostly because standard drugs cannot pass through the blood-brain barrier, the functional system that protects the brain by preventing certain molecules from reaching the central nervous system. In addition, not all types of brain tumors respond to chemotherapy. In general, chemotherapy for brain tumors is usually administered following surgery or radiation therapy.

The type of drug determines how it is administered. "Systemic delivery" drugs, which pass to the brain from the bloodstream, may be given by mouth, injected into a vein through an IV, or injected into an artery or a muscle. "Local delivery" drugs are placed within or around the brain tumor.

Scientists are working on several approaches to overcome the blood-brain barrier. Newer delivery methods include:

Interstitial chemotherapy uses disc-shaped polymer wafers (known as Gliadel wafers) soaked with carmustine, the standard chemotherapeutic drug for brain cancer. The surgeon implants the wafer directly into the surgical cavity after a tumor is removed.
Intrathecal chemotherapy delivers chemotherapeutic drugs directly into the spinal fluid.
Intraarterial chemotherapy delivers high-dose chemotherapy into arteries in the brain using tiny catheters. In one study, this approach was used within 2 weeks of radiotherapy in patients with high-grade astrocytomas, and the survival rates for glioblastoma multiforme tripled (20 months) compared to those who had chemotherapy and radiation at the same time.
Convection-enhanced delivery (CED) involves placing catheters into the brain tumor or nearby brain tissue to deliver slowly and continuously a cancer drug over several days.

Many different drugs, and drug combinations, are used for chemotherapy. Standard ones include:

Temozolomide (Temodar). Temozolomide, the first new drug approved for brain tumors in several decades, is taken by mouth as a pill. Temozolomide was first approved in 1999 for adult patients with anaplastic astrocytoma that did not respond to other treatments. In 2005, it was approved for use during and after radiation therapy for patients newly diagnosed with glioblastoma multiforme. The current first-line treatment for patients with glioblastoma is combined radiotherapy and temozolomide, followed by monthly doses of temozolomide after radiation treatment ends. A 2005 study, published in the New England Journal of Medicine, reported that adults with newly diagnosed glioblastoma who received temozolomide during and after radiation therapy had a higher rate of 2-year survival than patients who received radiation alone. A 2007 study in Neurology suggested that temozolomide works best for patients who are missing a particular gene (1p/19q). Temozolomide’s side effects are relatively minor, but may include constipation, nausea and vomiting, fatigue, and headache.

Carmustine (BCNU, BiCNU). Carmustine is used to treat many types of brain tumors, including glioblastoma, medulloblastoma, and astrocytoma. Carmustine is usually administered into the vein by IV. It can also be delivered through a wafer implant (Gliadel), which is surgically placed into the brain cavity after tumor removal. If carmustine is administered intravenously, side effects may include nausea and vomiting, fatigue, respiratory problems, and lung scarring (pulmonary fibrosis). Intravenous carmustine may cause bone marrow impairment, which results in decreased production of blood cells (a condition called myelosuppression). If carmustine is delivered through a wafer, side effects may include seizures, brain swelling, and infection within the brain cavity.

PCV Drug Regimen. PCV is an abbreviation for a chemotherapy regimen that combines procarbazine (Matulane), lomustine (CCNU), and vincristine (Oncovin). PCV is commonly used to treat oligodendrogliomas and oligoastrocytomas. The drugs may also be used alone or in other combinations. Procarbazine and lomustine are taken by mouth. Vincristine is given by either injection or IV. These drugs can cause significant side effects, including a drop in blood cell counts, nausea and vomiting, constipation, fatigue, and mouth sores. Procarbazine can cause high blood pressure when taken with foods high in tyramine. Patients should avoid foods such as beer, red wine, cheese, chocolate, processed meat, yogurt, and certain fruits and vegetables.

Platinum-Based Drugs. Cisplatin (Platinol) and carboplatin (Paraplatin) are standard cancer drugs that are sometimes used to treat glioma, medulloblastoma, and other types of brain tumors. These drugs are delivered by IV. In addition to nausea and vomiting, carboplatin can cause hair loss, and cisplatin can cause muscle weakness.

Patients with brain tumors, especially tumors that are in advanced stages, should consider enrolling in clinical trials. Many clinical trials are conducted through academic medical centers. Some promising areas of drug research include:

Other Chemotherapy Drugs. Researchers are investigating whether drugs used to treat other types of cancer may have benefits for brain tumors. These drugs include tamoxifen (Nolvadex) and paclitaxel (Taxol), which are used to treat breast cancer; topotecan (Hycamtin), which is used to treat ovarian and lung cancers; and vorinostat (Zolinza), which is approved for treatment of cutaneous T-cell lymphoma. Research presented at the 2007 meeting of the American Society of Clinical Oncology indicated that vorinostat may help patients with glioblastoma multiforme. Irinotecan (Campath) is another cancer drug that is being studied in combination treatment.

Molecular Targeted Therapy Drugs. One of the most promising developments in cancer treatment research has been the emergence of so-called "targeted therapies." Traditional chemotherapy drugs can be effective, but because they do not distinguish between healthy and cancerous cells their generalized toxicity can cause severe side effects. Targeted therapies work on a molecular level by blocking specific mechanisms associated with cancer cell growth and division. Because they selectively target cancerous cells, they may induce less severe side effects. In addition, these drugs hold the promise of creating options for more individualized cancer treatment based on a patient's genotypes.

Promising targeted therapies for brain tumors include:

Anti-angiogenesis drugs block molecules involved with the growth of blood vessels that feed the tumor (a process called "angiogenesis," which is particularly important in the growth of glioblastomas.) These drugs starve tumors of vital nutrients and oxygen. Bevacizumab (Avastin) is being studied in combination with irinotecan for treatment of recurrent malignant gliomas. Bevacizumab targets vascular endothelial growth factor (VEGF), a specific angiogenesis growth factor. Cediranib (Recentin, AZD2171) is another VEGF inhibitor. In 2007 clinical trials, cediranib appeared to help make recurrent glioblastomas more responsive to chemotherapy and radiation treatment.
Tyrosine kinase inhibitor drugs block proteins involved in tumor cell growth and production. Drugs that specifically target epidermal growth factor receptors (EGFR) are a type of tyrosine kinase inhibitor of special interest in brain tumor research. These drugs include erlotinib (Tarceva), imatinib (Gleevac), and gefitinib (Iressa).
Farnesyl protein transferase inhibitors, such as tipifarnib (Zarnestra) and lonafarnib (Sarasar), are drugs that target a protein involved in the functioning of the cancer-causing Ras protein. Lonafarnib is being studied in combination with temozolomide, and tipifarnib in combination with radiation therapy.
MTOR inhibitors target other enzymes involved in cell growth and replication. Everolimus (RAD-001) is being studied for glioblastoma multiforme and astrocytoma. Everolimus is related to rapamycin (Siroliumus) and tacrolimus (Prograf), which are also being investigated for brain tumor treatment. These drugs are commonly used to suppress the immune system to prevent rejection after organ transplantation.

Other Treatments

Researchers are testing several drugs that target specific mechanisms associated with brain cancer. Combinations of some of these drugs, with or without standard chemotherapy and radiotherapy, may prove to be more effective than the use of any one treatment. It should be noted that none of these drugs at this time are producing cures, although some are improving survival.

Immunotherapy aims at using modalities that boost the patient's own immune system's ability to seek out and destroy cancerous cells.

Radioimmunotherapy with Monoclonal Antibodies. Radioimmunotherapy is showing special promise as a treatment approach to brain tumors. It typically uses monoclonal antibodies (MAbs), genetically engineered drugs designed to work against a specific target. MAbs are bound with radioactive substances and delivered directly into the brain and sometimes into the tumor. The MAbs are specifically designed to lock with the surface of certain cells in the tumor. Once they do so, the radioactive substances destroy the cell. The approach is essentially mini-radiation therapy without the damage or severe side effects of standard radiation treatments. Numerous different radioimmunotherapies are being investigated, and trials of some are reporting improved survival rates in high-grade gliomas. Some doctors believe this approach could prove to be the most effective therapy against these cancers.

Interleukins. Interleukins are natural proteins created by the immune system. Certain tumor cells carry receptors for specific interleukins, which are being investigated for a possible therapeutic role. For example, some drugs combine an interleukin with a drug that is toxic to cancer cells. The interleukin locks onto the receptor on the cancer cell, and the toxic chemical enters the tumor with the intent to kill it. Some interleukins are also being investigated alone for their own tumor-cell killing properties.

Tumor Vaccines. Tumor vaccines are being created, in which tumor cells are removed from the patient and inactivated. When the tumor cells are transferred back to the patient, they are harmless but can elicit a powerful immunologic response against the tumor. Vitespan (Oncophage) is a tumor vaccine that is showing promise against recurrent high-grade glioma, according to preliminary results from early trials presented at the 2007 annual meeting of the American Association of Neurological Surgeons.

Much research is focusing on drugs that block small molecules involved with the growth of blood vessels that feed the tumor (a process called angiogenesis). Such drugs, when effective, would starve tumors of vital nutrients and oxygen. Angiogenesis is particularly important in the growth of glioblastomas, the most malignant brain tumors. Of particular promise are drugs that inhibit enzymes called tyrosine kinase, farnesyl protein transferase, and matrix metalloproteinase, which play critical roles in angiogenesis.

Farnesyl Protein Transferase Inhibitors. Farnesyl protein transferase inhibitors, such as tipifarnib, also called R115777 (Zarnestra) and lonafarnib (Sarasar), are drugs in a new class that block a mutated gene called the Ras gene, which is responsible for about 30% of cancers. Lonafarnib is in early trials in combination with temozolomide. Tipifarnib is also currently in early trials and may prove to be effective.

Tyrosine Kinase Inhibitors. Drugs that target growth factor receptors, such as tyrosine kinase, interfere with the pathway leading to angiogenesis. Some tyrosine kinase inhibitors -- including erlotinib (Tarceva), imatinib (Gleevac), gefitinib (Iressa), and others -- are being investigated in early trials for brain tumor treatment. Side effects include rash, diarrhea, nausea and vomiting. Some of these drugs may reduce white blood cell count or cause liver damage. Researchers are trying to identify biomarkers that could help predict which patients would best respond to tyrosine kinase inhibitor therapy.

Matrix metalloproteinase Inhibitors. Matrix metalloproteinase is an important enzyme in angiogenesis. Inhibitors of these enzymes, including marimastat, metastat, and prinomastat, are in early trials. Marimastat has been studied and has shown some benefits in early trials for patients with recurrent glioblastoma and anaplastic gliomas, particularly in combination with temozolomide.

Phophoinositide 3-Kinse (Pi3K) Inhibitors. Rapamycin and its analog (CCI-779) inhibit Pi3K, an enzyme involved in cell growth. Early trials using CCI-779 are underway. (Another rapamycin analog, everolimus, has different effects but is also being studied for its actions in inhibiting cell growth.)

Other Drugs that Block Angiogenesis. Thalidomide was one of the first drugs used to inhibit angiogenesis and has undergone several trials. There is some evidence that it may work more effectively for metastasized brain tumors than primary tumors. Other drugs in early trials with various effects on tumor growth include suramin, cilengitide, semaxanib, PTK787, and atrasentan.

Retinoids. Retinoids are vitamin A derivatives and act as differentiating drugs in cancer treatments. That is, they can convert immature, dividing tumor cells into mature cells, stopping tumor growth. Studies suggest that they have little benefits as single drugs. Combination with radiotherapy and other drugs may hold promise.

Inactivated Viruses. Investigators are finding that certain genetically inactivated viruses, such as the poliovirus or herpes virus, may prove to be valuable fighters of brain cancers. Such viruses can enter cells and destroy them but do not pose any danger for infection. For example, one specially designed herpes virus targets the enzyme thymidine kinase (an enzyme that promotes tumor growth). Some researchers believe that a combination of this virus with retinoids may be effective with few serious side effects. Other viruses are being investigated. A drug based on this model is years away, however.

Immunotoxins. Drugs called immunotoxins use natural toxins to kill malignant brain cells.

Drugs that use diphtheria toxins, including TransMID-107R and DAB(389)EGF), are the first immunotoxins to show some promise. Clinical trials are investigating them for gliomas and metastatic brain cancers. Other toxins under investigation include irofulven (a mushroom toxin) and chlorotoxin (a substance derived from scorpions).

Taurolidine. Taurolidine is a unique drug that prevents tumor formation and growth in animals. An early clinical trial in patients with high-grade gliomas is under way.

Protein-Blocking Drug. Another development is the discovery of a protein called BEHAB (Brain-Enriched Hyaluronan Binding Protein). BEHAB is produced only by invasive glioma tumor cells, not by normal brain tissue or noninvasive tumor cells. Breakdown of BEHAB releases a substance called HABD (hyaluronan-binding domain), which appears to give glioma cells the ability to invade other areas of the brain. Both BEHAB and HABD represent potential targets for new therapies.

Chemotherapy destroys not only cancer cells but also healthy cells, including special blood cells in the bone marrow called stem cells. Stem cells are immature cells from which all blood cells develop. Transplantation procedures using bone marrow or stem cells allow high-dose chemotherapy to be administered while protecting blood cells. The procedures are being tested for patients with recurrent brain tumors, such as medulloblastoma, primitive neuroectodermal tumors, and germ cell tumors. A 2003 study reported long-term survival in some patients who underwent this procedure

Photodynamic therapy uses a special drug (Photofrin) that is absorbed by the tumor and causes the cancer cells to become fluorescent when a laser is directed at them. It is being investigated in trials in combination with other treatments. A 2003 study reported encouraging results, notably in patients with recurring glioblastoma multiforme. In the study, more than half of these patients survived for at least a year.

Treatment of Complications

Some tumors, particularly medulloblastomas, interfere with the flow of cerebrospinal fluid and cause hydrocephalus (accumulation of fluid in the skull). This causes a build-up fluid in the ventricles (the cavities) in the brain. Symptoms include nausea and vomiting, severe headaches, lethargy, difficulty staying awake, seizures, visual impairment, irritability, and tiredness.

The ventricles of the brain are hollow chambers filled with cerebrospinal fluid (CSF), which supports the tissues of the brain.

Corticosteroids (commonly called steroids) such as dexamethasone (Decadron), prednisolone, and prednisone are used to treat hydrocephalus. Side effects include high blood pressure, mood swings, increased risk of infection, stronger appetite, facial swelling, and fluid retention.

Human corticotropin-releasing factor (hCRF), a naturally occurring neurohormone, appears to possess substantial anti-swelling properties and thus has been proposed as an alternative to corticosteroids in brain edema, with potentially fewer side effects. A hCRF drug called Xerecept is currently in clinical trials.

A shunt procedure may be performed to drain fluid. Shunts are flexible tubes used to reroute and drain the fluid.

Seizures are common in brain tumor cases, with younger patients having higher risks than older ones. Anti-epileptic medications, such as carbamazepine or phenobarbital, may treat seizures and are helpful in preventing recurrence. These drugs are not useful in preventing a first seizure, however, and they should not be used routinely to treat patients with newly diagnosed brain tumors. Anti-seizure medications should be used only for patients who are experiencing seizures. Despite these guidelines, a 2005 study in the Journal of the American Medical Association reported that nearly 90% of patients with newly diagnosed malignant glioma are treated with anti-epileptic drugs, although only 32% of the patients actually have seizures. Anti-seizure medications can interact with some of the chemotherapies used to treat brain cancers, including paclitaxel, irinotecan, interferon, and retinoic acid. Patients should discuss these interactions with their doctors.

Antidepressants are very useful for treating the emotional side effects of this disease. However, according to a 2005 Journal of the American Medical Association study, only 8% of patients with malignant gliomas receive antidepressant medication even though over 90% report depressive symptoms. Support groups can also have great benefit for both patients and families.

Resources

www.abta.org -- American Brain Tumor Association
www.cbtf.org -- Children's Brain Tumor Foundation
www.virtualtrials.com -- Musella Foundation for Brain Tumor Research and Information
www.braintumor.org -- National Brain Tumor Foundation
www.neurosurgery.org -- American Association of Neurologic Surgeons
www.cancer.org -- American Cancer Society
www.cancer.gov -- National Cancer Institute
www.asco.org -- American Society for Clinical Oncology
www.cancer.gov/clinicaltrials -- Find clinical trials
www.radiologyinfo.org -- RadiologyInfo
www.plwc.org -- People Living with CAncer

References

Bowers DC, Liu Y, Leisenring W, McNeil E, Stovall M, Gurney JG, et al. Late-occurring stroke among long-term survivors of childhood leukemia and brain tumors: a report from the Childhood Cancer Survivor Study. J Clin Oncol. 2006 Nov 20;24(33):5277-82. Epub 2006 Nov 6.

Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN, et al. Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11736-41. Epub 2007 Jul 2.

Flint-Richter P, Sadetzki S. Genetic predisposition for the development of radiation-associated meningioma: an epidemiological study. Lancet Oncol. 2007 May;8(5):403-10.

Kaloshi G, Benouaich-Amiel A, Diakite F, Taillibert S, Lejeune J, Laigle-Donadey F, et al. Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome. Neurology. 2007 May 22;68(21):1831-6.

Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007 Apr 12;356(15):1527-35.

Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, et al. New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

Sharma MK, Mansur DB, Reifenberger G, Perry A, Leonard JR, Aldape KD, et al. Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin. Cancer Res. 2007 Feb 1;67(3):890-900.

Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA,et al. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007 Feb 15;13(4):1253-9.

Review Date:
11/1/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

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Omega-3 fatty acids

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HEALTH GUIDE REFERENCE FROM A.D.A.M

Overview

Omega-3 fatty acids are considered essential fatty acids. They are essential to human health but cannot be manufactured by the body. For this reason, omega-3 fatty acids must be obtained from food. Omega-3 fatty acids can be found in fish, such as salmon, tuna, and halibut, other marine life such as algae and krill, certain plants (including purslane), and nut oils. Also known as polyunsaturated fatty acids (PUFAs), omega-3 fatty acids play a crucial role in brain function as well as normal growth and development. The American Heart Association recommends eating fish (particularly fatty fish such as mackerel, lake trout, herring, sardines, albacore tuna, and salmon) at least 2 times a week. It is advised that pregnant women and mothers, nursing mothers, young children, and women who might become pregnant not eat several types of fish, including swordfish, shark, and king mackerel. These individuals should also limit consumption of other fish, including albacore tuna, salmon, and herring. They can take omega-3 fatty acids in quality dietary supplements that are certified mercury-free by a reputable third-party lab.

There are three major types of omega 3 fatty acids that are ingested in foods and used by the body: alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Once eaten, the body converts ALA to EPA and DHA, the two types of omega-3 fatty acids more readily used by the body. Extensive research indicates that omega-3 fatty acids reduce inflammation and help prevent risk factors associated with chronic diseases such as heart disease, cancer, and arthritis. These essential fatty acids are highly concentrated in the brain and appear to be particularly important for cognitive (brain memory and performance) and behavioral function. In fact, infants who do not get enough omega-3 fatty acids from their mothers during pregnancy are at risk for developing vision and nerve problems. Symptoms of omega-3 fatty acid deficiency include extreme tiredness (fatigue), poor memory, dry skin, heart problems, mood swings or depression, and poor circulation.

It is important to maintain an appropriate balance of omega-3 and omega-6 (another essential fatty acid) in the diet, as these two substances work together to promote health. Omega-3 fatty acids help reduce inflammation, and most omega-6 fatty acids tend to promote inflammation. An inappropriate balance of these essential fatty acids contributes to the development of disease while a proper balance helps maintain and even improve health. A healthy diet should consist of roughly 2 - 4 times more omega-6 fatty acids than omega-3 fatty acids. The typical American diet tends to contain 14 - 25 times more omega-6 fatty acids than omega-3 fatty acids, and many researchers believe this imbalance is a significant factor in the rising rate of inflammatory disorders in the United States.

In contrast, however, the Mediterranean diet consists of a healthier balance between omega-3 and omega-6 fatty acids, and many studies have shown that people who follow this diet are less likely to develop heart disease. It also contains another fatty acid, omega-9 fatty acids, which have been reported to help lower risks associated with cancer and heart disease. The Mediterranean diet does not include much meat (which is high in omega-6 fatty acids) and emphasizes foods rich in omega-3 fatty acids, including whole grains, fresh fruits and vegetables, fish, olive oil, garlic, as well as moderate wine consumption.

Uses

Clinical studies suggest that omega-3 fatty acids may be helpful in treating a variety of health conditions. The evidence is strongest for heart disease and problems that contribute to heart disease, but the range of possible uses for omega-3 fatty acids include:

High cholesterol

Those who follow a Mediterranean-style diet tend to have higher high density lipoprotein (HDL or "good" )cholesterol levels. Similar to those who follow a Mediterranean diet, Inuit Eskimos, who consume high amounts of omega-3 fatty acids from fatty fish, also tend to have increased HDL cholesterol and decreased triglycerides (fatty material that circulates in the blood). In addition, fish oil supplements containing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been reported in several large clinical studies to reduce low density lipoprotein (LDL or "bad") cholesterol and triglyceride levels. Finally, walnuts (which are rich in alpha linolenic acid or ALA) have been reported to lower total cholesterol and triglycerides in individuals with high cholesterol levels.

High blood pressure

Several clinical studies suggest that diets or supplements rich in omega-3 fatty acids lower blood pressure significantly in individuals with hypertension. An analysis of 17 clinical studies using fish oil supplements found that supplementation with 3 or more grams of fish oil daily can lead to significant reductions in blood pressure in individuals with untreated hypertension.

Heart disease

One of the best ways to help prevent and treat heart disease is to eat a low-fat diet and to replace foods rich in saturated and trans-fat with those that are rich in monounsaturated and polyunsaturated fats (including omega-3 fatty acids). Clinical evidence suggests that EPA and DHA found in fish oil help reduce risk factors for heart disease including high cholesterol and high blood pressure. There is also strong evidence that these substances can help prevent and treat atherosclerosis by inhibiting the development of plaque and blood clots, each of which tends to clog arteries. Clinical studies of heart attack survivors have found that daily omega-3 fatty acid supplements dramatically reduce the risk of death, subsequent heart attacks, and stroke. Similarly, people who eat an ALA-rich diet are less likely to suffer a fatal heart attack.

Strong evidence from population-based clinical studies suggests that omega-3 fatty acid intake (primarily from fish) helps protect against stroke caused by plaque buildup and blood clots in the arteries that lead to the brain. In fact, eating at least 2 servings of fish per week can reduce the risk of stroke by as much as 50%. However, people who eat more than 3 grams of omega-3 fatty acids per day (equivalent to 3 servings of fish per day) may be at an increased risk for hemorrhagic stroke, a potentially fatal type of stroke in which an artery in the brain leaks or ruptures.

Diabetes

Individuals with diabetes tend to have high triglyceride and low HDL levels. Omega-3 fatty acids from fish oil can help lower triglycerides and apoproteins (markers of diabetes), and raise HDL, so people with diabetes may benefit from eating foods or taking supplements that contain DHA and EPA. ALA (from flaxseed, for example) may not have the same benefit as DHA and EPA because some people with diabetes lack the ability to efficiently convert ALA to a form of omega-3 fatty acids that the body can use readily. There have been slight increases reported in fasting blood sugar levels in patients with type 2 diabetes while taking fish oil supplements.

Weight loss

Many individuals who are overweight suffer from poor blood sugar control, diabetes, and high cholesterol. Clinical studies suggest that overweight people who follow a weight loss program that includes exercise tend to achieve better control over their blood sugar and cholesterol levels when fish rich in omega-3 fatty acids (such as salmon, mackerel, and herring) is a staple in their low-fat diet.

Arthritis

Most clinical studies investigating the use of omega-3 fatty acid supplements for inflammatory joint conditions have focused almost entirely on rheumatoid arthritis. Several articles reviewing the research in this area conclude that omega-3 fatty acid supplements reduce tenderness in joints, decrease morning stiffness, and allow for a reduction in the amount of medication needed for people with rheumatoid arthritis.

In addition, laboratory studies suggest that diets rich in omega-3 fatty acids (and low in the inflammatory omega-6 fatty acids) may benefit people with other inflammatory disorders, such as osteoarthritis. In fact, several test tube studies of cartilage-containing cells have found that omega-3 fatty acids decrease inflammation and reduce the activity of enzymes that destroy cartilage. Similarly, New Zealand green lipped mussel (Perna canaliculus), another potential source of omega-3 fatty acids, has been reported to reduce joint stiffness and pain, increase grip strength, and enhance walking pace in a small group of people with osteoarthritis. In some participants, symptoms worsened before they improved.

An analysis was conducted of 17 randomized, controlled clinical trials assessing the pain relieving effects of omega-3 fatty acid supplementation in patients with rheumatoid arthritis or joint pain caused by inflammatory bowel disease (IBS) and painful menstruation (dysmenorrhea). The results suggest that omega-3 fatty acids are effective treatment, along with conventional therapies such as anti-inflammatory drugs, for joint pain associated with rheumatoid arthritis, inflammatory bowel disease, and dysmenorrhea.

Osteoporosis

Clinical studies suggest that omega-3 fatty acids such as EPA help increase levels of calcium in the body, deposit calcium in the bones, and improve bone strength. In addition, studies also suggest that people who are deficient in certain essential fatty acids (particularly EPA and gamma-linolenic acid [GLA], an omega-6 fatty acid) are more likely to suffer from bone loss than those with normal levels of these fatty acids. In a study of women over 65 with osteoporosis, those given EPA and GLA supplements experienced significantly less bone loss over 3 years than those who were given a placebo. Many of these women also experienced an increase in bone density.

Depression

People who do not get enough omega-3 fatty acids or do not maintain a healthy balance of omega-3 to omega-6 fatty acids in their diet may be at an increased risk for depression. The omega-3 fatty acids are important components of nerve cell membranes. They help nerve cells communicate with each other, which is an essential step in maintaining good mental health. In particular, DHA is involved in a variety of nerve cell processes.

Levels of omega-3 fatty acids were found to be measurably low and the ratio of omega-6 to omega-3 fatty acids were particularly high in a clinical study of patients hospitalized for depression. In a clinical study of individuals with depression, those who ate a healthy diet consisting of fatty fish 2 - 3 times per week for 5 years experienced a significant reduction in feelings of depression and hostility.

Bipolar disorder

In a clinical study of 30 people with bipolar disorder, those who were treated with EPA and DHA (in combination with their usual mood stabilizing medications) for 4 months experienced fewer mood swings and recurrence of either depression or mania than those who received placebo. Another 4-month long clinical study treating individuals with bipolar depression and rapid cycling bipolar disorder did not find evidence of efficacy for the use of in EPA in these patients.

Schizophrenia

Preliminary clinical evidence suggests that people with schizophrenia experience an improvement in symptoms when given omega-3 fatty acids. However, a recent well-designed study concluded that EPA supplements are no better than placebo in improving symptoms of this condition. The conflicting results suggest that more research is needed before conclusions can be drawn about the benefit of omega-3 fatty acids for schizophrenia. Similar to diabetes, individuals with schizophrenia may not be able to convert ALA to EPA or DHA efficiently.

Attention deficit/hyperactivity disorder (ADHD)

Children with attention deficit/hyperactivity disorder (ADHD) may have low levels of certain essential fatty acids (including EPA and DHA) in their bodies. In a clinical study of nearly 100 boys, those with lower levels of omega-3 fatty acids demonstrated more learning and behavioral problems (such as temper tantrums and sleep disturbances) than boys with normal omega-3 fatty acid levels. In animal studies, low levels of omega-3 fatty acids have been shown to lower the concentration of certain brain chemicals (such as dopamine and serotonin) related to attention and motivation. Clinical studies that examine the ability of omega-3 supplements to improve symptoms of ADHD are still needed. At this point in time, eating foods high in omega-3 fatty acids is a reasonable approach for someone with ADHD. A clinical study used omega-3 and omega-6 fatty acid supplementation in 117 children with ADHD. They study found significant improvements in reading, spelling, and behavior in the children over the 3 months of therapy. Another clinical study found that omega-3 fatty acid supplementation helped to decrease physical aggression in school children with ADHD. More studies, including comparisons with drug therapies (such as stimulants), should be performed.

Eating disorders

Clinical studies suggest that men and women with anorexia nervosa have lower than optimal levels of polyunsaturated fatty acids (including ALA and GLA). To prevent the complications associated with essential fatty acid deficiencies, some experts recommend that treatment programs for anorexia nervosa include PUFA-rich foods such as fish and organ meats (which include omega-6 fatty acids).

Burns

Essential fatty acids have been used to reduce inflammation and promote wound healing in burn victims. Animal research indicates that omega-3 fatty acids help promote a healthy balance of proteins in the body -- protein balance is important for recovery after sustaining a burn. Further research is necessary to determine whether omega-3s benefit people in the same way.

Skin disorders

In one clinical study, 13 people with a particular sensitivity to the sun known as photo dermatitis showed significantly less sensitivity to UV rays after taking fish oil supplements. Still, research indicates that topical sunscreens are much better at protecting the skin from damaging effects of the sun than omega-3 fatty acids. In another study of 40 people with psoriasis, those who were treated with medications and EPA supplements did better than those treated with the medications alone. In addition, many clinicians believe that flaxseed (which contains omega-3 fatty acids) is helpful for treating acne.

Inflammatory bowel disease (IBD)

When added to medication, such as sulfasalazine (a standard medication for IBD), omega-3 fatty acids may reduce symptoms of Crohn's disease and ulcerative colitis -- the 2 types of IBD. More studies to investigate this preliminary finding are under way. In animals, it appears that ALA works better at decreasing bowel inflammation than EPA and DHA. Plus, fish oil supplements can cause side effects that are similar to symptoms of IBD (such as flatulence, belching, bloating, and diarrhea).

Asthma

Clinical research suggests that omega-3 fatty acid supplements (in the form of perilla seed oil, which is rich in ALA) may decrease inflammation and improve lung function in adults with asthma. Omega-6 fatty acids have the opposite effect: they tend to increase inflammation and worsen respiratory function. In a small, well-designed clinical study of 29 children with asthma, those who took fish oil supplements rich in EPA and DHA for 10 months had improvement in their symptoms compared to children who took a placebo pill.

Macular Degeneration

A questionnaire administered to more than 3,000 people over the age of 49 found that those who consumed more fish in their diet were less likely to have macular degeneration (a serious age-related eye condition that can progress to blindness) than those who consumed less fish. Similarly, a clinical study comparing 350 people with macular degeneration to 500 without the eye disease found that those with a healthy dietary balance of omega-3 and omega-6 fatty acids and higher intake of fish in their diets were less likely to have this particular eye disorder. Another larger clinical study confirms that EPA and DHA from fish, 4 or more times per week, may reduce the risk of developing macular degeneration. Notably, however, this same study suggests that ALA may actually increase the risk of this eye condition.

Menstrual pain

In a clinical study of nearly 200 Danish women, those with the highest dietary intake of omega-3 fatty acids had the mildest symptoms, such as hot flashes and increased sweating, during menstruation.

Colon cancer

Consuming significant amounts of foods rich in omega-3 fatty acids appears to reduce the risk of colorectal cancer. For example, Eskimos, who tend to follow a high-fat diet but eat significant amounts of fish rich in omega-3 fatty acids, have a low rate of colorectal cancer. Animal studies and laboratory studies have found that omega-3 fatty acids prevent worsening of colon cancer while omega-6 fatty acids promote the growth of colon tumors. Daily consumption of EPA and DHA also appeared to slow or even reverse the progression of colon cancer in people with early stages of the disease.

Clinical studies have reported that low levels of omega-3 fatty acids in the body are a marker for an increased risk of colon cancer.

However, in an animal study of rats with metastatic colon cancer (in other words, cancer that has spread to other parts of the body such as the liver), omega-3 fatty acids actually promoted the growth of cancer cells in the liver. Until more information is available, it is best for people with advanced stages of colorectal cancer to avoid omega-3 fatty acid supplements and diets rich in this substance.

Breast cancer

Although not all experts agree, women who regularly consume foods rich in omega-3 fatty acids over many years may be less likely to develop breast cancer. In addition, the risk of dying from breast cancer may be significantly less for those who eat large quantities of omega-3 from fish and brown kelp seaweed (common in Japan). This is particularly true among women who substitute fish for meat. The balance between omega-3 and omega-6 fatty acids appears to play an important role in the development and growth of breast cancer. Further research is still needed to understand the effect that omega-3 fatty acids may have on the prevention or treatment of breast cancer. For example, researchers speculate that omega-3 fatty acids in combination with other nutrients (namely, vitamin C, vitamin E, beta-carotene, selenium, and coenzyme Q10) may prove to be of particular value for preventing and treating breast cancer.

Prostate cancer

Laboratory and animal studies indicate that omega-3 fatty acids (specifically, DHA and EPA) may inhibit the growth of prostate cancer. Similarly, population based clinical studies of groups of men suggest that a low-fat diet with the addition of omega-3 fatty acids from fish or fish oil help prevent the development of prostate cancer. Like breast cancer, the balance of omega-3 to omega-6 fatty acids appears to be particularly important for reducing the risk of this condition. ALA, however, may not offer the same benefits as EPA and DHA. In fact, one recent clinical study evaluating 67 men with prostate cancer found that they had higher levels of ALA compared to men without prostate cancer. More research in this area is needed.

Other

Although further research is needed, preliminary evidence suggests that omega-3 fatty acids may also prove helpful in protecting against certain infections and treating a variety of conditions, including autism, ulcers, migraine headaches, preterm labor, emphysema, psoriasis, glaucoma, Lyme disease, systemic lupus erythmatosus (lupus), irregular heart beats (arrhythmias), multiple sclerosis, and panic attacks. Omega-3 fatty acid supplementation may also help to reduce stress and the effects it has on the body.

Dietary Sources

Fish, plant, and nut oils are the primary dietary source of omega-3 fatty acids. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in cold-water fish such as salmon, mackerel, halibut, sardines, tuna, and herring. ALA is found in flaxseeds, flaxseed oil, canola (rapeseed) oil, soybeans, soybean oil, pumpkin seeds, pumpkin seed oil, purslane, perilla seed oil, walnuts, and walnut oil. Other sources of omega-3 fatty acids include sea life such as krill and algae.

Available Forms

In addition to the dietary sources described, EPA and DHA can be taken in the form of fish oil capsules. Flaxseed, flaxseed oil, fish and krill oils should be kept refrigerated. Whole flaxseeds must be ground within 24 hours of use, otherwise the ingredients lose their activity. Flaxseeds are also available in ground form in a special mylar package so that the components in the flaxseeds stay active.

Be sure to buy omega-3 fatty acid supplements made by established companies who certify that their products are free of heavy metals such as mercury, lead, and cadmium.

How to Take It

Dosing for fish oil supplements should be based on the amount of EPA and DHA in the product, not on the total amount of fish oil. Supplements vary in the amounts and ratios of EPA and DHA. A common amount of omega-3 fatty acids in fish oil capsules is 0.18 grams (180 mg) of EPA and 0.12 grams (120 mg) of DHA. Five grams of fish oil contains approximately 0.17 - 0.56 grams (170 -560 mg) of EPA and 0.072 - 0.31 grams (72 - 310 mg) of DHA. Different types of fish contain variable amounts of omega-3 fatty acids, and different types of nuts or oil contain variable amounts of a-linolenic acid. Fish oils contain approximately 9 calories per gram of oil.

Children (18 years and younger)

The precise safe and effective doses of all types of omega-3 fatty acid supplements in children have not been established. Omega-3 fatty acids are used in some infant formulas, although effective doses are not clearly established. Ingestion of fresh fish should be limited in young children due to the presence of potentially harmful environmental contaminants, including mercury. Fish oil capsules should not be used in children except under the direction of a health care provider.

Adults

Individuals taking more than 3 grams daily of omega-3 fatty acids from capsules should do so only under the supervision of a health care provider due to an increase risk of bleeding.

For healthy adults with no history of heart disease: The American Heart Association (AHA) recommends eating fish at least 2 times per week.

For adults with coronary heart disease: The American Heart Association (AHA) recommends an omega-3 fatty acid supplement (as fish oils), 1 gram daily of EPA and DHA. It may take 2 - 3 weeks for benefits of fish oil supplements to be seen.

For adults with high cholesterol levels: The American Heart Association (AHA) recommends an omega-3 fatty acid supplement (as fish oils), 2 - 4 grams daily of EPA and DHA. It may take 2 - 3 weeks for benefits of fish oil supplements to be seen.

Precautions

Because of the potential for side effects and interactions with medications, dietary supplements should be taken only under the supervision of a knowledgeable health care provider.

Omega-3 fatty acids should be used cautiously by people who bruise easily, have a bleeding disorder, or take blood-thinning medications, including warfarin (Coumadin) or clopidogrel (Plavix), because excessive amounts of omega-3 fatty acids may lead to bleeding. In fact, people who eat more than three grams of omega-3 fatty acids per day (equivalent to 3 servings of fish per day) may be at an increased risk for hemorrhagic stroke, a potentially fatal condition in which an artery in the brain leaks or ruptures.

Fish oil can cause flatulence, bloating, belching, and diarrhea. Time-release preparations may reduce these side effects, however.

People with either diabetes or schizophrenia may lack the ability to convert alpha-linolenic acid (ALA) to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the forms more readily used in the body. Therefore, people with these conditions should obtain their omega-3 fatty acids from dietary sources rich in EPA and DHA. Also, individuals with type 2 diabetes may experience increases in fasting blood sugar levels while taking fish oil supplements. If you have type 2 diabetes, only use fish oil supplements under the supervision of a health care provider.

Although studies have found that regular consumption of fish (which includes the omega-3 fatty acids EPA and DHA) may reduce the risk of macular degeneration, a recent study including 2 large groups of men and women found that diets rich in ALA may substantially increase the risk of this disease. More research is needed in this area. Until this information becomes available, it is best for people with macular degeneration to obtain omega-3 fatty acids from sources of EPA and DHA, rather than ALA.

Similar to macular degeneration, fish and fish oil may protect against prostate cancer, but ALA may be associated with increased risk of prostate cancer in men. More research in this area is needed.

Fish (and fish oil supplements) may contain potentially harmful contaminants, such as heavy metals (including mercury), dioxins, and polychlorinated biphenyls (PCBs). For sport-caught fish, the U.S. Environmental Protection Agency (EPA) recommends that intake be limited in pregnant or nursing women to a single 6-ounce meal per week, and in young children to less than 2 ounces per week. For farm-raised, imported, or marine fish, the U.S. Food and Drug Administration recommends that pregnant or nursing women and young children avoid eating types with higher levels of mercury (such as mackerel, shark, swordfish, or tilefish), and less than 12 ounces per week of other fish types. Unrefined fish oil preparations may contain pesticides.

Possible Interactions

If you are currently being treated with any of the following medications, you should not use omega-3 fatty acid supplements, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), without first talking to your health care provider.

Blood-thinning medications -- Omega-3 fatty acids may increase the effects of blood thinning medications, including aspirin, warfarin (Coumadin), and clopedigrel (Plavix). While the combination of aspirin and omega-3 fatty acids may actually be helpful under certain circumstances (such as in heart disease), they should only be taken together under the guidance and supervision of a health care provider.

Blood sugar lowering medications -- Taking omega-3 fatty acid supplements may increase fasting blood sugar levels. Use with caution if taking blood sugar lowering medications, such as glipizide (Glucotrol and Glucotrol XL), glyburide (Micronase or Diabeta), glucophage (Metformin), or insulin, as omega-3 fatty acid supplements may increase your need for the medication(s).

Cyclosporine -- Taking omega-3 fatty acids during cyclosporine (Sandimmune) therapy may reduce toxic side effects, such as high blood pressure and kidney damage, associated with this medication in transplant patients.

Etretinate and topical steroids -- The addition of omega-3 fatty acids (specifically EPA) to the drug therapy etretinate (Tegison) and topical corticosteroids may improve symptoms of psoriasis.

Cholesterol-lowering medications -- Following certain nutritional guidelines, including increasing the amount of omega-3 fatty acids in your diet and reducing the omega-6 to omega-3 ratio, may allow a group of cholesterol lowering medications known as "statins", including atorvastatin (Liptor), lovastatin (Mevacor), and simvastatin (Zocor) to work more effectively.

Nonsteroidal anti-inflammatory drugs (NSAIDs) -- In an animal study, treatment with omega-3 fatty acids reduced the risk of ulcers from nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen (Motrin or Advil) and naproxen (Alleve or Naprosyn). More research is needed to evaluate whether omega-3 fatty acids would have the same effects in people.

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Review Date:
5/1/2007
Reviewed By:
Ernest B. Hawkins, MS, BSPharm, RPh, Health Education Resources; and Steven D. Ehrlich, N.M.D., private practice specializing in complementary and alternative medicine, Phoenix, AZ. Review provided by VeriMed Healthcare Network.

A.D.A.M. Copyright

adam.com

Uterine fibroids and hysterectomy

FitSugar — Wed, 08 Oct 2008 17:35:01 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Complications
Diagnosis
Lifestyle Changes
Medications
Surgery
Other Procedures
Hysterectomy
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Uterine Artery Embolization Versus Standard Surgery

Many women with fibroids are considering a procedure called uterine artery embolization (UAE) as an alternative to standard surgery such as hysterectomy or myomectomy. A study published in 2007 in the New England Journal of Medicine compared these treatment approaches. The study suggested that UAE results in shorter hospital stay and faster recovery time, but a small percentage of women may later need repeat embolization or a hysterectomy. There were similar improvements in quality of life regardless of whether a woman had UAE or standard surgery.

Magnetic-Resonance Guided Focused Ultrasound (MRgFUS)

MRgFUS is a new non-surgical approach for treating fibroids. A 2006 study in Obstetrics and Gynecology indicated that taking gonadotropin-releasing hormone (GnRH) agonist drugs before this procedure may help reduce fibroid volume and improve outcomes.

Predictors of Hysterectomy

Combined factors can predict whether a woman will decide to have a hysterectomy, according to a 2007 study published in the Journal of the American College of Surgeons. Women who met all three criteria had a 95% chance of having a hysterectomy:

Presence of symptoms (pelvic pain, bleeding, symptomatic fibroids)
Lack of symptom improvement despite treatment
Previous use of GnRH agonist drugs

Hysterectomy and Sexual Function

Women who have both their uterus and cervix removed (total hysterectomy) are no more likely to experience sexual problems than women who have only their uterus removed (subtotal hysterectomy), suggests a 2006 review in the Cochrane Database. The review also found no differences between total and subtotal hysterectomy for urinary and bowel problems. However, women who had subtotal hysterectomy were more likely to experience cyclical bleeding during the year after surgery than women who had a total hysterectomy.

Hormone Replacement Therapy (HRT) and Breast Cancer Risk

Estrogen-only HRT after hysterectomy does not appear to increase breast cancer risk when used in the short term (up to 20 years), according to several 2006 studies. Combination estrogen-progestin HRT does increase breast cancer risk.

Introduction

A uterine fibroid (known medically as a leiomyoma or myoma ) is a noncancerous (benign) growth composed of smooth muscle and connective tissue. The size of a fibroid varies from that of a pinhead to larger than a melon. Fibroids have been reported weighing more than 20 pounds.

Fibroids originate from the thick wall of the uterus and are categorized by the direction in which they grow:

Intramural fibroids grow within the middle and thickest layer of the uterus (called the myometrium). They are the most common fibroids.
Subserosal fibroids grow out from the thin outer fibrous layer of the uterus (called the serosa). Subserosal can be either stalk-like (pedunculated) or broad-based (sessile). These are the second most common fibroids.
Submucous fibroids grow from the uterine wall toward and into the inner lining of the uterus (the endometrium). Submucous fibroids can also be stalk-like or broad-based. Only about 5% of fibroids are submucous.

Fibroid tumors may not need to be removed if they are not causing pain, bleeding excessively, or growing rapidly.

The Primary Organs and Structures in the Reproductive System. The primary structures in the reproductive system are as follows:

The uterus is a pear-shaped organ located between the bladder and lower intestine. It consists of two parts, the body and the cervix.
When a woman is not pregnant the body of the uterus is about the size of a fist, with its walls collapsed and flattened against each other. During pregnancy the walls of the uterus are pushed apart as the fetus grows.
The cervix is the lower portion of the uterus. It has a canal opening into the vagina with an opening called the os, which allows menstrual blood to flow out of the uterus into the vagina.
Leading off each side of the body of the uterus are two tubes known as the fallopian tubes. Near the end of each tube is an ovary.
Ovaries are egg-producing organs that hold 200,000 - 400,000 follicles (from folliculus, meaning "sack" in Latin). These cellular sacks contain the materials needed to produce ripened eggs, or ova.

The inner lining of the uterus is called the endometrium. During pregnancy this inner lining thickens and becomes enriched with blood vessels to house and support the growing fetus. If pregnancy does not occur, the endometrium is shed as part of the menstrual flow. Menstrual flow also consists of blood and mucus from the cervix and vagina.

Reproductive Hormones. The hypothalamus (an area in the brain) and the pituitary gland regulate the reproductive hormones. The pituitary gland is often referred to as the master gland because of its important role in many vital functions, many of which require hormones.

In women, six key hormones serve as chemical messengers that regulate the reproductive system:

The hypothalamus first releases the gonadotropin-releasing hormone (GnRH).
This chemical, in turn, stimulates the pituitary gland to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Estrogen, progesterone, and the male hormone testosterone are secreted by the ovaries at the command of FSH and LH and complete the hormonal group necessary for reproductive health.

Click the icon to see an image of the uterus.

Click the icon to see an image of the pituitary gland.

Click the icon to see an image of the hypothalamus.

Causes

Inherited genetic factors may be important in many cases of fibroids. Researchers are investigating unique genetic factors that regulate hormones. Proteins called growth factors may be responsible for some of the abnormalities leading to uterine muscle overgrowth and fibroids. Scientists have identified chromosomes carrying a total of 145 genes that may affect fibroid growth. Some experts report that uterine fibroids are inherited from paternal (the father's) genes.

Uterine fibroids often grow during pregnancy, and they degenerate after menopause. From these observations and certain studies researchers are fairly certain that the female hormones, both estrogen and progesterone, play a role in their growth. Their role, however, is not clear. Some theories about the relationship to fibroids and estrogen include the following:

Estrogen patterns in fibroids are similar to those in pregnancy. That is, like smooth muscle cells in the uterus during pregnancy, fibroid cells exposed to female hormones do not respond normally to signals that would make them self-destruct and return to a nonpregnant state. (This natural self-destruction is a process called apoptosis). Instead, they continue to grow.
Some evidence suggests that estrogen may inhibit a tumor-suppressor gene called p53 in fibroid tissue, therefore triggering cell proliferation leading to fibroid growth. (P53 plays a role in some cancer-cell growth, although in this case the process is not cancerous.)

The formation of fibroids may be attributable to abnormalities in substances called growth factors. These are special proteins, secreted by different cell types, that are responsible for cell-to-cell interaction. Many of these substances regulate a process called angiogenesis, which causes new blood vessels to sprout from pre-existing ones. The production of new blood vessels then feeds any existing growth, such as fibroids.

The growth factors that appear to play an important role in many female reproductive disorders are Basic Fibroblast Growth Factor (BFGF) and Vascular Endothelial Growth Factor (VEGF). BFGFs are involved in the proliferation of cells that form connective tissue, which supports the body's organs and structure. VEGFs are involved with cell growth in smooth muscles that line blood vessels. Some evidence suggests they play a role in uterine fibroids.

Other growth factors being studied specifically for fibroids include Insulin-like Growth Factor (IGF)-I, Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF), and Transforming Growth Factor (TGF).

Symptoms

Fewer than 25% of patients with fibroids experience symptoms. When they do, they include:

The most common symptom is prolonged and heavy bleeding during menstruation. This is caused by fibroid growth bordering the uterine cavity. In severe cases, heavy bleeding may last as many as 2 weeks. Fibroids rarely bleed between periods, except in a few cases of very large fibroids.
Large fibroids can also cause pressure and pain in the abdomen or lower back that sometimes feels like menstrual cramps.
As the fibroids grow larger, some women feel them as hard lumps in the lower abdomen.
Very large fibroids may give the abdomen the appearance of pregnancy and cause a feeling of heaviness and pressure. In fact, large fibroids are defined by comparing the size of the uterus to the size it would be at specific months during gestation.
Unusually large fibroids may press against the bladder and urinary tract and cause frequent urination or the urge to urinate, particularly during the night when a woman is lying down.
Abnormal pain during intercourse (called dyspareunia).
If the fibroids press on the ureters (the tubes going from the kidneys to the bladder), obstruction or blockage of urine may result.
Fibroid pressure against the rectum can cause constipation.

Risk Factors

Uterine fibroids are the most common tumor found in female reproductive organs. It is estimated that over 50% of women age 30 - 50 have fibroids, although they cause symptoms in only about 25%. A survey of 1,364 women suggested an even higher prevalence of over 80% in African-American women and almost 70% in white women. A number of possible risk factors have been identified, but very little research exists to confirm them.

Uterine fibroids are particularly common in African-American women, with an estimated prevalence of 50 - 75%. These women are also more likely to have severe pain, anemia, and larger and more numerous fibroids than women in other population groups. Although genetics may play a role, women of African descent who live in other countries do not appear to have as high an incidence of fibroids. This suggests that diet or other environmental factors are at work in the development of fibroids in African-American women.

Fibroids can start to grow soon after puberty, although usually they are detected when a woman reaches young adulthood. Women with fibroids are at risk for accelerated fibroid growth when estrogen levels are high or when lifestyle behaviors keep estrogen levels high.

Some examples of risk factors for fibroids that are also associated with high estrogen exposure include:

Early onset of menstrual period (before age 12)
Being overweight and sedentary
Never being pregnant. The risk for fibroids decreases with more children. (This risk factor, however, may be due to a greater risk for infertility caused by fibroids in the first place.)

Combined Oral Contraceptives. Combined oral contraceptives contain estrogen and progesterone and the evidence on their effects on fibroids have been conflicting. Early reports suggested they might be a risk factor. Most studies conducted more recently, however, have found no association and some even suggest that the newer low-dose OC combinations may be protective.

Hormone Replacement Therapy. Hormone replacement therapies (HRT) contain estrogen alone or estrogen plus progesterone. After menopause, fibroids usually shrink. Researchers are investigating whether the hormones used in HRT could cause existing fibroids to persist or even grow. Some studies, but not all, have found greater fibroid growth with the use of patch-administered hormone drugs. (In one of the studies, taking oral estrogen, however, had no effect.) A 2001 systematic review of studies reported some fibroid growth in women taking HRT, but usually without any significant symptoms.

If HRT has an effect on fibroid growth, it is unlikely to be severe. Any increase in fibroid growth during menopause must be evaluated surgically by a gynecologist since such growth, even if a woman is on hormone replacement therapy, may mean cancer.

High blood pressure (hypertension) may be associated with increased fibroid risk according to a 2005 epidemiologic study. The prospective study tracked women in the Nurses’ Health Study for 10 years and found that for every 10 mm/Hg increase in diastolic blood pressure, the risk for developing fibroids increased by 8 - 10%. (Interestingly, women who used antihypertensive medications had the highest risk.). Researchers reported that women with hypertension were 24% more likely to develop fibroids and that the longer a woman had hypertension, the greater her risk.

Complications

Effect on Fertility. The effect of fibroids on fertility is controversial. A 2002 analysis suggested that they may account for infertility in only 1 - 2.4% of women who have trouble conceiving. Large fibroids may cause infertility by:

Impairing the uterine lining
Blocking the fallopian tubes
Distorting the shape of the uterine cavity
Altering the position of the cervix and preventing sperm from reaching the uterus

Some evidence suggests that even small fibroids may reduce the chances of pregnancy in women who are undergoing assisted reproductive techniques. Treatments to reduce fibroids may be helpful in such women, although there has been little research on this subject.

Effect on Pregnancy.Fibroids can increase pregnancy complications and delivery risks. These include:

Cesarean section delivery
Breech presentation (baby enters the birth canal upside down with feet or buttocks emerging first)
Preterm birth
Placenta previa (placenta covers the cervix)
Excessive bleeding after giving birth (postpartum hemorrhage)

A 2006 study found that pregnant women with at least one fibroid had the following increased risks: cesarean delivery (57%), breech birth (64%), preterm delivery (45%), placenta previa (86%), and postpartum hemorrhage (157%).

Anemia due to iron deficiency can develop if fibroids cause excessive bleeding. Oddly enough, smaller fibroids, usually submucous, are more likely to cause abnormally heavy bleeding than larger ones.

Most cases of anemia are mild. Mild anemia can cause weakness and fatigue. Moderate-to-severe anemia can cause shortness of breath, rapid heart rate, lightheadedness, headaches, ringing in the ears (tinnitus), irritability, pale skin, restless legs syndrome, and mental confusion. Heart problems can occur if prolonged and severe anemia is not treated. Pregnant women who are anemic, particularly in the first trimester, have an increased risk for a poor pregnancy outcome.

Large fibroids that press against the bladder occasionally result in urinary tract infections. Pressure on the ureters may cause urinary obstruction and kidney damage.

The female and male urinary tracts are relatively the same except for the length of the urethra.

Fibroids can cause cramping during a period, which can be quite intense at times.

Pain can also develop if the blood supply is cut off from the fibroid tissue. In such cases, the cells blacken and die (a process called necrosis) from lack of oxygen. This event may occur under the following circumstances:

A very large fibroid outgrows its own blood supply.
A pedunculated fibroid (one that grows on a stem from the uterine wall) becomes twisted, thus cutting off its blood supply.
Pregnancy occurs, in which the risk for fibroid cell degeneration and necrosis increases.

Rarely, a fibroid breaks away from the uterus and develops in other locations. They are typically one of the following:

Benign Metastasizing Leiomyoma or BML (which usually spreads to the lung)
Disseminated Peritoneal Leiomyomatosis (which spreads to the abdominal wall)

Neither is cancerous, although there is some evidence that BML, which often occurs after menopause, may represent a slow-growing variant of leiomyosarcoma.

Fibroids are nearly always noncancerous, even if they have abnormal cell shapes. Cancer of the uterus nearly always develops in the lining of the uterus (endometrial cancer). Only in rare cases (less than 0.1%) does cancer develop from a malignant change in a fibroid (called leiomyosarcoma). Nevertheless, rapidly enlarging fibroids in a premenopausal woman or even slowly enlarging fibroids in a postmenopausal woman require surgical evaluation to rule out cancer.

Click the icon to see an image of uterine cancer.

Diagnosis

A doctor will perform a pelvic examination to check for pregnancy-related conditions and signs of fibroids or other abnormalities, such as ovarian cysts.

The doctor needs to have a complete history of any medical or personal conditions that might be causing heavy bleeding:

Any family history of menstrual problems or bleeding disorders.
The presence or history of any medical conditions that might be causing heavy bleeding. Women who visit their gynecologist with menstrual complaints, particularly heavy bleeding, pelvic pain, or both may actually have an underlying medical disorder, which must be ruled out.
The pattern of the menstrual bleeding. (If it occurs during regular menstruation, nonhormonal treatments are tried first. If bleeding is irregular, occurs between periods, with premenstrual pain, after sex, or is associated with pelvic pain, the doctor should look for specific conditions that may cause these problems.)
Regular use of any medications (including vitamins and over-the-counter drugs).
Diet history, including caffeine and alcohol intake.
Past or present contraceptive use.
Any recent stressful events.
Sexual history. (It is very important that the patient trust the doctor enough to describe any sexual activity that might be risky.)

Almost all women, at some time in their reproductive life, experience heavy bleeding during menstrual periods ( menorrhagia ). Being taller, older, and having a higher number of pregnancies increase the chances for heavier-than-average bleeding. In some cases the cause of heavy bleeding is unknown, but a number of conditions can cause menorrhagia or contribute to the risk:

Miscarriage. An isolated instance of heavy bleeding usually after the period due date may be due to a miscarriage. If the bleeding occurs at the usual time of menstruation, however, miscarriage is less likely to be a cause.
Having late periods or approaching menopause. These events may cause occasional menorrhagia.
Uterine polyps. (These are small benign growths in the uterus.)
Certain contraceptives. (Oral contraceptives or an intrauterine device, an IUD.)

The intrauterine device (IUD) shown uses copper as the active contraceptive; others use progesterone in a plastic device. IUDs are very effective at preventing pregnancy (less than 2% chance per year for the progesterone IUD, less than 1% chance per year for the copper IUD). IUDs come with an increased risk of ectopic pregnancy and perforation of the uterus, and do not protect against sexually transmitted disease. IUDs are prescribed and placed in the uterus by a health care provider.

Bleeding disorders. Bleeding disorders that impair blood clotting can cause heavy menstrual bleeding and, according to different studies, have been associated with between 10 - 17% of menorrhagia cases. Von Willebrand disease, a genetic condition, is the most common of these bleeding disorders. Most, but not all, studies report this problem to be more common in African-American than Caucasian women. Most bleeding disorders have a genetic basis and should be suspected in adolescent girls who experience heavy bleeding.
Uterine cancer.
Pelvic infections.
Endometriosis. (These are small implants of uterine tissue. They are more likely to cause pain than bleeding.)

Click the icon to see an image of endometriosis.

Adenomyosis. This condition occurs when glands from the uterine lining become embedded in the uterine muscle. Its symptoms are nearly identical to fibroids (heavy bleeding and pain), and in one study fibroids were also present in 62% of cases. It is most likely to develop in middle-aged women who have had many children.
A number of medical conditions, including thyroid problems, systemic lupus erythematosus, diabetes, certain cancers and chemotherapies, and some uncommon blood disorder.
Certain drugs, including anticoagulants and anti-inflammatory medications.
In many cases, the cause of heavy bleeding is unknown.

Hysteroscopy is a procedure that may be used to detect the presence of fibroids, polyps, or other causes of bleeding. Although less invasive procedures can also detect causes of abnormal uterine bleeding, hysteroscopy has the added advantage of serving as a surgical procedure for the removal of submucous fibroids. It is also quite useful in ruling out cancer. If cancer is suspected, more invasive procedures, such as dilation and curettage (D&C) or endometrial biopsy, are warranted.

It is done in the office setting and requires no incisions. The procedure uses a long flexible or rigid tube called a hysteroscope, which is inserted into the vagina and through the cervix to reach the uterus. A fiber optic light source and a tiny camera in the tube allow the doctor to view the cavity. The uterus is filled with saline or carbon dioxide to inflate the cavity and provide better viewing. This can cause cramping.

Hysteroscopy is non-invasive; however, 30% of women report severe pain with the procedure. The use of an anesthetic spray, such as lidocaine, may be highly effective in preventing pain during this procedure. Other complications include excessive fluid absorption, infection, and uterine perforation.

Ultrasound and Sonohysterography. Ultrasound is the standard imaging technique for evaluating the uterus and ovaries, detecting fibroids, ovarian cysts and tumors, and also obstructions in the urinary tract. It uses sound waves to produce an image of the organs and entails no risk and very little discomfort.

Transvaginal sonohysterography uses ultrasound along with saline infused into the uterus, which enhances the visualization of the uterus. This technique is proving to be more accurate than standard ultrasound in identifying potential problems. Some experts believe it should be the first-line tool for diagnosing heavy bleeding.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) provides a better image of any fibroids that might be causing bleeding. An MRI can help the doctor decide if a woman is a candidate for minimally invasive uterine artery embolization (UAE). Fibroids with low blood flow (“nonviable tumors”) may not be suitable for UAE. An MRI may also be better than an ultrasound for evaluating uterine size and fibroid location.

When heavy or abnormal bleeding occurs, an endometrial (uterine) biopsy can be performed in the office along with an ultrasound. It is usually used with a procedure called dilation and curettage (D&C), which is particularly important to rule out uterine (endometrial) cancer. A D&C is a somewhat invasive procedure:

A D&C is usually done in an outpatient setting so that the patient can return home the same day, but it sometimes requires a general anesthetic. It may need to be performed in the operating room to rule out serious conditions or treat some minor ones that may be causing the bleeding.
The cervix (the neck of the uterus) is dilated (opened).
The surgeon scrapes the inside lining of the uterus and cervix.

Click the icon to see an image of a D&C.

The procedure is used to take samples of the tissue and to relieve heavy bleeding in some instances. D&C can also be effective in scraping off small endometrial polyps, but it is not very useful for most fibroids, which tend to be larger and more firmly attached.

Lifestyle Changes

Because fibroids are almost never life-threatening, watchful waiting is a reasonable option for many women (even those with large fibroids), particularly if they are approaching menopause.

Any woman who chooses watchful waiting should be sure other causes of heavy bleeding have been ruled out. She should also have regular pelvic examinations and ultrasounds performed to monitor the growth of the fibroid.

Foods for Maintaining Healthy Iron Stores. The following are some suggestions for increasing iron levels in the diet:

The best foods for increasing or maintaining healthy iron levels contain absorbable iron, called heme iron. Such foods include (in order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
About 60% of iron in meat is poorly absorbed; this is a form called non-heme iron. Eggs, dairy products, and vegetables that contain iron only have the non-heme form. Such plants include dried beans and peas, iron-fortified cereals, bread, and pasta products, dark green leafy vegetables (chard, spinach, mustard greens, kale), dried fruits, nuts, and seeds.
Increasing intake of vitamin-C rich foods can enhance absorption of non-heme iron during a single meal, although regular intake of vitamin C does not appear to have any significant effect on iron stores. In any case, vitamin-C rich foods are healthy and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries. One orange or 6 ounces of orange juice can double the amount of iron your body absorbs from plant foods.

Like most vitamins, vitamin C may be obtained in the recommended amount with a well-balanced diet, including some enriched or fortified foods.

Foods containing riboflavin (vitamin B2) may help enhance the response of hemoglobin to iron. Sources include liver, dried fortified cereals, and yogurt.
Cooking in cast iron pans and skillets is known to increase iron content of food. According to one study, however, boiling, steaming, or stir-frying many vegetables in utensils composed of any material significantly increases the release of iron stored in plants so it is available to the body.
Certain nutrients, such as tannin (found in tea) or phytic acid (found in foods such as seeds and bran) interfere with the body's absorption of dietary iron. (It is commonly believed that fiber impedes iron absorption, but researchers report that it most likely has no effect.)

Sources of Vitamins B12 and Folate. Vitamins B12 and folate are important for prevention of anemia related to nutritional deficiencies. Although this anemia is not necessarily related to fibroids, these vitamins are very important for good health in general and for reproductive health in women.

The only natural dietary sources of B12 are animal products such as meats, dairy products, eggs, and fish (clams and oily fish are very high in B12). Like other B vitamins, B12 is added to commercial dried cereals. The recommended daily allowance (RDA) is 2.4 mcg a day. Deficiencies are rare in young people, although the elderly may have trouble absorbing natural vitamin B12 and require synthetic forms from supplements and fortified foods.

Click the icon to see an image of vitamin B12 sources.

Folate is best found in avocado, bananas, orange juice, cold cereal, asparagus, fruits, green, leafy vegetables, dried beans and peas, and yeast. The synthetic form, folic acid, is added to commercial grain products. Vitamins are usually made from folic acid, which is about twice as strong as folate. Many experts recommend that adults have 400 mcg of folic acid daily, which is considerably higher than standard recommendations of 400 mcg of folate. Low levels of folate during pregnancy are common without supplements; deficiencies at that time increase the risk of neural tube defects in newborns. Women who are planning to get pregnant should take 400 mcg of folic acid before conception as well as when they are pregnant or breast feeding.

Click the icon to see an image of folate sources.

Iron Supplements. Iron supplements are best for restoring iron levels, but they should be used only when dietary measures have failed. Women should always discuss such supplements with their doctor.

See In-Depth Report #57: Anemia.]

Many women with menstrual disorders may resort to alternative treatments. There has been little research on whether any such therapies benefit fibroids.

Acupuncture. Some women report relief from pelvic pain and heaviness after acupuncture

Click the icon to see an image of acupuncture.

Yoga. Yoga exercises help some women relieve sensations of heaviness and pressure.

Herbal Remedies. Herbal remedies used for fibroids include ginseng or herbal combinations of rhubarb, cinnamon, and sargassum seaweed. There is no scientific evidence that these herbs are effective. Pycnogenol is a plant extract from the bark of the French maritime tree. Studies suggest it may provide some relief for menstrual pain (dysmenorrhea).

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Patients should check with their doctor before using any herbal remedies or dietary supplements.

Medications

Because fibroid growth tends to stop and regress after menopause, the important reproductive hormones -- estrogen, progesterone, or both -- most likely play a critical role in their survival. Some drugs that block either of these hormones are used to treat severe fibroids with some success.

Oral contraceptives (OCs) are sometimes used to control the heavy menstrual bleeding (menorrhagia) associated with fibroids, but they do not help prevent fibroid growth. Newer types of continuous-dosing OCs, such as Seasonique, reduce the number of periods a woman has per year. In May 2007, the FDA approved Lybrel, a continuous-dosing OC that completely eliminates periods.

Intrauterine devices (IUDs) that release progestin can be very beneficial for menorrhagia. Specifically, the levonorgestrel-releasing intrauterine system, or LNG-IUS (Mirena, FibroPlant), has shown excellent results. Many experts now recommend the LNG-IUS as a first-line treatment for menorrhagia, particularly for women who may face hysterectomy (removal of uterus), conservative surgery such as endometrial resection (removal of endometrial lining), or endometrial ablation (destruction of endometrial lining). [See In-Depth Report #100: Menstrual disorders.]

Gonadotropin releasing hormone (GnRH) blocks the release of the reproductive hormones LH (luteinizing hormone) and FSH (follicular-stimulating hormone). As a result, the ovaries stop ovulating and no longer produce estrogen. GnRH agonists include goserelin (Zoladex), buserelin, a monthly injection of leuprolide (depot Lupron), and nafarelin (Synarel), a nasal spray. Such drugs may be used alone or in preparation for procedures used to destroy the uterine lining.

These drugs may be used in the following situations:

As preoperative treatment 3 - 4 months before uterine surgery. In a major analysis, the use of GnRH agonists reduced fibroid size and uterus volume, helped correct any existing anemia due to blood loss, reduced blood loss during surgery, and reduced the duration of hospital stay. (Some experts question, however, whether the benefits outweigh the costs.)
For women with fibroids nearing menopause. (Such women only need them for a short period.)
Possibly helpful in improving subsequent fertility. (However, women should not try to become pregnant while taking these drugs, as they pose a risk for birth defects.)

While GnRH agonists can reduce fibroids by between 30 - 90% of original size, they have certain limitations:

They are not permanent cures, and fibroids regrow after the drugs are discontinued.
They are injected drugs and cannot be taken orally.
They are expensive.
Long-term use of GnRh agonists causes bone density loss, which can lead to osteoporosis.

Before using these drugs, the doctor should be certain that no other complicating conditions are present, particularly leiomyosarcoma (cancer). The use of these drugs can delay treatment of the malignancy and cause severe complications.

Commonly reported side effects, which can be severe in some women, include menopausal-like symptoms. These symptoms include hot flashes, night sweats, changes in the vagina, weight change, and depression. The side effects vary in intensity, depending on the GnRH agonist. They may be more intense with leuprolide and persist after the drug has been stopped.

The most important concern is possible osteoporosis from estrogen loss. Women should not take these drugs for more than 6 months. Certain approaches may preserve enough estrogen to protect bones and still effectively relieve endometriosis symptoms:

Add-back therapy, which provides doses of estrogen and progestin that are high enough to maintain bone density but too low to offset the beneficial effects of the GnRH agonist.
Intermittent leuprolide, which uses repeated 6-month courses of GnRH agonists followed by an average of 9 months of symptom control only.
Taking GnRH agonists in very low doses is an alternate approach, but is still largely untested.
Adding a bone-protective drug may be helpful. The standard ones are bisphosphonates, which include alendronate (Fosamax), risedronate (Actonel), and etidronate (Didronel). Other drugs are being tested in combination with a GnRH agonist to preserve bone. They include the parathyroid hormone teriparatide (Forteo) and selective estrogen-receptor modulators (SERMs), such as raloxifene (Evista).

GnRH treatments used alone do not prevent pregnancy. Furthermore, if a woman becomes pregnant during their use, there is some risk for birth defects. Women who are taking GnRH agonists should use non-hormonal birth control methods, such as the diaphragm, cervical cap, or condoms while on the treatments.

Danazol (Danocrine) resembles a male hormone. It suppresses estrogen and is effective for heavy menstrual bleeding caused by fibroids. In some women it produces male characteristics, such as facial hair and voice change. Other side effects include weight gain, acne, and dandruff. It may increase the risk for unhealthy cholesterol levels. A few cases of blood clots and strokes have been reported. There is no available long-term experience using danazol for fibroids.

Gestrinone. Antiprogestins are promising drugs for fibroids. Gestrinone has been shown to reduce uterine volume and stop bleeding. In addition, benefits appear to persist. In one study, 89% of the women maintained smaller uterine volume for at least 18 months after stopping the treatment. In another study, bone density even increased slightly. Adverse effects of gestrinone include male hormone symptoms, such as acne, and possibly the development of unhealthy cholesterol levels.

Mifepristone. Mifepristone (Mifeprex) is an anti-progestin that has reduced fibroid size in some studies. In one study, it reduced fibroids as significantly as GnRH agonists, and the fibroids were less likely to recur. However, this medicine can have severe side effects.

Asoprisnil. A promising new antiprogestin called Asoprisnil has been shown to reduce fibroids. The drug is in late-stage clinical trials.

Although they have not been studied for fibroids, nonsteroidal anti-inflammatory drugs (NSAIDs) taken on a regular schedule reduce heavy menstrual bleeding and pain from unknown causes. These drugs reduce inflammation, in part by their action against prostaglandins, the chemicals that stimulate uterine contractions and cause pain. Aspirin is the most common NSAID, but there are dozens of others, including ibuprofen (Advil, Motrin) and naproxen (Aleve, Anaprox, Naprosyn). Both ibuprofen and naproxen are recommended for menstrual pain. However, long-term use of any NSAID can increase the risk for gastrointestinal bleeding and ulcers. In addition, long-term use of high-dose NSAIDs (with the exception of aspirin) can increase the risk for heart attacks and strokes. To reduce these risks, it is best to take the lowest dose of NSAIDs for the shortest time possible.

A number of other drugs are under investigation for treating fibroids:

Selective estrogen-receptor modulators (SERMs) are drugs that have some of the effects of estrogen but do not produce some of its complications, such as a higher risk for uterine cancer. Raloxifene (Evista) is proving to help prevent bone loss in patients taking GnRH agonists for uterine fibroids, and may also be helpful as a single drug for preventing fibroid growth.
Drugs that block growth factors believed to play a role in fibroids are also under investigation. Pirfenidone is one such drug, which blocks fibroid cell reproduction. Another is interferon alpha, substance that inhibits angiogenesis (the growth of new blood vessels).
Drugs derived from retinoids (vitamin A compounds) may inhibit cell proliferation in fibroid tissue.
Fulvestrant (Faslodex) blocks estrogen and has been studied for uterine fibroids and endometriosis, although progress in these areas has stalled in favor of research for its use in breast cancer.

Surgery

If nonsurgical strategies do not relieve symptoms, surgery may be the best option for treatment. Surgery may be indicated depending on a number of factors:

Intractable Side Effects. Surgery may be warranted if fibroids are causing distressing and intractable symptoms that have not been relieved by nonsurgical or minimally invasive therapies. Assuming, however, that symptoms do not pose serious health or life-threatening conditions, a woman should make her decision based on the factors she deems important (the desire for children, for example).

Ureteral Obstruction. Large fibroids sometimes press down on the ureters (the tubes going from each kidney to the bladder), thereby blocking urine from emptying into the bladder. Because ureteral obstructions can permanently damage kidneys, surgery may be indicated.

Inability to Evaluate Ovaries. The risk for missing a diagnosis of ovarian cancer is higher when fibroids are too large to permit evaluation of the ovaries by pelvic examination or ultrasound. Ovarian cancer is particularly deadly because it is so difficult to catch early enough for curative treatment. The risk for this cancer, however, is very low in women without a family history, especially before menopause. Women with a family history of ovarian cancer and large fibroids may need to consider surgery.

Enlarging Fibroids. Rapidly growing fibroids may signify cancer (leiomyosarcoma), which must be ruled out. In postmenopausal women, even slow growth raises suspicions for cancer. However, many hysterectomies have been inappropriately performed because of large noncancerous fibroids that were only suspected to be cancerous. Women should be sure that diagnostic procedures have been as thorough as possible if they want to avoid an unnecessary hysterectomy.

Severe Anemia from Heavy Bleeding. When iron supplementation, resection (surgical removal) of submucous fibroids by hysteroscopy, or GnRH agonist therapy fails to resolve anemia and bleeding, major surgery (myomectomy or hysterectomy) may be recommended.

Hysterectomy. Until recently, hysterectomy was the only surgical option for uterine fibroids. This procedure involves the surgical removal of the uterus and is often accompanied by oophorectomy (the removal of the ovaries). With this procedure, fertility is not preserved. Other options may be available for many women, even those who have large fibroids. Discuss all possibilities with your physician.
Myomectomy. Myomectomy is the surgical removal of only one or more fibroids. Myomectomy usually involves a laparotomy (a procedure that uses a wide abdominal incision) or less invasive surgical techniques, such as laparoscopy and hysteroscopy. In such cases, unlike with hysterectomy, this technique may preserve fertility.
Uterine Artery Embolization (UAE). UAE, also called uterine fibroid embolization (UFE), is a non-surgical radiology procedure. An interventional radiologist injects small plastic particles through a catheter placed in the uterine artery. The particles block the blood supply to the fibroids and cause them to shrink
Other Procedures. Endometrial ablation (destruction of the lining of the uterus) may be useful in women with small fibroids and heavy bleeding. Myolysis is another procedure best suited for women with specific types of small fibroids. Magnetic resonance-guided focused ultrasound (MRgFUS) is the newest type of fibroid procedure. Myolysis and MRgFUS use heat to cut off the blood supply to fibroids.

Women should discuss each option with their doctor. Deciding on the surgical procedure depends on the location, size, and number of fibroids. Certain procedures affect a women’s fertility and are recommended only for women who are past childbearing age or who do not want to become pregnant. The risk for bleeding increases with the surgeon's inexperience, so patients are urged to investigate the surgeon's track record.

A study published in 2007 in the New England Journal of Medicine compared outcomes for uterine artery embolization (UAE) versus standard surgery (hysterectomy or myomectomy). Researchers found that after 1 year, women experienced similar improvements in quality of life regardless of the procedure. Women who had UAE had shorter hospitalizations and faster recovery than those who had standard surgery. However, around 10% of women who had UAE required a repeat procedure (embolization or hysterectomy) during the first year, and another 10% required additional treatment after the first year.

Other Procedures

In order to operate on the uterus, the surgeon may choose to reach the area through a wide abdominal incision (laparotomy) or use less invasive measures with the use of endoscopy. The decision is usually based on the severity of the case. Women should discuss all options very carefully and be sure that their surgeons have had experience with any procedure they choose.

Laparotomy. Laparotomy is the standard abdominal surgical procedure. It is invasive and usually requires a wide abdominal horizontal incision right above the pubic bone, the so-called bikini incision.

Endoscopy. Endoscopic techniques used for uterine disorders are hysteroscopy and laparoscopy. Endoscopic techniques are used increasingly to replace conventional surgical techniques for many disorders. A common factor in all endoscopic procedures is the use of a fiberoptic scope and tubes, tiny camera lenses, and minuscule surgical instruments. Any incisions made are very small, Band-Aid size.

Operative Hysteroscopy. In this procedure, the cervix is dilated, which requires either a local or general anesthetic. A device called a hysteroscopy is inserted up through the vagina and cervix into the uterine cavity. It contains tiny surgical instruments as well as a mini-camera and light source to view images of the uterus, which are transmitted to a video monitor. This approach is becoming increasingly common. Complication rates include excessive fluid absorption, infection, and uterine perforation.
Laparoscopy. This procedure uses two or more small incisions, one at the navel, and one or more in the lower abdomen. Carbon dioxide gas is injected into the abdomen, distending it and pushing the bowel away. A laparoscope is inserted through the navel incision and a probe is inserted through a second incision above the pubic hairline. The probe allows the doctor to directly view the abdominal cavity, including the outer walls of the uterus, fallopian tubes, and ovaries. The doctor manipulates surgical instruments that are passed through additional small abdominal incisions, using the image of the uterus on the video monitor as the guide.

GnRH agonists, usually depo-Lupron or Synarel, are often used for 2 - 3 months before many uterine surgical procedures.

These drugs may help by:

Reducing the volume of fibroids by 40 - 60%, in some cases to the extent that a less invasive procedure may be performed
Reducing the risk of bleeding
Shortening surgical time
Reducing postoperative symptoms

Treatments may not be useful, however, for small fibroids, which may shrink to the point that they are no longer visible at the time of surgery. Since fibroids regrow after treatment, the problem would recur.

There has also been some question whether these drugs provide any additional advantages for myomectomies that use conventional surgical techniques. Ultrasound may be useful in helping to detect fibroids most likely to benefit from GnRH agonists before such a procedure.

A myomectomy surgically removes only the fibroids and leaves the uterus intact, often preserving fertility. Myomectomy may also help regulate abnormal uterine bleeding caused by fibroids. Not all women are candidates for myomectomy. If the fibroids are numerous or large, myomectomy can become complicated, resulting in increased blood loss. If cancer is found, conversion to a full hysterectomy may be necessary.

To perform a myomectomy, the surgeon may use standard surgical approaches (laparotomy) or less invasive ones (hysteroscopy or laparoscopy).

Laparotomy. Laparotomy uses a wide abdominal incision and conventional surgery. It is used for subserosal or intramural fibroids that are very large (usually more than 4 inches), that are numerous, or when cancer is suspected. Using this approach, the doctor may be able to feel the fibroids, particularly intramural types, which can be missed during laparoscopy or hysteroscopy. (The doctor can only view the uterine cavity or outside surface with these latter procedures.) After the fibroids are removed, careful reconstruction of the uterine wall is critical in both laparotomy and laparoscopy, so that bleeding and infection do not occur. While complete recovery takes less than a week with laparoscopy and hysteroscopy, recovery from a standard abdominal myomectomy takes as many as 6 - 8 weeks. It also poses a higher risk for scarring and blood loss than with the less invasive procedures, which is a concern for women who want to retain fertility.
Hysteroscopy. A hysteroscopic myomectomy may be used for submucous fibroids found in the uterine cavity. With this procedure, fibroids are removed using an instrument called a hysteroscopic resectoscope, which is passed up into the uterine cavity through the vagina and cervical canal. A wire loop carrying electrical current is then used to shave off the fibroid. In one study, nearly 60% of patients conceived after this procedure. However, it is not appropriate for many women.
Laparoscopy. Women whose uterus is no larger than it would be at a 6-week pregnancy and who have a small number of subserous fibroids may be eligible for treatment with laparoscopy. Laparoscopy requires incisions, but they are much smaller than with laparotomy. As with hysteroscopy, a thin scope is employed that contains surgical and viewing instruments. In centers with extensive experience, laparoscopy has fewer complications, and also shorter recovery time and lower costs than laparotomy. On the other hand, compared to the invasive surgery, laparoscopy has a greater chance for fibroid recurrence (over 16% at 5 years in one study), and a greater danger for a weakened uterine wall, which could threaten pregnancies.

Complications and Postoperative Factors. Any procedure for myomectomy is very complex. To reduce the risk for complication, patients should seek a surgeon experienced in myomectomies. Complications that occur during a myomectomy from any procedure include:

Excessive blood loss (occurs more often with laparotomy)
Uterine weakening and rupture during pregnancy (more of a concern with laparoscopy)
Development of scar tissue called adhesions (more common with laparotomy)
Infection
Damage to the bowel or bladder (more common with laparotomy)

Pregnancies After Myomectomy. Studies suggest that pregnancy can be restored in more than half of women after the procedure. In appropriate candidates, there appears to be no differences in fertility rates and pregnancy complications between laparotomy or laparoscopy. The best candidates for retaining fertility include women with pedunculated and superficial serosal fibroids (stalk-like fibroids that grow out from the uterine surface). Women with deep intramural fibroids are at higher risk for infertility after myomectomy.

Although studies indicate that between 40 - 58% of women become pregnant after myomectomy, only about a quarter of the women carry their babies to term. Women who become pregnant face a higher risk for cesarean section or miscarriage. It is unclear whether laparoscopic myomectomy weakens the uterine walls and poses a higher risk for rupture during pregnancy than laparotomy.

Recurrence of Fibroids and Recurrent Surgeries. The recurrence rate for fibroid growth after myomectomy is high. Between 11 - 26% of patients will have recurring fibroids that are severe enough to need additional treatment. One study suggested that women who had uteruses that were less than the equivalent size of a 12-week pregnancy and women who were overweight had a higher risk for needing repeat surgery.

Uterine Artery Embolization (UAE), also called uterine fibroid embolization (UFE), is a relatively new way of treating fibroids. UAE deprives fibroids of their blood supply, causing them to shrink. UAE is a minimally invasive radiology treatment and is technically a nonsurgical therapy. It is much less invasive than hysterectomy and myomectomy, and involves a shorter recovery time than the other procedures. The patient remains conscious, although sedated, during the procedure, which takes around 60 - 90 minutes.

The procedure is typically performed in the following manner:

The patient receives a sedative to cause drowsiness, and a local anesthetic is applied to the skin around the groin.
An interventional radiologist makes a small quarter-inch incision in the skin and inserts a catheter (a thin tube) into the femoral artery. The femoral artery is a large artery that begins in the lower abdomen and extends down to the thigh. The radiologist then threads the catheter into the uterine artery.
Small plastic particles are injected into the artery. These particles block the blood supply to the tiny arteries that feed fibroid cells, and the tissue eventually dies.
Patients usually stay in the hospital overnight after UAE and are given pain medication. Pelvic cramps are common for the first 24 hours after the procedure.
It takes 1 - 2 weeks for the patient to recover from the procedure and return to work. It may take 2 - 3 months for the fibroids to shrink enough so that symptoms improve.

Effect on Fertility. In general, UAE is considered an option for only those who have completed childbearing. Although UAE may protect fertility in many women, the procedure does pose some risk for ovarian failure and infertility. In 2004, the American College of Obstetricians and Gynecologists issued an opinion statement advising women who wish to have children that it is not yet known how this procedure affects their potential for becoming pregnant. A 2005 British study of 671 women who underwent UAE found that the procedure did not interfere with fertility. The study did find a slight increase in caesarean section delivery.

Complications and Postoperative Effects. UAE has a lower rate of complication than hysterectomy and myomectomy and a shorter hospital stay. Compared to other procedures, women who undergo UAE miss fewer days of work. Serious complications occur in less than 0.5% of cases, and no deaths have been associated with the procedure.

Pain. Abdominal cramps and pelvic pain after the procedure are nearly universal and may be intense. Pain usually begins soon after the procedure and typically plateaus by 6 hours. On-demand painkillers may be required. The pain usually improves each day over the next several days. A low-grade fever is also common in the first week after the procedure.
Fibroid slough. Around 2 – 3% of patients pass small fragments of fibroid tissue during the first few days after UAE. This can cause intense labor-like pain and also increase the risk for infection. Some women may require dilation and curettage (D&C) to make sure that infection does not develop.
Early menopause. Most women who have UAE will continue to have normal menstrual periods. Around 1 – 5% of women, however, experience menopause after the procedure. Menopause is more likely to occur in women over age 45 who undergo UAE.

Success Rates. Studies on uterine artery embolization show high patient satisfaction (over 90%) and low complication rates. A 2003 study reported 83% improvement in heavy bleeding, 77% reduction in menstrual cramps, and 85% improvement in urinary symptoms. Results from the first long-term UAE study, presented at the 2005 annual scientific meeting of the Society of Interventional Radiology, reported that 73% of women experienced symptom relief that lasted for 5 years. The success rate for UAE was comparable to that of myomectomy. A 2006 study reported a success rate of 89% for UAE compared to 100% for hysterectomy.

For around 10 - 20% of women, symptom control fails or fibroids reoccur. Some studies suggest that women with large fibroids are not good candidates for UAE.

In either endometrial ablation or endometrial resection, the entire lining of the uterus (the endometrium) is removed or destroyed. These procedures are useful for women with severe heavy menstrual bleeding, including some with fibroids. They are generally not useful for large fibroids. Standard resection uses an electrosurgical wire loop to surgically remove the lining. With ablation, uterine tissue is usually vaporized using a thin powerful laser beam or high electric voltage. Newer ablation procedures include balloon ablation (ThermaChoice) and techniques that use electric wands, freezing, hot saline, lasers, microwaves, and radiofrequency.

Myolysis, or laparoscopic leiomyoma coagulation, uses either lasers or electrosurgery to heat and coagulate and destroy the fibroid tissue. This approach may prove to be beneficial for women with fibroids that measure a diameter of 10 cm (about 4 inches) or less and that respond to hormone treatments with GnRH agonists.

Myolysis uses a needle or a Nd:YAG laser that rapidly punctures a number of holes in the fibroid, heating and destroying the tissue in various locations. This widespread destruction cuts off the blood supply and shrinks the fibroid over ensuing months. The uterus is left intact, but tissue destruction makes childbearing unlikely.

In one study, myolysis performed either alone or with endometrial resection was successful in avoiding the need for major surgery in 97% of women. Advanced techniques that are performed by surgeons who are highly skilled in the procedure may make it possible to destroy even large intramural fibroids, but further study is required.

In most cases, patients return home the same day and can return to normal activities within a week. There are few side effects. However, as the fibroids degenerate over time, many women report considerable pain.

MRgFUS is a non-invasive procedure that uses high-intensity ultrasound waves to heat and destroy (ablate) uterine fibroids. This “thermal ablation” procedure is performed with a device that combines magnetic resonance imaging (MRI) with ultrasound. The FDA approved this device, the ExAblate 2000 System, in 2004.

During the 3-hour procedure, the patient lies inside an MRI machine. The patient receives a mild sedative to help relax but remains conscious throughout the procedure. The radiologist uses the MRI to target the fibroid tissue and direct the ultrasound beam. The MRI also helps the radiologist monitor the temperature generated by the ultrasound.

MRgFUS is appropriate only for women who have completed childbearing or who do not intend to become pregnant. The procedure cannot treat all types of fibroids. Fibroids that are located near the bowel and bladder, or outside of the imaging area, cannot be treated.

Research presented at the 2005 Radiological Society of North America annual meeting reported that MRgFUS helps improve fibroid symptoms and reduce fibroid size. A 2006 study indicated that the procedure provides symptom relief for up to 1 year. Another 2006 study indicated that pre-treatment with GnRH-agonist drugs before the MRgFUS procedure may help improve outcomes. However, because this procedure is new and long-term results are not yet available, some insurance companies do not pay for this treatment.

Hysterectomy

Hysterectomy, the surgical removal of the uterus, is the second most frequently performed surgery in premenopausal women (Cesarean sections are first). About 600,000 hysterectomies are performed each year in the U.S., which is among the highest rate of all countries. By age 60, about a third of American women have had this procedure. The highest hysterectomy rates are in women age 40 - 44. Women in the southern and midwestern areas of the United States are more likely to have the operation than those in the northeast and west.

A 2007 study suggested that a combination of factors predicts whether a woman will decide to have a hysterectomy. A woman who meets all three of these factors has a 95% chance of having a hysterectomy:

Presence of symptoms (pelvic pain, bleeding, symptomatic fibroids)
Lack of symptom improvement or resolution despite treatment
Previous use of GnRH agonist drugs

The number of procedures has continued to increase, but the rise has slowed substantially in recent years. The percentage of hysterectomies performed because of fibroids, however, has risen significantly. Fibroids now account for 38% of these operations, but the rates vary widely by ethnic group. In a major 2002 government report, 68% of fibroid-related hysterectomies were performed in African-American women, 33% in Caucasians, and 45% among women of other ethnic groups.

Most women are satisfied with the procedure. A major analysis on hysterectomies reported that symptoms related to menstrual problems decline significantly in most women (although none completely disappear for all women). Most women also experience improved quality of life and mood. Women who have a hysterectomy are less likely to experience hot flashes than women who have a natural menopause.

Still, in one study in 70% of cases when doctors recommended hysterectomies, they did not give their patients alternative choices or adequate diagnostic evaluations. Any woman, even one who has reached menopause, uncertain about a recommendation for a hysterectomy for fibroids should certainly seek a second opinion.

Once a decision for a hysterectomy has been made, the patient should discuss with her doctor what will be removed. The common choices are:

Total Hysterectomy (removal of uterus and cervix).
Supracervical Hysterectomy (removal of uterus and preservation of the cervix); performed in about 20 - 25% of cases.
Bilateral Salpingo-Oophorectomy (removal of the fallopian tubes and ovaries); used with either total or supracervical hysterectomy.

Total Hysterectomy. In a total hysterectomy the uterus and cervix are removed, which eliminates the risk of uterine and cervical cancer. (Given technical advances and growing surgical experience, a total hysterectomy may eventually be unnecessary except in special circumstances, such as when cancer is present.)

Supracervical Hysterectomy. In a supracervical hysterectomy (also called subtotal hysterectomy) the uterine body is removed, and the cervix is retained. Retaining the cervix helps support the pelvic floor and may help maintain full sexual sensation, but the risk for cervical cancer remains. Women may experience cyclical bleeding for up to a year after surgery.

Bilateral Oophorectomy. Bilateral oophorectomy is the removal of both ovaries. (When only one ovary is removed, the procedure is called oophorectomy.) Bilateral salpingo-oophorectomy is the removal of both fallopian tubes and ovaries. These procedures may be performed with either total or supracervical hysterectomy. When deciding to remove the ovaries, a woman must be aware of various consequences, both positive and negative.

Oophorectomy helps to reduce the risk for ovarian cancer, by elimination of ovaries, and breast cancer, by causing estrogen loss. Ovarian cancer is very rare, in any case, except in women with a family history of the disease. Even in these women, removal is not 100% preventive. Cancer can still develop from cancer cells that may be present in the lining of the pelvis (the peritoneum).
Removal of the ovaries ceases estrogen and testosterone production, which can increase the risk for menopause-related conditions. These include osteoporosis, heart disease, skin wrinkling, and reduced muscle tone. Estrogen replacement, however, can help offset these problems. Women who have a bilateral oophorectomy and do not receive hormone replacement therapy may experience more severe hot flashes than women who enter menopause naturally.

There is still a further choice, which is whether the hysterectomy should be performed through an incision in the abdomen or through the vagina. A variant of vaginal hysterectomy, called laparoscopic-assisted vaginal hysterectomy (LAVH), is yet another option.

Abdominal Hysterectomy. Abdominal hysterectomy is the most common procedure and is used in over 80% of hysterectomies in African American women and about 60% in Caucasian and other ethnic groups. It is best suited for women with large fibroids, when the ovaries need to be removed, or when cancer or pelvic disease is present. With the abdominal procedure, a wide incision is required to open the abdominal area from which the surgeon removes the uterus. If possible, the incision should cut horizontally across the top of the pubic hairline (the bikini incision). This incision heals faster and is less noticeable than a vertical incision, which is used in more complicated cases. The patient may need to remain in the hospital for 3 - 4 days, and recuperation at home takes about 4 - 6 weeks.

Vaginal Hysterectomy. Vaginal hysterectomy requires only a vaginal incision through which the uterus is removed. This approach is most often performed for small fibroids (although advances in imaging and other techniques may allow it to be used on larger fibroids). At this time, it is used in fewer than 20% of African-American women and slightly under 40% of Caucasians and other groups.

A variation of the vaginal approach is called laparoscopic-assisted vaginal hysterectomy (LAVH). It uses several small abdominal incisions through which the surgeon severs the attachments to the uterus and ovaries. They can then be removed through the vaginal incision, as in the standard approach. Hospital stays may be longer and costs are greater than with standard vaginal hysterectomy. The use of LAVH has risen significantly and is used in over a quarter of vaginal procedures. LAVH is very costly and time consuming, however, and some experts question whether it adds any significant benefits compared to the standard vaginal procedure.

The patient should ask a family member or friend to help out for the first few days at home. The following are some of the precautions and tips for postoperative care:

For a day or two after surgery, the patient is given medications to prevent nausea and painkillers to relieve pain at the incision site.
As soon as the doctor recommends it, usually within a day of the operation, the patient should get up and walk in order to help prevent pneumonia, reduce the risk of blood-clot formation, and speed recovery.
Walking and slow, deep breathing exercises may help to relieve gas pains, which can cause major distress for the first few days.
Coughing can cause pain, which may be reduced by holding a pillow over a surgical abdominal wound or by crossing the legs after vaginal surgery.
Patients are advised not to lift heavy objects, not to douche or take baths, and not to climb stairs or drive for several weeks.
For the first few days after surgery, many women weep frequently and unexpectedly. These mood swings may be due to depression from the loss of reproductive capabilities and from abrupt changes in hormones, particularly if the ovaries have been removed.

The patient should discuss with the doctor when exercise programs more intense than walking can be started. The abdominal muscles are important for supporting the upper body, and recovering strength may take a long time. Even after the wound has healed, the patient may experience an on-going feeling of overall weakness, which can be demoralizing, particularly in women used to physical health. Some women do not feel completely well for as long as a year while others may recover in only a few weeks.

Minor complications after hysterectomy are very common. About half of women develop minor and treatable urinary tract infections. There is usually mild pain and light vaginal bleeding post operation. The infrequent occurrence of severe bleeding or hemorrhaging after vaginal hysterectomy, or laparoscopic-assisted vaginal hysterectomy, may be promptly treated by laparoscopy.

More serious complications, such as those described below, are uncommon, but patients should be aware of their symptoms and call the doctor immediately if they occur.

Among the three procedures, a 2001 study reported that complication rates were 44% for abdominal hysterectomy, 24% for vaginal hysterectomy, and only 2% for LAVH. (LAVH is used in less than 4% of hysterectomies, however.)

Infection. Infection occurs in 10 - 15% of patients, the risk being higher with abdominal than with vaginal surgery. Risk factors for infection include obesity, a longer than normal operative time, and low socioeconomic status. Patients should be aware of any symptoms and call the doctor immediately if they occur. Symptoms of infection include:

Continuing or increasingly severe pain
Fever
Heavy discharge
Bleeding (antibiotics given at the time of surgery help to reduce this risk)

Blood Clots. There is a slight risk for small blood clots, usually in veins of the legs (thrombophlebitis). A sudden swelling or discoloration in the leg can indicate this condition and require immediate medical attention.

Other Serious Complications. Other serious and even life-threatening complications are rare but can include:

Pulmonary embolism (blood clots that travel to the lung).
Surgical injury of the urinary or intestinal tracts.
Abscesses.
Perforation of the bowel.
Fistulas (a passage that bores from an organ to the skin or to another organ).
Dehiscence (opening of the surgical wound).

Long-Term Complications. Women who have had a total hysterectomy are at higher risk for the following long-term complications:

Muscle weakness in the pelvic area.
Prolapse (descent) of the bladder, vagina, and rectum if the muscle's walls are overly weakened; may require further surgery.
Bowel problems if adhesions (extensive scarring) have formed and obstruct the intestines; may require additional surgery.
Shortening of the vagina is a possible complication specific to vaginal hysterectomy. It can cause pain during intercourse.

Such complications are uncommon.

After hysterectomy, women may experience hot flashes, a symptom of menopause, even if they retain their ovaries. However, women who have a hysterectomy are less likely to experience hot flashes than women who have a natural menopause. Surgery may have temporarily blocked blood flow to the ovaries, therefore suppressing estrogen release. If both ovaries have been removed in premenopausal women, the procedure causes premature menopause. Other menopausal symptoms include vaginal dryness and irritation, insomnia, and weight gain.

The most important complications occur in women who have had their ovaries removed. This causes estrogen loss, which places women at risk for osteoporosis (loss of bone density) and a possible increase in risks for heart disease and stroke. A number of drugs are available that can help protect both bones and heart.

Women have typically taken hormone replacement therapy (HRT) after surgery if their ovaries have been removed. HRT can help prevent hot flashes. There have been concerns about HRT-related health risks, including the risk for breast cancer. However, several 2006 studies of postmenopausal women who had hysterectomy indicated that estrogen-only HRT does not increase the risk for breast cancer, except if it is taken for many decades. (Two studies showed no increased risk for breast cancer after 7 years and 15 years, respectively. Women who took estrogen-only HRT for more than 20 years after hysterectomy had only a moderately increased risk.) Combination estrogen-progestin HRT does increase breast cancer risk.

In premenopausal women, such preventive measures are not needed if the ovaries are left intact. The ovaries will usually continue to function and secrete hormones even after the uterus is removed, but the lifespan of the ovaries is reduced by an average of 3 - 5 years. In rare cases, complete ovarian failure occurs right after hysterectomy, presumably because the surgery has permanently cut off the ovaries' blood supply.

Sexual intercourse may resume 4 - 6 weeks following surgery. The effect of hysterectomy on sexuality is unclear. Studies have reported that up to 25% of women experience increased sexual drive. Nevertheless, some women report no change, and other women develop problems related to sexual function. For example, around 10% of women experience vaginal dryness, about 2% of women develop pain during sex, and another 2% also appear to lose capacity for orgasm.

Two procedures associated with hysterectomy may affect sexuality directly:

Although the clitoris can trigger orgasm even if the cervix is removed, many experts believe that uterine contractions stimulated by sexual intercourse also cause a so-called “deep orgasm.” Retaining the cervix may help to retain this sensation. However, a 2006 review found that women who undergo a total hysterectomy (removal of both uterus and cervix) are no more likely to have sexual difficulties or problems with urinary and bowel function than women who have only their uterus removed.
Patients who have both ovaries removed may be at higher risk for loss of sexuality. Ovaries produce small amounts of testosterone (the male hormone responsible for sexual drive) even after menopause.

Testosterone Replacement. Testosterone replacement therapy may restore sexuality in women who experience a decline in sexual drive. Occasionally, oral or injection treatments can produce male characteristics such as facial hair and voice change. A slow-release pellet inserted every 6 months under the skin in the hip appears to reduce these side effects. Taking hormones long term almost always carries some risk, and it is not yet known what danger testosterone replacement may pose in women.

Annual Pap smears are recommended for all women with an intact cervix who are 18 years or older or who have become sexually active. After a total hysterectomy, in which the cervix has been removed, a woman does not need annual Pap smears of the cervix. However, she still should get regular pelvic and breast exams.

Resources

www.asrm.com -- American Society for Reproductive Medicine
www.acog.com -- American College of Obstetricians and Gynecologists
www.sirweb.org -- Society of Interventional Radiology
www.nuff.org -- National Uterine Fibroids Foundation
www.rsna.org -- Radiological Society of North America
www.radiologyinfo.org -- Radiology info from the American College of Radiology and the Radiological Society of North America
www.radiologyinfo.org/content/interventional/ufibroid-embol.htm -- Information on uterine fibroid embolization
www.fibroids.net -- Brigham and Women's Hospital, Center for Uterine Fibroids
www.nichd.nih.gov -- National Institute of Child Health and Human Development

References

Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006 May 8;166(9):1027-32.

Edwards RD, Moss JG, Lumsden MA, Wu O, Murray LS, Twaddle S, et al. Uterine-artery embolization versus surgery for symptomatic uterine fibroids. N Engl J Med. 2007 Jan 25;356(4):360-70.

Learman LA, Kuppermann M, Gates E, Gregorich SE, Lewis J, Washington AE. Predictors of hysterectomy in women with common pelvic problems: a uterine survival analysis. J Am Coll Surg. 2007 Apr;204(4):633-41. Epub 2007 Feb 23.

Lethaby A, Ivanova V, Johnson NP. Total versus subtotal hysterectomy for benign gynaecological conditions. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD004993.

Smart OC, Hindley JT, Regan L, Gedroyc WG. Gonadotrophin-releasing hormone and magnetic-resonance-guided ultrasound surgery for uterine leiomyomata. Obstet Gynecol. 2006 Jul;108(1):49-54.

Stefanick ML, Anderson GL, Margolis KL, Hendrix SL, Rodabough RJ, Paskett ED, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA. 2006 Apr 12;295(14):1647-57.

Review Date:
2/28/2008
Reviewed By:
A.D.A.M. Editorial Team: David Zieve, MD, MHA, Greg Juhn, MTPW, David R. Eltz, Kelli A. Stacy, ELS. Previously reviewed by Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (6/16/2007).

A.D.A.M. Copyright

adam.com

Endometriosis

FitSugar — Wed, 08 Oct 2008 17:34:57 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Risk Factors
Complications
Diagnosis
Treatment
Lifestyle Changes
Medications
Conservative Surgery
Hysterectomy
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Drug Approval

Women with menstrual pain due to endometriosis have a new treatment option. In May 2007, the FDA approved Lybrel, a continuous-dose oral contraceptive that completely eliminates menstrual periods. Lybrel, which contains low doses of the estrogen estradiol and the progesterone levonorgestrol, is taken 365 days a year with active pills. Some women may, however, experience unscheduled bleeding or spotting.

Endometriosis and Adenomyosis

Women who continue to experience menstrual and pelvic pain after surgery for endometriosis may actually have adenomyosis, suggests a 2006 study in Fertility and Sterility. Adenomyosis occurs when knots of endometrial tissue develop within the muscles of the uterus. With endometriosis, endometrial tissue grows outside of the uterus.

Predictors of Hysterectomy

Three factors combined can predict whether a woman will decide to have a hysterectomy, according to a 2007 study published in the Journal of the American College of Surgeons. Women who met all three criteria had a 95% chance of having a hysterectomy:

Presence of symptoms (pelvic pain, bleeding, symptomatic fibroids)
Lack of symptom improvement despite treatment
Previous use of GnRH agonist drugs

Hysterectomy and Sexual Function

Hormone Replacement Therapy (HRT) and Breast Cancer Risk

Estrogen-only HRT after hysterectomy does not increase breast cancer risk in the short term (up to 20 years), according to several 2006 studies. Combination estrogen-progestin HRT does increase breast cancer risk.

Introduction

Endometriosis is a condition in which the cells that line the uterus grow outside of the uterus. The condition can interfere with a woman's fertility and ability to become pregnant. Endometriosis can also cause severe pelvic pain, especially during menstruation.

Endometriosis is a common gynecological condition. It was described in medical literature more than 300 years ago and has since been recognized as a chronic, painful, and often progressive disease in women. However, the causes of endometriosis are unknown, it is widely variable in symptoms and severity, and it is difficult to diagnose. In fact, some experts believe that endometriosis is actually several disorders, not just one.

Endometriosis. Endometriosis occurs when cells from the mucus membrane lining the uterus (endometrium) form implants that attach, grow, and function outside the uterus, generally in the pelvic region. Endometrial implants consist of both following cell types:

Gland cells. These cells secrete hormones and other fluids and are normally located in the uterine lining.
Stroma cells. These are the framework cells that build supportive tissue.

Endometrial cells contain receptors that bind to estrogen and progesterone, which promote uterine growth and thickening. During endometriosis these cells become implanted in organs and structures outside the uterus, where these hormonal activities continue to occur, causing bleeding and scarring.

Endometriosis is the condition in which the tissue that normally lines the uterus (endometrium) grows on other areas of the body, causing pain and irregular bleeding.

Endometrial implants vary widely in size, shape, and color. Over the years, they may diminish in size or disappear, or they may grow.

Early implants are usually very small and look like clear pimples.
If they continue to grow they may form flat injured areas (lesions), small nodules, or cysts called endometriomas, which can range from sizes smaller than a pea to larger than a grapefruit.
Implants also vary in color; they may be colorless, red, or very dark brown. These so-called chocolate cysts are endometriomas filled with thick, old, dark brown blood that usually appear on the ovaries.

Implants can form in many areas, most commonly in the following:

The peritoneum. This is the smooth surface lining that covers the entire wall of the abdomen and folds over inner organs in the pelvic area.
On or next to the ovaries.

Less commonly they occur in other areas:

Cul-de-sac, an area between the uterus and rectum
Connective tissue that supports the uterus (called the uterosacral ligaments)
Vagina
Fallopian tube
Urinary tract (in about 20% of cases, usually without causing symptoms).
Gastrointestinal tract (in 12 - 37% of patients)

Click the icon to see an image of the female reproductive anatomy.

Very rarely, they appear in areas far from the pelvis, including the lungs and even the arms and thighs.

The process of endometriosis mimics menstruation at certain stages:

Each month, the exiled endometrial implants respond to the monthly cycle just as they would in the uterus. They fill with blood, thicken, break down and bleed.
Products of the endometrial process cannot be shed through the vagina as menstrual blood and debris are. Instead, the implants develop into collections of blood that form cysts, spots, or patches.
Lesions may grow or reseed as the cycle continues.

The lesions are not cancerous, but they can develop to the point that they cause obstruction or adhesions (web-like scar tissue) that attach to nearby organs, causing pain, inflammation, and sometimes infertility.

The primary structures in the reproductive system are as follows:

The uterus is a pear-shaped organ located between the bladder and lower intestine. It consists of two parts, the body and the cervix.
When a woman is not pregnant the body of the uterus is about the size of a fist, with its walls collapsed and flattened against each other. During pregnancy the walls of the uterus are pushed apart as the fetus grows.
The cervix is the lower portion of the uterus. It has a canal opening into the vagina with an opening called the os, which allows menstrual blood to flow out of the uterus into the vagina.
Leading off each side of the body of the uterus are two tubes known as the fallopian tubes. Near the end of each tube is an ovary.
Ovaries are egg-producing organs that hold 200,000 - 400,000 follicles (from folliculus, meaning "sack" in Latin). These cellular sacks contain the materials needed to produce ripened eggs, or ova.

The inner lining of the uterus is called the endometrium, and during pregnancy it thickens and becomes enriched with blood vessels to house and support the growing fetus. If pregnancy does not occur, the endometrium is shed as part of the menstrual flow. Menstrual flow also consists of blood and mucus from the cervix and vagina.

The hypothalamus first releases the gonadotropin-releasing hormone (GnRH).
This chemical, in turn, stimulates the pituitary gland to produce follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
Estrogen, progesterone, and the male hormone testosterone are secreted by the ovaries at the command of FSH and LH and complete the hormonal group necessary for reproductive health.

Causes

Endometriosis occurs among women all over the world, but researchers have been unable to determine its cause. A combination of genetic, biologic, and environmental factors appear to work together to trigger the initial process, to produce implantation, and to trigger subsequent reseeding and spreading of the implants.

Retrograde Menstruation. One explanation for the development of endometriosis implants involves retrograde menstruation. This occurs during a woman's period, when menstrual tissue flows backward through the fallopian tubes rather than out through the vagina. Early theorists suggested that, in some cases, the redistributed uterine tissue attached and grew in areas outside the uterus, forming endometriosis implants. This theory does not fully explain endometriosis, however. Many women experience some retrograde menstruation, but not all of them develop endometrial cysts. Consequently, other factors must explain why uterine tissue becomes implanted and grows in areas outside the uterus.

Lymphatic Transport. This theory suggests that endometriosis first develops when uterine tissue is separated and then is transported to other organs by way of the lymphatic system or the bloodstream.

The lymphatic system filters fluid from around cells. It is an important part of the immune system. When people refer to swollen glands in the neck, they are usually referring to swollen lymph nodes. Common areas where lymph nodes can be easily felt, especially if they are enlarged, are: the groin, armpits (axilla), above the clavicle (supraclavicular), in the neck (cervical), and the back of the head just above hairline (occipital).

Environmental Toxins. Other suspects for causing initial development of endometriosis are chemicals called organochlorines, which include dioxins (such as PCBs and furans). These chemicals have estrogen-like effects and are widely found in pesticides and other common products. The organochlorines have a particularly powerful impact on the ovary. Organochlorines have been associated with infertility, certain reproductive cancers, and autoimmune disorders, conditions that also occur with higher frequency in women with endometriosis.

Candida. There is absolutely no evidence that endometriosis is caused by candida (commonly called yeast infection), as claimed in some consumer publications.

There are two basic mysteries surrounding the persistence and growth of endometriosis:

Why do endometrial implants survive the attack by the immune system, which is typically launched against any foreign presence in the body?
How do these endometrial travelers develop new blood vessels and implant themselves in other locations?

Impaired Immune System.Some research is focused on possible immune disorders in women with endometriosis. One theory proposes that women with endometriosis have fewer natural killer (NK) cells, which are factors in the immune system important for surveillance. In their absence, the immune system is weakened and may allow endometrial tissue to invade and take root. A recent study suggests that other types of immune system cells are also underactive in women with endometriosis, allowing the woman's body to tolerate the implanted tissue.

Some evidence suggests that endometriosis represents an autoimmune condition, in which the immune system launches an attack on its own cells and tissue. Much of the evidence rests on the relatively high incidence of other inflammatory autoimmune disorders (multiple sclerosis, rheumatoid arthritis, lupus) that occur in women with endometriosis. It is unclear, however, how this response relates to endometriosis itself and whether endometriosis should be treated as an autoimmune condition.

Growth Factors and Angiogenesis. Macrophages also produce growth factors, which are of particular interest because they play important roles in angiogenesis, a natural process by which new blood vessels form.

Vascular endothelial growth factor (VEGF) is secreted by endometrial cells, and so is of special interest. Under normal conditions, VEGF is secreted within the uterus. When oxygen levels drop following menstruation and blood loss, VEGF levels rise and promote the growth of new blood vessels. This process is important for repairing the uterus following menstruation.

When endometrial cells land outside the uterus, however, investigators theorize that this same process occurs with unfortunate results. The cells secrete VEGF when they are deprived of blood and oxygen, which in turn stimulates blood vessel growth. In this case, however, blood vessel growth serves to promote implantation outside the womb.

Other growth factors involved in angiogenesis that may play a role in endometriosis include transforming growth factors (such as TGF-beta), platelet-derived endothelial growth factor (PD-ECGF), and tumor necrosis growth factors.

Inflammatory Response. The damage, infertility, and pain produced by endometriosis may be due to an overactive response by the immune system to the early presence of endometrial implants. The body, perceiving the implants as hostile, launches an attack. Levels of large white blood cells called macrophages are elevated in endometriosis. Macrophages produce very potent factors, which include cytokines (particularly those known as interleukins) and prostaglandins. Such factors are known to produce inflammation and damage in tissues and cells.

A major study is underway to uncover the genetic factors that predispose certain women to endometriosis. The incidence of endometriosis in women who have a mother or sister with the disorder may be up to 10 times higher than average.

Symptoms

Pain at the time of menstruation (dysmenorrhea ) is the primary symptom and occurs in nearly all girls and women with endometriosis. Studies suggest that endometriosis is the cause of about 15% of cases of pain in the pelvic region in women.

Timing of Pain. In addition to menstruation, endometrial pain can occur at other times of the month. A survey published by the Endometriosis Association reported the following findings on the timing of endometrial pain:

71% of women reported pain within 2 days after their periods started.
47% reported pain in the middle of a cycle. (A sharp pain during ovulation may be due to an endometrial cyst located in the fallopian tube that ruptures as the egg passes through.)
40% reported pain at other times of the month.
20% reported continual pain.
7% said there was no pattern.
Many women with endometriosis experience pain during intercourse.
Adolescents are more likely to experience pain that occurs both during their periods and at other times in the cycle, while in older women endometrial pain is more likely to occur during menstruation.

Location of Pain. Nearly all women with endometrial pain experience it in the pelvic area (the lower part of the trunk of the body). The pain is often a severe cramping that occurs on both sides of the pelvis, radiating to the lower back and rectal area and even down the legs.

Occasionally, however, pain may also occur in other regions if endometriosis affects other part of the pelvic area, such as the bladder or intestine.

Severity of Pain. The severity of the pain also varies widely and does not appear to be related to the extent of the endometriosis itself. In other words, a woman can have very small or few implants and have severe pain, while those with extensive endometriosis may have very few signs of the disorder except for infertility. Large cysts can rupture and cause very severe pain at any time.

Patients may experience additional symptoms, which include the following:

Joint and muscle aches
Fatigue
Bloating
Nausea
Dizziness
Heavy menstrual bleeding
Headaches
Depression and malaise (feeling generally low)
Sleep problems

Risk Factors

Endometriosis affects at least 5.5 million women in North America and millions more worldwide. An estimated 2 - 4% of all premenopausal adult women have detectable endometriosis, and over a third of these women experience noticeable pain. Because many women with endometriosis have no symptoms, the actual percentage of premenopausal women with the disorder may be as high as 15%. Some experts believe endometriosis may be responsible for between 45 - 70% of chronic menstrual pain in adolescence.

Age. Endometriosis can occur in women of all ages. It has been reported in girls as young as age 8 (and has been documented before the onset of menstruation), and in women over age 75, with the average age being between 25 - 29. About 40 - 60% of women with endometriosis report symptoms before age 25.

Ethnic Groups. Endometriosis is most common among Asian women, with Caucasians next. It is reported least frequently in African-American women.

Women at higher risk for endometriosis tend to have more problems with menstruation. Those at higher risk have a shorter than normal cycle, heavier periods, and longer periods. Heavier, more frequent periods, or longer exposure may simply make the risk for retrograde menstruation more likely. (This is the condition in which menstrual flows backward and is believed to be at least partially responsible for the initial development of endometriosis.) Menopause usually brings an end to mild-to-moderate endometriosis, although if women with a history of endometriosis take hormone replacement therapy (HRT), the condition may be reactivated.

Not having children has been associated with a greater risk for endometriosis. Some evidence suggests that early pregnancy may be protective against endometriosis because the cervix becomes dilated during labor, which reduces the risk for retrograde menstruation (menstrual backflow). On the other hand, endometriosis itself can increase the risk for infertility, so it may be a cause rather than a result of not having children. Some studies have found no protection against endometriosis with pregnancy, although women with the condition find relief from symptoms during pregnancy.

Some experts report that almost 7% of first-degree female relatives of endometriosis patients also develop it. A family history of endometriosis not only puts women at high risk for the condition but possibly a more severe manifestation of it as well.

Women may also be at higher risk for endometriosis if they were born with uterine abnormalities that obstruct the normal outflow of blood and cause retrograde menstruation.

There have been reports of endometriosis developing after cesarean sections, including implants developing in surgical scars and in the urinary tract. Some experts believe endometriosis should be suspected in women with urinary tract symptoms and a history of cesarean section.

Various disorders occur in greater rates in women who have endometriosis. In some cases, these disorders and endometriosis may be caused by common factors, but it is not clear what they are.

They include:

Certain cancers, particularly for early-onset breast and ovarian cancers, non-Hodgkin's lymphomas, and melanoma.
Autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. In all of these diseases, the immune system launches a destructive inflammatory response against the body's own cells (which differ in location depending on the disease). These are uncommon disorders, but in a major 2002 survey of women with endometriosis, they occurred in 12% of these women. This provides some support to the theory that endometriosis, too, is an autoimmune condition.
Hypothyroidism. In the same 2002 survey mentioned above, 42% of women had low thyroid or some other hormonal disorder.
Fibromyalgia and chronic fatigue syndrome. In the same survey, 31% reported one of these conditions.
Diabetes.
Allergies and asthma. Endometriosis is more prevalent in women with a family history of asthma and allergies, including food and skin allergies and hay fever.
Migraine. A small 2006 study suggested that women who have migraine headaches are at increased risk of endometriosis.

Some studies have reported a higher incidence of certain factors in women with endometriosis:

Women with endometriosis tend to be taller and thinner than average.
Women with red hair have an increased risk for endometriosis. Experts guess that the gene determining red hair might be located near other genes that make such women susceptible to endometriosis.

Alcohol and caffeine use have been associated with a higher risk.

Complications

Endometriosis is a chronic disease that is difficult to diagnose and treat. Without treatment, endometriosis gets progressively worse in 65 - 80% of patients. Even with treatment, endometriosis continues to advance in 20% of patients. Cysts and implants may grow and spread to other parts of the pelvis, and in very severe cases, to the urinary or intestinal tracts. Eventually adhesions may form. These are dense, web-like structures of scar tissue that can attach to nearby organs and cause pain, infertility, and intestinal obstruction.

Pain is the most common complaint for women with endometriosis, and it can significantly impair the quality of life. The pain experienced around menstruation can be so debilitating that up to 25% of women with the condition are incapacitated for 2 - 6 days of each month. In severe cases, regular activities may be curtailed for up to 2 weeks per month. Sleeping problems have been reported in 75% of patients, mostly due to pain.

Endometriosis may account for as many as 30% of infertility cases. Some evidence suggests that between 30 - 50% of women with endometriosis are infertile. Often, however, it is difficult to determine if endometriosis is the primary cause of infertility, particularly in women who have mild endometriosis. In an attempt to determine the chances for infertility with endometriosis, researchers have come up with a staging system based on findings during diagnostic surgery.

Endometriosis rarely causes an absolute inability to conceive, but it can contribute to infertility both directly and indirectly.

Direct Effect of Endometrial Cysts. Endometrial cysts may directly prevent infertility in a number of ways:

If implants occur in the fallopian tubes, they may block the egg's passage.
Implants that occur in the ovaries prevent the release of the egg.
Severe endometriosis can eventually form rigid webs of scar tissue (adhesions) between the uterus, ovaries, and fallopian tubes, thereby preventing the transfer of the egg to the tube.

Immune Factors and the Inflammatory Response. Researchers are focusing on defects in the immune system that not only may be responsible for endometriosis in the first place but also may cause the infertility associated with endometriosis. Even in early stage endometriosis, investigators have observed increased immune system activity. It is possible that in such cases, the body perceives these foreign endometrial implants as hostile, and launches an attack.

In this process, the body overproduces specific immune factors that contribute to infertility:

Cytokines. Cytokines are very potent immune factors that, when overproduced, cause damage and inflammation in the very regions that are directed to protect. Such damage could produce scarring and obstructions that interfere with implantation and development of a fertilized egg. In severe endometriosis, there is inflammation in the fluid surrounding the uterus, which could create a hostile environment for the sperm.
Prostaglandins. Elevated levels of these hormone-like factors not only produce inflammation but also increase uterine contractions. (Women with endometriosis have a higher than average risk for miscarriage.)
Other Immune Factors. Growth factors, which stimulate growth of new blood vessels, and toxins produced by implants may impair fertility.

Other Conditions Linking Endometriosis and Infertility. Researchers have noted unusually low levels of specific substances that enable a fertilized egg to adhere to the uterine lining. Such abnormalities are more often a factor in infertility in women with mild-to-moderate endometriosis than in those with severe cases.

One study found that the eggs in women with endometriosis appeared to have more genetic abnormalities than those in women without the disorder.

Implants can also occur in the bladder (although rare) and cause pain and even bleeding during urination. Implants also sometimes form in the intestine and cause painful bowel movements, constipation, or diarrhea. Hormonal treatments, the standard therapies for endometriosis, are not helpful in such cases, and surgery may be needed.

Endometriosis has characteristics that are similar to cancerous tumors, including cellular invasion of other tissues, unrestrained growth, development of new blood vessels, and impaired ability of cells to naturally self-destruct. It is not a malignant disease, however, but experts have been debating for years whether it represents any significant danger.

The possible risks for ovarian and endometrial cancers are of specific concern. Some researchers have identified certain genetic mutations that may transform endometrial cells into ovarian or endometrial cancers in rare cases. Some evidence suggests that ovarian cancer associated with endometriosis may differ from most ovarian cancer cases, and, in fact, have a better outlook.

Of additional concern are studies suggesting that women with endometriosis have a higher risk for other cancers, particularly for early-onset breast cancer and non-Hodgkin's lymphoma (NHL).

The emotional effect of severe endometriosis can be almost as devastating as the pain. It can affect marriage and work. In one survey conducted by the Endometriosis Association, patients reported the following emotional effects from this disease:

84% of patients reported feeling depressed during periods of pain
75% felt irritable
More than 50% reported feelings of anxiety and anger
About 20% said they felt hopeless

In one study, during the days around menstruation 30% of women with endometriosis increased their alcohol intake compared to 14% of women with other gynecological problems and only 9.5% of women with no gynecological disorders.

Diagnosis

Although endometriosis is the most commonly diagnosed uterine disorder, it is often misdiagnosed or missed altogether. In a study of women with proven endometriosis, more than half of them had been told by a doctor that nothing was wrong. In another study, half of women with endometriosis reported that they visited a doctor five or more times before they were diagnosed.

Endometriosis frequently begins to develop in adolescence, but it is not typically diagnosed until a woman is in her mid-20s or early 30s. There are a number of reasons for this:

The symptoms vary widely, and sometimes do not occur at all. Some women do not know they have endometriosis until they fail to become pregnant and seek help for infertility.
Pain in the pelvic or abdominal area can be caused by so many conditions that it is often difficult to pin down the precise cause.

Endometriosis should be highly suspected in women with severe menstrual cramps who are also infertile. Laparoscopy, an invasive diagnostic procedure, is the only definitive method for diagnosing endometriosis. However, a trial using one of several hormonal therapies is usually sufficient to confirm or rule out endometriosis. Such drugs include danazol, GnRH agonists, and progestins.

Many conditions cause pelvic pain. In many cases, the cause is unknown and it often resolves on its own. In one study, pelvic pain improved or resolved without treatment in 77% of women over a 15-month period. However, some causes of pelvic pain can be serious and should be ruled out during a work-up for endometriosis.

Primary Dysmenorrhea. Primary dysmenorrhea is recurrent pelvic pain associated with menstruation. Dysmenorrhea is common in many women. [See In-Depth Report #100: Menstrual disorders.]

Adenomyosis. A condition called adenomyosis occurs when nodules (knots) of endometrial tissue develop within the deep muscle layers of the uterus. This disorder is often classified with endometriosis, but adenomyosis is a different disease. (Endometriosis occurs when endometrial tissue grows and functions outside the uterus.) Adenomyosis is a significant cause of severe pelvic pain and menstrual irregularities. Until recently adenomyosis was diagnosed only after a hysterectomy, but advanced imaging techniques using ultrasound and magnetic resonance imaging scans may be able to detect it. A 2006 study indicated that women who have had surgery for endometriosis, yet continue to suffer from menstrual and pelvic pain, may actually have adenomyosis.

Adenomyosis typically occurs in women who have uterine fibroids, women age 40 - 50, and women who have had children. [See In-Depth Report #73: Uterine fibroids.]

Fibroid tumors may not need to be removed if they are not causing pain, bleeding excessively, or growing rapidly.

Other Causes of Pelvic Pain. Many conditions cause pelvic pain that may or may not be related to menstruation. Some causes of pelvic pain can be serious and should be ruled out:

Uterine fibroids
Pelvic inflammatory disease (which is a result of infections in the pelvic area)
Miscarriage
Ectopic pregnancy

Click the icon to see an image of an ectopic pregnancy.

Pelvic cancer (rare)
Uterine polyps
The use of an intrauterine device (IUD) for contraception

Conditions that may mimic symptoms of endometriosis but which are unrelated to problems in the reproductive organs include:

Severe kidney or urinary tract infections
Celiac disease
Appendicitis
Interstitial cystitis
Inflammatory bowel disease
Diverticulitis
Irritable bowel syndrome

The doctor may be able to feel tender masses or nodules during a pelvic examination, but these signs can indicate many conditions and do not necessarily mean endometriosis is present.

Laparoscopy. Diagnostic laparoscopy, an invasive surgical procedure, is currently the only definitive method for diagnosing endometriosis. Laparoscopy normally requires a general anesthetic, although the patient can go home the same day.

Click the icon to see an image of laparoscopy.

The procedure is as follows:

The surgeon makes tiny abdominal incisions through which a fiber optic tube, equipped with small camera lenses, is inserted. The doctor uses these devices to view the uterus, ovaries, tubes, and peritoneum (lining of the pelvis) on a video monitor.
Carbon dioxide gas is injected into the abdomen, distending it and pushing the bowel away so that the doctor has a wider view.
A blue dye may be flushed through the fallopian tubes to determine blockage; if there is an obstruction, the dye will not flow through the tube.
If the surgeon needs to remove small endometrial cysts or other lesions during the procedure (operative laparoscopy), tiny surgical instruments are passed through a tube.

The procedure is used for detecting and staging endometriosis to determine its severity. In some cases, the procedure itself will restore fertility in women with endometriosis.

Transvaginal Hydrolaparoscopy. Transvaginal hydrolaparoscopy is a new and less invasive approach than laparoscopy, since the instruments are inserted through the vagina, not through incisions in the abdomen. It requires only sedation, does not use CO2 to distend the abdomen, and has a much shorter and easier recovery than with standard laparoscopy. When used by a skilled professional, it is as accurate as laparoscopy, but is not yet widely available.

Hysteroscopy. Hysteroscopy is a procedure that may be used to detect the presence of fibroids, polyps, or other causes of bleeding. (It may miss cases of uterine cancer, however, and is not substitute for more invasive procedures, such as D&C or endometrial biopsy, if cancer is suspected.)

Hysteroscopy is non-invasive, but 30% of women report severe pain with the procedure. The use of an anesthetic spray such as lidocaine may be highly effective in preventing pain from this procedure. Other complications include excessive fluid absorption, infection, and uterine perforation. Hysteroscopy is also used as part of surgical procedures.

An ultrasound is performed in cases where other conditions are suspected, such as uterine fibroids, ovarian cysts, or ectopic pregnancy. This non-invasive imaging technique can detect endometriomas, or cysts that are usually located on the ovaries and filled with thick dark blood. Ultrasound can also pick up cysts larger than 1 cm (about 1/3 inch), but will miss smaller cysts, or small and shallow endometrial implants on the surface of ovaries, or on the peritoneum (lining of the pelvis).

Once a diagnosis is made, more sophisticated imaging techniques, such as computed tomography (CT) scanning or magnetic resonance imaging (MRI), may be used to obtain a more accurate image of severe endometriosis.

Investigators are studying certain chemicals detected in blood tests that may prove to help diagnose endometriosis and so avoid invasive diagnostic procedures in many women. Among the most studied to date are CA-125 and CA19-9. Both are elevated in women with severe endometriosis. Higher levels of both chemicals occur in many other diseases, however, including ovarian cancer, so results using this test alone do not provide enough information for a definitive diagnosis of endometriosis.

During laparoscopy, the surgeon determines the number, size, and location of endometrial implants and adhesions. This information helps rank endometriosis by the extent of the disease and give the likelihood of infertility:

Minimal (stage I)
Mild (stage II)
Moderate (stage III)
Severe (stage IV)

A number of experts do not believe these categories are useful, because they often do not relate to the intensity of the pain, or to treatment success rates.

Some experts believe it is more accurate to further categorize endometriosis by the depth of penetration:

Superficial Endometriosis. Endometriosis that lies more on the surface is more highly associated with infertility than deep implants.
Infiltrative Endometriosis. Implants deeper than 5 - 6 mm; deep implants are believed to be the best indicator of progression and severe symptoms.

Treatment

There is no perfect way of managing endometriosis. The three basic treatment approaches are:

Watchful waiting (to relieve symptoms)
Hormonal therapy (to reduce endometrial implants)
Surgery (to reduce endometrial implants, restore fertility, or possibly cure the condition)

The choice depends on a number of factors, including the woman's symptoms, her age, whether fertility is a factor, and the severity of the disease.

In general, watchful waiting is a good initial choice for:

Women with mild pain who, if fertile, do not wish to become pregnant. If women with mild endometriosis wish to become pregnant, the doctor may recommend unprotected sex for 6 months to year. If pregnancy does not occur, then treatment may be started.
Women approaching menopause.

Some experts believe that early diagnosis and treatment in young women without symptoms might prevent some cases of infertility later on. Unfortunately, however, some treatments for endometriosis may actually trigger symptoms in those who do not yet experience them.

Hormone therapies are used to mimic states in which ovulation does not occur (such as pregnancy or menopause) or to directly block ovulation. Hormonal drugs include oral contraceptives, progestins, GnRH agonists, and danazol. They can be very effective in relieving endometriosis symptoms. Some of these drugs may also be used after surgery to help prevent recurrence of endometriosis. There is also some evidence that GnRH agonists and danazol may improve immune factors associated with endometriosis. But there are downsides:

None of these drugs can cure the problem. Symptoms recur in about half of patients within 5 years of treatment.
They do not improve fertility rates and may delay conception in women who use them.
Side effects of these drugs can be distressing. There is a high dropout rate with the use of nearly all these hormonal treatments.
Women who take GnRH agonists, danazol, or similar drugs should use non-hormonal birth control methods (such as the diaphragm, cervical cap, or condoms) because these drugs can increase the risk for birth defects.

Surgery is an option for the following women:

Women with severe pain that does not respond to watchful waiting and medical treatment.
Women who want to become pregnant and endometriosis is most likely the major contributor to infertility.

There are two basic surgical approaches for endometriosis:

Conservative Surgery (Laparoscopy or Laparotomy). Conservative surgery uses laparotomy or laparoscopy to remove the endometriosis implants without removing any other reproductive organs. It is a good option for women who wish to become pregnant or who cannot tolerate hormone therapy. Some experts believe that laparoscopy surgery should be the treatment of choice for women with endometriosis. Endometriosis often recurs after conservative surgery, however. Recurrence rates at 2 years range from 2 - 47%. The risk for recurrence or residual pain after any procedure increases with the severity of the condition, particularly if endometriosis has affected areas outside the uterus.
Radical Surgical Therapy (Hysterectomy). Hysterectomy with removal of ovaries (oophorectomy) along with all endometrial implants is the only potential cure for endometriosis. If endometriosis has developed outside the uterus than even this procedure is not curative. Removing only the uterus with hysterectomy, in any case, has the same risk for recurrence as conservative surgery.

Click the icon to see an illustrated series detailing hysterectomy.

In choosing between hysterectomy (with or without oophorectomy) and conservative surgeries, age and the desire for children are important factors. One study reported a greater sense of loss, more residual symptoms, and more pain in younger women (under age 30) who have undergone hysterectomy than in older women. In one study, 37% of such younger women regretted their decision to have a hysterectomy.

Once careful instruction is given for all the risks and benefits of the different surgical options, the doctor must respect any decision a patient makes to retain as much of her reproductive system as she wants, even if she is past menopause. Both the patient and the doctor should also be clear about the possibility of changing procedures once the operation has begun, depending on what the surgeon may observe. For example, the surgeon may find abnormalities that require more extensive surgery.

Much of the success of any procedure relies on the experience of the surgeon. A woman should always ask for a doctor's track record, or the number of times the doctor has performed the procedure in question. The more, the better. Asking for complication rates may be helpful, but a patient should realize that an experienced surgeon may have a higher number of high-risk patients, and therefore, a higher complication rate than a less experienced surgeon with fewer serious cases.

For women with severe endometriosis who want to become pregnant, conservative surgery (typically laparoscopy) is the appropriate approach for restoring fertility. Hormonal therapies that treat endometriosis itself, such as GnRH agonist or progestins, are generally considered not to help fertility. However, a 2002 study suggested that the use of the GnRH agonists after surgery helped improve conception rates in women who subsequently undergo assisted reproductive techniques (ART), such as in vitro fertilization (IVF). A 2006 study indicated that GnRH agonists given along with infertility treatments may help improve a woman's chance of becoming pregnant. This research is still preliminary.

In any case, ART and hyperstimulation of the ovary using fertility drugs to produce eggs are the standard fertility treatments available to women if surgery fails. ART includes techniques such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). Hyperstimulation is the less expensive approach. In a 2003 study, however, ART achieved much greater conception rates in women with endometriosis, particularly those with late-stage disease.

It is not clear whether women with early -stage endometriosis do any better with fertility treatment than simply trying to become pregnant through non-aggressive means. Women with endometriosis who are trying to conceive should discuss all treatment options with a specialist. [See In-Depth Report #22: Infertility in women.]

Lifestyle Changes

Some women report relief by avoiding dairy products and having a diet rich in fiber and low in saturated (animal) fats. Fiber-rich foods (such as fruits and vegetables) along with plenty of fluids (water or juice, not caffeine) are not only healthy but help prevent constipation, which can intensify symptoms. If women choose a diet that limits dairy products, they should be sure to have sufficient calcium from other sources.

A 2005 study involving over 500 women reported that red meat and ham consumption increased the risk for endometriosis. Diets high in green vegetables and fresh fruit appeared to protect against it.

Fat compounds called omega-3 fatty acids may have specific anti-inflammatory effects. They are found in certain oily fish (sardines, mackerel) and can be obtained in supplements. Supplements may be labeled either omega-3 fatty acids or EPA-DHA (which are the important compounds). Evening primrose oil and black currant oil, found in health food stores, contain similar fatty acids that may be helpful. However, food sources are the healthier choice.

Omega-3 fatty acids, found plentifully in oily fish and flaxseed and canola oils, are beneficial to people who have IBD (inflammatory bowel disease).

Drinking alcohol and and smoking cigarettes may increase endometriosis risk. It is unclear whether caffeine is a significant risk factor.

A sitz bath is simply sitting in a basin of water. Some people report relief by alternating between sitting 3 minutes in a hot water basin and then 1 minute in a cold water basin. This is repeated three times. The procedure is performed twice a day 3 - 4 days a week, except during menstruation.

A warm bath or application of heated abdominal pad may help relieve painful menstrual cramps.

Kegel exercises are designed to strengthen the muscles of the pelvic floor that both support the bladder and close the sphincters. Some people find they help endometriosis. The exercises consist of tightening and releasing the pelvic muscle. Since the muscle is internal and sometimes difficult to isolate, doctors often recommend practicing while urinating on the toilet. The patient tries to contract the muscle until the flow of urine is slowed or stopped and then releases it. (However, once learned, Kegel exercises should not be regularly performed while urinating as this practice may eventually weaken the muscles.)

Exercise may be very helpful for women with endometriosis. It relieves stress and tension and may reduce hormonal levels that can contribute to endometrial growth.

Acupuncture and Acupressure. Some studies have reported relief from pelvic pain after acupuncture or acupressure, a technique that applies small pins or pressure to specific points on the body. Some women report relief with reflexology, a technique that uses manual pressure on acupuncture points on the ears, hands, and feet.

Click the icon to see an image of acupuncture.

Transcutaneous Electrical Nerve Stimulation. Transcutaneous electric nerve stimulation (TENS) applies electrodes to certain parts of the body and administers low-level electrical pulses to those locations. Research suggests that it works by altering the body's ability to receive pain signals. The standard approach is to give 80 - 100 pulses per second, for 45 minutes, three times a day. TENS is painless and patients are barely aware of the sensation. A 2002 analysis suggested that this approach may help some women with dysmenorrhea.

Yoga and Meditative Techniques. Yoga and meditative techniques that promote relaxation may also be helpful for menstrual cramps.

Chiropractic. Some women with primary dysmenorrhea have sought help from chiropractors trained in spinal manipulation. One study compared a high-force spinal manipulation technique with a low-force maneuver used as a placebo technique. Both showed lower scores on tests that measure pain, perhaps indicating that a simple back rub by a sympathetic partner or friend may be helpful.

Herbal and Other So-Called Natural Remedies for Cramp Relief. Researchers have not conducted many rigorous studies on herbal remedies for menstrual and pelvic pain. Small studies have suggested that pycnogenol, a plant extract derived from the bark of the French maritime pine tree, may help reduce endometriosis symptoms. Some patients have reported relief from menstrual cramps with aromatherapy using lavender, sage, and rose oils.

Generally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been a number of reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements.

Medications

The basic approach in hormonal treatments for endometriosis is to block production of female hormones (estrogen and progesterone) or to prevent ovulation. Hormonal drugs are used for pain relief only. None have been proven to improve fertility rates and in some cases may delay conception. Specific hormonal drugs may have different effects for women with endometriosis.

Inducing Pseudopregnancy. Oral contraceptives that contain estrogen and progestins mimic a pregnant state and block ovulation. (Progestins are natural or synthetic forms of progesterone). Progestins may also be used alone, since they have specific effects that can cause the endometrial tissue itself to atrophy.
Inducing Pseudomenopause. Gonadotropin-releasing hormone (GnRH) agonists or gestrinone, an anti-progesterone that mimic menopause. They reduce estrogen and progesterone to their lowest level.
Inducing On-going Blockage of Ovulation. Danazol, a derivative of male hormones, is a powerful ovulation blocker.

Studies report that around 80% of women achieve pain relief after taking these drugs. To date, comparison studies have found few differences in effectiveness among the major hormonal treatments. Differences occur mostly in their side effects. Women should discuss the effects of particular medications with their doctors to determine the best choice.

Oral contraceptives (OCs), commonly called "the Pill," contain combinations of an estrogen and a progestin (either a natural progesterone or the synthetic form called progestin). For some patients, OCs may provide better endometriosis pain relief than gonadotropin releasing hormone agonist drugs. OCs may reduce the risk of ovarian cancer by 30 - 50% and of endometrial cancer by 50%, a potentially important benefit in women with endometriosis. Patch contraceptives are available, but they may increase the risk for menstrual cramping.

Click the icon to see an illustrated series detailing the birth control pill.

When used throughout a menstrual cycle, OCs suppress the actions of other reproductive hormones (luteinizing hormone, or LH, and follicle stimulating hormone, or FSH) and prevent ovulation. There are many brands available. The estrogen compound used in most oral contraceptives is estradiol. Many different progestins are used, and there are many brands. None to date have proven to be superior over others. Women should discuss the best options for their individual situations with their doctor.

Standard OCs come in a 28-pill pack that contains 21 active pills and 7 inactive pills. Newer “continuous-dosing” (also called “continuous-use”) oral contraceptives aim to reduce -- or even eliminate -- monthly periods and thereby prevent the pain and discomfort that often accompanies menstruation. These OCs contain a combination of estradiol and the progesterone levonorgestrel, but use extending dosing of active pills.

Seasonale, the first continuous-dosing contraceptive, was approved in 2003. It contains 81 days of active pills followed by 7 days of inactive pills. Women who take Seasonale have on average a period every 3 months. Seasonique, a follow-up to Seasonale, was approved in 2006. As with Seasonale, it produces about 4 periods a year. With Seasonique, a woman takes 84 days of levonorgestrol-estradiol pills followed by 7 days of pills that contain only low-dose estradiol.

In 2007, the FDA approved Lybrel, which supplies a daily low dose of levonorgestrel and estradiol with no inactive pills. Because Lybrel contains only active pills, which are taken 365 days a year, it completely eliminates monthly menstrual periods. In clinical trials, 59% of women who took Lybrel completely stopped menstrual periods by the end of the first year. Some women, however, experienced occasional unscheduled bleeding or spotting during the first 3 - 6 months.

Estrogen and progestin each cause different side effects. The most serious side effects are due to the estrogen in the combined pill. Uncommon but more dangerous complications of OCs include high blood pressure and deep-vein blood clots (thrombosis), which may contribute to heart attack or stroke. Studies have been conflicting about whether estrogen in oral contraception increases the chances for breast cancer and, if it does, which women are at risk.

Progestins alone may be helpful and are the oldest drugs used for endometriosis. Progestins can prevent ovulation and reduce the risk for endometriosis in the following ways:

They block luteinizing hormone (LH), one of the reproductive hormones important in ovulation.
They change the lining of the uterus and eventually cause it to atrophy.
They may provide pain relief equivalent to the more powerful hormone drugs. Some experts recommend them as the first choice for women with endometriosis who do not want to become pregnant.

Specific Progestins. Progestins are available in pill or injectable form, or as a progestin-releasing intrauterine device (IUD). Medroxyprogesterone (Depo-Provera), which is administered by injection every 3 months, is one of the standard progestins used. A new low-dose formulation, Depo-subQ Provera 104, was approved in 2005. Oral progestins include norethindrone (Micronor, Aygestin, Norlutate). Norethindrone is also known as norethisterone.

A 2006 study compared low-dose depot medroxyprogesterone with the gonadotropin releasing hormone (GnRH) agonist leuprolide (Lupron). The two drugs worked equally well in controlling endometriosis pain. However, leuprolide caused more loss of bone mineral density, a condition associated with osteoporosis. Patients who received medroxyprogesterone injections had fewer hot flashes than those who received leuprolide, but they had more episodes of bleeding and spotting.

Progestin-releasing IUDs can be very helpful for many women with endometriosis, particularly an advanced version called the levonorgestrel-releasing intrauterine system, or LNG-IUS (Mirena). Studies suggest that the LNG-IUS reduces endometrial cell proliferation and increases cell self-destruction. Progestin released by the IUD mainly affects the uterus and cervix and causes fewer widespread side effects than other forms of progestins.

The LNG-IUS has proved effective for heavy bleeding (menorrhagia), and studies indicate that it helps control the symptoms of minimal-to-moderate endometriosis. Studies indicate that the LNG-IUS works as well as GnRH agonists in managing endometriosis pain, and causes less loss of estrogen. Some experts think that the LNG-IUS could become the treatment of choice for women with endometriosis pelvic pain who do not wish to become pregnant.

Click the icon to see an image of an IUD.

Side Effects of Progestins. Side effects of progestin occur in both the combination oral contraceptives and any contraceptive that uses only progestin, although they may be less or more severe depending on the form and dosage of the contraceptive. Side effects may include:

Changes in uterine bleeding, such as higher amounts during periods, spotting and bleeding between periods (called break-through bleeding), or absence of periods
Unexpected flow of breast milk
Abdominal pain or cramps
Diarrhea
Fatigue, unusual tiredness, weakness
Hot flashes
Decreased sex drive
Nausea
Trouble sleeping
Acne or skin rash (although low-dose OCs actually improve acne)
Depression, irritability, or other mood changes
Swelling in the face, ankles, or feet
Weight gain

Newer formulations of combination pills that use low-dose estrogen and newer progestins may reduce and even avoid many of these side effects. Progestins used in non-oral contraceptives, such as the LNG-IUS IUD, also may not pose as high a risk for these side effects. If side effects persist or are severe, a woman should always talk to her doctor. Many women do not experience these side effects, or if they do, their bodies eventually adjust.

Gonadotropin releasing hormone (GnRH) agonists are effective hormone treatments for endometriosis. They are able to block the release of the reproductive hormones LH (luteinizing hormone) and FSH (follicular-stimulating hormone). As a result, the ovaries stop ovulating and no longer produce estrogen. Ovulation and menstruation resume around 4 - 10 weeks after stopping the drug. The specific length of time depends on the type of GnRH agonist used.

Women with endometriosis often have a difficult time getting pregnant. A 2006 review suggested that GnRH agonists may help women with endometriosis become pregnant when the drug is given along with in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). (IVF and ICSI are standard infertility treatments.) The review found that 3 - 6 months of GnRH therapy in combination with infertility treatment quadrupled the pregnancy rate. However, the study did not supply data on how many women actually gave birth. In addition, there is not enough information on whether these drugs may adversely affect a woman or her fetus.

Specific GnRH Agonists. GnRH agonists include goserelin (Zoladex), buserelin, a monthly injection of leuprolide (depot Lupron), and a nasal spray, Nafarelin (Synarel). Studies have reported that nafarelin shrank all implants and significantly relieved symptoms in 85% of patients, delayed recurrence of endometriosis after surgery, and in comparison with leuprolide, was less expensive, had fewer side effects, and a provided better quality of life.

Side Effects and Complications. Commonly reported side effects (which can be severe in some women) include menopause-like symptoms that include hot flashes, night sweat, and changes in the vagina, weight change, and depression. The side effects vary in intensity depending on the GnRH agonist. They may be more intense with leuprolide and persist after the drug has been stopped.

The most important concern is possible osteoporosis from estrogen loss. Women ordinarily should not take GnRH agonists for more than 6 months. Certain approaches may preserve enough estrogen to protect bones and still effectively relieve endometriosis symptoms:

Add-back therapy provides doses of estrogen and progestin that are high enough to maintain bone density, but are too low to offset the beneficial effects of the GnRH agonist. Studies suggest this is safe and effective for protecting bone.
Intermittent leuprolide uses repeated 6-month courses of GnRH agonists followed by an average of 9 months of symptom control only.
Taking GnRH agonists in very low doses is an alternate approach, but is still largely untested.
Adding bone-protective drugs may be helpful. The standard ones are bisphosphonates and include alendronate (Fosamax), risedronate (Actonel), and etidronate (Didronel). Other drugs are being tested in combination with a GnRH agonist to preserve bone. They include the parathyroid hormone teriparatide (Forteo) and selective estrogen-receptor modulators (SERMs), such as raloxifene (Evista).

Danazol (Danocrine) is a synthetic drug that resembles a male hormone (androgen). It suppresses the pathway leading to ovulation. Studies have shown symptomatic improvement in 90% of women, although in one study, only about 58% of women expressed satisfaction with this therapy. A high drop-out rate occurs, most often because of adverse side effects, particularly male characteristics, such as growth of facial hair, acne, weight gain, dandruff and deepening of the voice.

Danazol may increase the risk for unhealthy cholesterol levels. A few cases of blood clots and strokes have also been reported, as well as rare cases of liver damage. One study reported that taking a low dose may relieve endometrial symptoms and reduce the risk for these side effects. Exercise may also help reduce side effects. As with GnRH drugs, pregnant women or those trying to become pregnant should not take this drug because it may cause birth defects.

Antiprogestins are promising drugs for endometriosis because they reduce both estrogen and progesterone receptors.

Gestrinone. Gestrinone is the most studied antiprogestin and appears comparable to GnRH agonists in reducing pain and while causing fewer menopausal symptoms. In one study, bone density even increased slightly. Adverse effects of gestrinone include male hormone symptoms, such as acne, and possibly the development of unhealthy cholesterol levels.

Mifepristone. Mifepristone (Mifeprex) is another antiprogestin that may be helpful for treating endometriosis. In one 6-month study, mifepristone improved symptoms and reduced endometrial implants without causing menopausal side effects. Long-term use, however, may cause changes in the uterine tissue and cell proliferation.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs). Over-the-counter NSAIDs may be sufficient for about 75% of women with endometrial pain. NSAIDs block prostaglandins (the substances that increase uterine contractions). They are effective painkillers and also have other properties that act against inflammatory factors. Aspirin is the most common NSAID, but there are dozens of others available over the counter or by prescription. Among the most effective NSAIDs for menstrual disorders are ibuprofen (Advil, Motrin, Midol PMS), naproxen (Aleve, Naprosyn, Naprelan, Anaprox), and mefenamic acid (Ponstel). For maximum benefit, they should be taken 7 - 10 days before a period is expected. However, long-term use of NSAIDs can increase the risk for gastrointestinal bleeding and ulcers. One study of women with iron deficiency anemia reported that overuse of NSAIDs for menstrual disorders contributes to anemia.

Acetaminophen. Acetaminophen (Tylenol) reduces levels of female hormones (gonadotropins and estradiol, an estrogen), which may have some beneficial effect on menstrual disorders. A combination of acetaminophen and pamabrom (Women's Tylenol Menstrual Relief) is specifically aimed at treating menstrual pain and bloating. (Pamabrom is a diuretic, a drug used to reduce fluid build-up and bloating.)

Opioids. Drugs containing codeine should not generally be used for endometriosis pain management. They can cause pelvic congestion and constipation, which can worsen symptoms in patients with gastrointestinal distress.

GnRH Antagonists. GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). These newer drugs differ from GnRH agonists in that they have a direct effect on the pituitary gland. The result is quicker action. They also pose a lower risk for complications and side effects.

Aromatase Inhibitors.Drugs that inhibit aromatase, an enzyme that is a major source of estrogen, are being studied for effects against endometriosis. Such drugs include anastrozole, letrozole, exemestane, and vorozole. Aromatase levels may be abnormal in women with endometriosis. A 2004 pilot study of letrozole combined with a progestin showed reduction of endometriosis as well as decrease in pelvic pain, suggesting that this treatment holds promise.

Selective Estrogen-Receptor Modulators (SERMs). Drugs known as selective estrogen-receptor modulators (SERMs) are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. They have not been widely studied for endometriosis since tamoxifen (Nolvadex), the most commonly used SERM, may worsen endometriosis. However, the actions of other SERMs, such as raloxifene (Evista) or tibolone (only available in Europe), may be beneficial and warrant more research.

Selective Progesterone Receptor Modulators (SPRMs). SPRMs, also called mesoprogestins, have both agonist and antagonist properties. This new class of drugs may be effective for suppressing endometrial growth.

Other investigational drugs for treatment of endometriosis include tumor necrosis factor alpha (TNF-alpha) inhibitors, angiogenesis inhibitors, and various immune modulators.

Conservative Surgery

The goal of conservative surgery is to aggressively remove as many endometrial implants and cysts as possible without causing surgical scarring and subsequent adhesions that could cause fertility problems. The two conservative procedures used are either laparoscopy or laparotomy.

Improving Fertility. Surgery has been shown to improve infertility rates in women with severe endometriosis (stages III and IV). Whether it offers any advantage in pregnancy rates in women with mild-to-moderate endometriosis (stage I or II) is unclear. Nevertheless, some doctors recommend conservative surgery even in early-stage endometriosis, because of the progressive nature of the disorder some evidence suggests it improves fertility. Fertility can often be restored even if the surgery does not remove all the endometrial implants. However, the best fertility rates in such cases occur in the early postoperative period. They decline over time if implants have not been completely eliminated. Subsequent surgeries become less effective in restoring fertility.

Reducing Pain and its Recurrence. Studies report pain reduction after surgery in more than 60% of women. Conservative surgery, however, can miss microscopic implants that may continue to cause pain and other symptoms after the procedure.

Even with very successful surgery, endometriosis usually recurs within a period of between 2 months and several years. In one study, the risk for recurrence after conservative surgery was highest in women who have had previous surgery or who have stage IV disease (large endometriotic cysts). Other factors including age, pregnancy, or the number of cysts, did not seem to influence the degree of risk. An earlier study indicated that women who became pregnant after surgery for endometriosis had a lower risk for recurrence, but pregnancy itself does not cure endometriosis. The use of GnRH agonists after surgery may delay recurrence without affecting fertility.

Both laparoscopy and laparotomy are effective, but there are differences. Some experts believe that laparoscopy surgery should be the treatment of choice for women with endometriosis.

Laparoscopy is currently the gold standard treatment for endometriosis. It is usually done under general anesthetic and involves the following:

Carbon dioxide gas is injected into the abdomen, distending it and pushing the bowel away so that the doctor has a wider view.
The procedure requires making small incisions at the navel and above the pubic bone.
The laparoscope (a hollow tube equipped with camera lenses and a fiber optic light source) is inserted through the incision at the navel (the umbilical incision).
A probe is then inserted through the second incision, allowing the doctor to directly view the outside surface of the uterus, fallopian tubes, and ovaries.
One or two additional small incisions can be made on either side of the lower abdomen through these incisions. Surgical instruments or other devices are passed through these accessory incisions to destroy or remove abnormal tissue. Implants can be removed by excision (surgical removal) using a laser or scissors or by destroying the area with lasers or with electricity (or electrocautery).

In one study, laparoscopy achieved pain relief in over 62% of women. A more recent study conducted 3 - 12 months post-surgery in women with severe (stage III/IV) endometriosis suggested 88% of patients were satisfied with the procedure.

In addition, pregnancy rates can range from 20% to over 50% after laparoscopy. (The procedure does not reduce the chances for pregnancy in women who must still undergo assisted reproductive techniques to conceive.) Still, recurrence rates for laparoscopy are no better than those with laparotomy -- the more invasive procedure.

Laparotomy uses a wide abdominal incision and conventional surgical instruments. It is more invasive and requires a longer recovery time. In some severe cases, the doctor may need a wider view of the pelvic area and will perform this procedure. Laparotomy is typically used for infiltrating endometriosis, although the less invasive laparoscopy is showing increasing effectiveness, even for deep implants.

Complications after Surgery. Many patients experience temporary but severe discomfort in the shoulders after laparoscopy due to residual carbon dioxide gas that puts pressure on the diaphragm. The incisions, even with laparoscopy, may cause pain afterward, which can usually be treated effectively with mild pain relievers. There are small risks for bleeding, infection, and reaction to anesthesia. Surgery in the pelvic area may also cause scarring, which may cause pain and interfere with fertility.

Preoperative Drug Treatment. Hormonal drugs administered before laparoscopy and laparotomy are being investigated to reduce the size of endometrial cysts and so perhaps to improve outlook. A 2000 study, for example, reported that the GnRH agonist goserelin injected monthly 12 weeks before laparoscopy resulted in much smaller implants and better treatment of the disease than treatment with surgery alone.

Postoperative Drug Treatment. A number of studies have also been conducted to determine if taking hormonal drugs after surgery can provide further pain relief. Results have been mixed, and the benefits, if any, are probably slight.

Some evidence suggests that surgically cutting the pain-conducting nerve fibers leading from the uterus diminishes the pain from dysmenorrhea. Two procedures, uterine nerve ablation and laparoscopic presacral neurectomy, can block such nerves. Small studies have shown benefits from these procedures, but stronger evidence is needed before they can be recommended for women with severe primary dysmenorrhea.

Laparoscopic Uterosacral Nerve Ablation (LUNA). LUNA is a recent approach that uses either laser or cauterization to destroy nerves in a small segment of the ligaments that connect the cervix with the lower back. The ligaments do not appear to provide any structural support. There are few side effects from the procedure. The patient does not lose any sensations associated with sexual activity.

Laparoscopic Presacral Neurectomy (LPSN). LPSN uses laser techniques to sever a web of nerves between the lower spine and tail bone that transmit pain from the uterus. The procedure does not affect fertility. Studies suggest that it may work better than LUNA in the long term, but it also poses a higher risk of complications. These complications include constipation, diarrhea, and urinary problems. However, many women find that these symptoms eventually improve.

Hysterectomy

Presence of symptoms (pelvic pain, bleeding, symptomatic fibroids)
Lack of symptom improvement or resolution despite treatment
Previous use of GnRH agonist drugs

The number of procedures has continued to increase, but only slightly in recent years. Endometriosis accounts for 18% of these procedures, but the rates vary widely by ethnic group, with the great majority of endometriosis-related hysterectomies performed in Caucasian women.

Hysterectomy does not necessarily cure endometriosis. One study reported that endometriosis reappeared in 13% of women within 3 years of a hysterectomy and in 40% after 5 years.

Most women are satisfied with the procedure. A major analysis of evidence on hysterectomies reported that symptoms related to menstrual problems decline significantly in most women, although none completely disappear for all women. The majority of women also experience improved quality of life and emotional functioning. Women who have a hysterectomy are less likely to experience hot flashes than women who have a natural menopause.

Still, one study suggested that 70% of recommendations for hysterectomies did not meet the standard of care as determined by expert groups. In such cases, patients were not given alternative choices or adequate diagnostic evaluations. Any woman, even one who has reached menopause, who is uncertain about a recommendation for a hysterectomy should certainly seek a second opinion.

Once a decision for a hysterectomy has been made, the patient should discuss with her doctor what will be removed. The common choices are:

Total Hysterectomy (Removal of uterus and cervix). Removing only the uterus with hysterectomy has the same risk for recurrence as conservative surgery.
Supracervical Hysterectomy (Removal of uterus and preservation of the cervix). Procedure is performed in about 20 - 25% of cases.
Bilateral Salpingo-Oophorectomy (Removal of the fallopian tubes and ovaries). It can be used with either total or supracervical hysterectomy. This is the only potential cure for endometriosis. If endometriosis has developed outside the uterus then even this procedure is not curative.

Hysterectomy is surgical removal of the uterus, resulting in inability to become pregnant. This surgery may be done for a variety of reasons including, but not restricted to, chronic pelvic inflammatory disease, uterine fibroids and cancer. A hysterectomy may be done through an abdominal or a vaginal incision.

Total Hysterectomy. In a total hysterectomy the uterus and cervix are removed; this eliminates the risk of uterine and cervical cancer. (Given technical advances and growing surgical experience, a total hysterectomy may eventually be unnecessary except in special circumstances, such as when cancer is present.)

Supracervical Hysterectomy. In a supracervical hysterectomy (also called subtotal hysterectomy), only the uterus is removed. Retaining the cervix helps support the pelvic floor and may help maintain full sexual sensation, but the risk for cervical cancer remains. Women may experience cyclical bleeding for up to a year after surgery.

Bilateral Oophorectomy. Bilateral oophorectomy is the removal of both ovaries. (When only one ovary is removed, the procedure is called oophorectomy.) Bilatera salpingo-oophorectomy is the removal of both fallopian tubes plus both ovaries. These procedures may be performed with either total or supracervical hysterectomy. When a woman decides to have her ovaries removed, she should be aware of both the positive and negative consequences.

Oophorectomy significantly reduces the rates of re-operation and endometrial pain recurrence compared to hysterectomy alone. By removing the ovaries, oophorectomy causes estrogen loss and helps to reduce the risk for ovarian cancer and breast cancer. Premenopausal women should realize, however, that oophorectomy causes immediate menopause, which poses a risk for a number of health problems. These problems include osteoporosis, heart disease, skin wrinkling, and reduction in muscle tone. Estrogen replacement can help offset them. Women who have a bilateral oophorectomy and do not receive hormone replacement therapy may experience more severe hot flashes than women who enter menopause naturally.

Abdominal Hysterectomy. Abdominal hysterectomy is the most common procedure and is used in over 80% of hysterectomies in African-American women and about 60% in Caucasian and other ethnic groups. With the abdominal procedure, a wide incision is required to open the abdominal area, from which the surgeon removes the uterus. If possible, the incision should cut horizontally across the top of the pubic hairline (called a bikini incision). This incision heals faster and is less noticeable than a vertical incision, which is used in more complicated cases. The patient may need to remain in the hospital for 3 - 4 days, and recuperation at home takes about 4 - 6 weeks.

Vaginal Hysterectomy. Vaginal hysterectomy requires only a vaginal incision through which the uterus is removed. It is used in less than 20% of cases in African-American women and slightly under 40% among Caucasian and other groups.

A variation of the vaginal approach is called laparoscopic-assisted vaginal hysterectomy (LAVH). It uses several small abdominal incisions through which the surgeon severs the attachments to the uterus and ovaries. They can then be removed through the vaginal incision, as in the standard approach. Hospitalization stays may be longer and costs are greater than with standard vaginal hysterectomy. The use of LAVH has risen significantly and is now employed in over a quarter of vaginal procedures. LAVH is very costly, however, and some experts question whether it adds any significant benefits compared to the standard vaginal procedure.

If possible, a patient should ask a family member or friend to help out for the first few days at home. The following are some of the precautions and tips for postoperative care:

For a day or two after surgery, the patient is given medications to prevent nausea and painkillers to relieve pain at the incision site.
As soon as the doctor recommends it, usually within a day of the operation, the patient should get up and walk in order to help prevent pneumonia, reduce the risk of blood-clot formation, and to hasten recovery.
Walking and slow, deep breathing exercises may help to relieve gas pains, which can cause major distress for the first few days.
Coughing can cause pain, which may be reduced by holding a pillow over a surgical abdominal wound or by crossing the legs after vaginal surgery.
Patients are advised not to lift heavy objects, not to douche or take baths, and not to climb stairs or drive for several weeks.
For the first few days after surgery, many women weep frequently and unexpectedly. These mood swings may be due to depression from the loss of reproductive capabilities and form abrupt changes in hormones, particularly if the ovaries have been removed.

The patient should discuss with the doctor when they can start exercise programs that more intense than walking. The abdominal muscles are important for supporting the upper body, and recovering strength may take a long time. Even after the wound has healed, the patient may experience an on-going feeling of overall weakness, which can be demoralizing, particularly in women used to physical health. Some women do not feel completely well for as long as a year; others may recover in only a few weeks.

More serious complications, such as those described below, are uncommon, but patients should be aware of their symptoms and call the doctor immediately if they occur.

Infection. Infection occurs in 10 - 15% of patients, the risk being higher with abdominal than with vaginal surgery. Risk factors for infection appear to be obesity, a longer than normal operative time, and low socioeconomic status. Patients should be aware of any symptoms and call the doctor immediately if they occur:

Continuing or increasingly severe pain
Fever
Heavy discharge
Bleeding (antibiotics given at the time of surgery help to reduce this risk)

Click the icon to see an image of thrombophlebitis.

Other Serious Complications. Other serious and even life-threatening complications are rare but can include:

Pulmonary embolism (blood clots that travel to the lung)

Click the icon to see an image of a pulmonary embolism.

Surgical injury of the urinary or intestinal tracts.
Abscesses.
Perforation of the bowel.
Fistulas (a passage that bores from an organ to the skin or to another organ).
Dehiscence (opening of the surgical wound).

Long-Term Complications. Women who have had a total hysterectomy are at higher risk for the following long-term complications:

Muscle weakness in the pelvic area.
Prolapse (descent) of the bladder, vagina, and rectum if the muscle’s walls are overly weakened; may require further surgery.
Bowel problems may develop if adhesions (extensive scarring) have formed and obstruct the intestines, sometimes requiring additional surgery.
Shortening of the vagina is a possible complication specific to vaginal hysterectomy. It can cause pain during intercourse.

Such complications are uncommon.

Two procedures associated with hysterectomy may affect sexuality directly.

Although the clitoris can trigger orgasm even if the cervix is removed, some experts believe that uterine contractions stimulated by sexual intercourse also cause a so-called “deep orgasm.” Retaining the cervix may help to retain this sensation. However, a 2006 review found that women who undergo a total hysterectomy (removal of both uterus and cervix) are no more likely to have sexual difficulties or problems with urinary and bowel function than women who have only their uterus removed.
Patients who have both ovaries removed may be at higher risk for loss of sexuality. Ovaries produce small amounts of testosterone (the male hormone responsible for sexual drive) even after menopause.

Testosterone Replacement. Testosterone replacement therapy may restore sexuality in women who experience a decline in sexual drive. Occasionally, oral or injection treatments can produce male characteristics such as facial hair and voice change. A slow-release pellet inserted every 6 months under the skin in the hip appears to reduce these side effects. Taking hormones long-term almost always carries some risk, and it is not yet known what danger testosterone replacement may pose in women.

Resources

www.asrm.com -- American Society for Reproductive Medicine
www.acog.com -- American College of Obstetricians and Gynecologists
www.endometriosisassn.org -- The Endometriosis Association
www.nichd.nih.gov -- National Institute of Child Health and Human Development
www.endozone.org -- Endometriosis Zone
www.pelvicpain.org -- International Pelvic Pain Society
www.endocenter.org -- Endometriosis Research Center
www.resolve.org -- National Infertility Association

References

Archer DF, Jensen JT, Johnson JV, Borisute H, Grubb GS, Constantine GD. Evaluation of a continuous regimen of levonorgestrel/ethinyl estradiol: phase 3 study results. Contraception. 2006 Dec;74(6):439-45. Epub 2006 Sep 18.

Chen WY, Manson JE, Hankinson SE, Rosner B, Holmes MD, Willett WC, et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Arch Intern Med. 2006 May 8;166(9):1027-32.

Han SH, Hur MH, Buckle J, Choi J, Lee MS. Effect of aromatherapy on symptoms of dysmenorrhea in college students: A randomized placebo-controlled clinical trial. J Altern Complement Med. 2006 Jul-Aug;12(6):535-41.

Lethaby A, Ivanova V, Johnson NP. Total versus subtotal hysterectomy for benign gynaecological conditions. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD004993.

Parker JD, Leondires M, Sinaii N, Premkumar A, Nieman LK, Stratton P. Persistence of dysmenorrhea and nonmenstrual pain after optimal endometriosis surgery may indicate adenomyosis. Fertil Steril. 2006 Sep;86(3):711-5. Epub 2006 Jun 16.

Review Date:
6/16/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Weight control and diet

FitSugar — Wed, 08 Oct 2008 17:34:58 -0700

In This Report

Highlights
Introduction
Biological and Medical Caus...
Cultural and Emotional Caus...
Risk Factors
Complications
Weight Loss and Maintenance...
Weight Management
Medications
Other Treatments
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Cancer and Weight Control:

Cancer prevention guidelines from the American Cancer Society stress the importance of maintaining a healthy weight throughout life. A healthy weight is even more important than eating specific healthy foods, when it comes to cancer prevention.

Drug Warning:

The US Food and Drug Administration (FDA) is warning consumers not to buy a product known as the "Brazilian diet pill." This product is labeled as a dietary supplement, but contains several chemicals found in powerful prescription drugs. The products are also known as Emagrece Sim and Herbathin dietary supplements.

New Over-the-Counter Medication:

In February 2007, the FDA approved the first over-the-counter (OTC) weight-loss drug. Orlistat, previously available only by prescription as Xenical, will be available OTC at half its prescription strength. It will be sold under the name alli. Those eager to use the new pill should consider its cost and modest benefits compared with its side effects, most commonly oily diarrhea. This pill, which prevents fat absorption from food, also increases the risk of not absorbing important nutrients from food while using it. The FDA recommends taking a daily multivitamin supplement when using alli.

Research News:

A small study in Norway found that a diet low in fat and high in carbohydrates ("carbs") increases symptoms of psychological distress, such as depression and anger. The study compared three different diets with varying amounts of fat and carbohydrates.
A study released in March 2007 found that obesity in young girls results in early puberty -- as early as age 9.

Effects of Obesity on the Body:

Obesity is associated with certain problems related to infertility, such as uterine fibroids or menstrual irregularities. In men, obesity can contribute to reduced testosterone levels.
People who are obese are at higher risk for carpal tunnel syndrome and other problems involving nerves in their wrists and hands.
The Pickwickian syndrome, named for an overweight character in a Dickens novel, occurs in severe obesity when lack of oxygen produces intense and chronic sleepiness and, eventually, heart failure.

Introduction

A stable weight depends on a good balance between the energy you get from food and the energy you use. You use energy during the day in three ways:

As energy expended during rest (basal metabolism)
As energy used to break down food (thermogenesis)
As energy used during physical activity

Basal metabolism accounts for about two-thirds of spent energy. Your body generally uses this energy to keep your body temperature steady and keep the muscles of your heart and intestine working. Thermogenesis accounts for about 10% of spent energy.

When a person consumes more calories than the energy they use, the body stores the extra calories in fat cells. Fat cells function as energy reservoirs. They enlarge or shrink depending on how people use energy. If people do not balance energy input and output by eating right and exercising, fat can build up. This can lead to weight gain.

When energy input is equal to energy output, there is no expansion of fat cells (lipocytes) to accommodate excess. It is only when more calories are taken in than used that the extra fat is stored in the lipocytes and the person begins to accumulate fat.

Obesity is determined by measuring body fat, not just body weight. People might be over the weight limit for normal standards, but if they are very muscular with low body fat, they are not obese. Others might be normal or underweight, but still have excessive body fat. The following measurements and factors are used to determine whether or not a person is overweight to a degree that threatens their health:

Body mass index (BMI) (a measure of body fat)
Waist circumference (size around the waist)
Waist-hip ratio
Skin fold measurement (anthropometry)
The presence or absence of other disease risk factors (e.g., smoking, high blood pressure, unhealthy cholesterol levels, diabetes, relatives with heart disease)

A person's disease risk factors plus BMI may be the most important components in determining health risks with weight.

The Body Mass Index (BMI). The current standard measurement for obesity is the body mass index (BMI). In general, a BMI of 25 - 29.9 means you are overweight. Obesity is a BMI of 30 and above. Obesity is then classified into three categories:

Class 1: BMI of 30 - 34.9
Class II: BMI 35 - 39.9
Class III: BMI of 40 and greater

These guidelines are very important for people at risk for diabetes, heart disease, or certain cancers. It is also used to determine treatment approaches such as when surgery may be appropriate. The higher the BMI, the greater the risk for significant health problems.

Calculating Body Mass Index (BMI). One's body mass index (BMI) is calculated by multiplying a person's weight in pounds by 703, dividing by the height in inches, and then dividing that number by the height in inches. The steps are as follows:

Multiply one's weight in pounds by 703
Divide that answer by height in inches
Divide that answer again by height in inches

For example, a woman who weighs 150 pounds and is five feet eight inches (or 68 inches) tall has a BMI of 22.8.

Waist Circumference and Waist-Hip Ratio. The extent of abdominal fat can also be used in assessing risk of disease. Some studies suggest that:

Women whose waistlines are over 31.5 inches and men whose waists measure over 37 inches should watch their weight.
A waist size greater than 35 inches in women and 40 inches in men is associated with a higher risk for heart disease, diabetes, and impaired functioning.

Evidence strongly suggests that more body fat around the abdomen and hips (the apple-shape) is a more consistent predictor of heart problems and health risks than BMI.

The distribution of fat can be evaluated by dividing waist size by hip size. For example, a woman with a 30-inch waist and 40-inch hip circumference would have a ratio of 0.75; one with a 41-inch waist and 39-inch hips would have a ratio of 1.05. The lower the ratio the better. The risk of heart disease rises sharply for women with ratios above 0.8 and for men with ratios above 1.0.

Click the icon to see a depiction of the waist-to-hip ratio.

Anthropometry. Anthropometry is the measurement of skin fold thickness in different areas, particularly around the triceps, shoulder blades, and hips. This measurement is useful in determining how much weight is due to muscle or fat.

Biological and Medical Causes

Obesity results when a person consumes more calories than they need for the energy they use. Several different factors may influence weight gain.

About 90% of people who lose weight through dieting gain every pound back regardless of their weight-loss method.

Some evidence suggests that every person has an inherited weight. This range varies by only about 10% either up or down from some set point. For instance, a man whose "genetically-determined" weight is 200 pounds would tend to swing from 180 - 220 pounds. He would be unlikely to lose or gain more than this.

Genetic factors may play some part in 70 - 80% of obesity cases.

Appetite is determined by processes that occur both in the brain and gastrointestinal tract. Eating patterns are controlled by areas in the hypothalamus and pituitary glands (in the brain). The body produces a number of molecules that increases or decreases appetite. In some cases, the following factors may produce imbalances in this process:

Insulin. Insulin is a hormone that helps change blood sugar (glucose) into energy. During digestion, carbohydrates from our diet break down into different types of sugar molecules (including glucose). Proteins from our diet break down into smaller molecules called amino acids. Immediately after eating, blood glucose levels rise. This triggers the release of insulin, which pours into the bloodstream. Insulin pushes the glucose and amino acids into cells and muscles. Insulin and other hormones determine which nutrients will be burned for energy or stored for future use. The inability to use insulin efficiently (insulin resistance) has been associated with both obesity and diabetes.
Leptin. Leptin is a hormone that is released by fat cells. A number of scientists think this hormone may also be released by cells in the stomach. Leptin appears to play an important role in insulin resistance and fat storage in the body, but its role in obesity is unclear. The most likely scenario is that leptin levels rise as the cells store more fat. This increase in leptin levels decreases appetite. Falling levels of leptin make you feel hungry. In people who have genetically lower levels of leptin, however, the brain may be tricked into thinking that it is always starving because there is no leptin to decrease appetite. This can lead to weight gain.
Resistin. Resistin is a hormone produced by fat cells. It makes the body resistant to insulin activity. Some experts believe it may help explain the role of obesity in diabetes type 2.
Intestinal Chemicals. Ghrelin is a chemical produced in the stomach. It appears to be important in triggering the desire to eat. Peptide YY3–36 (PYY) is a substance secreted in the intestines after a meal. The level of PYY is proportionate to the number of calories a person eats. PYY tells the brain that you feel full. Deficiencies in ghrelin and PYY may contribute to some cases of obesity. Researchers are hoping that blocking ghrelin or infusing PYY may be possible treatments for obesity.
Other Chemicals. Many brain chemicals are being studied for their role in appetite stimulation and weight gain. Among them are neuropeptide Y, melanocortins, agouti-related protein, and melanocyte stimulating hormone. Pain-relieving chemicals called endorphins may be critical in reducing appetite and regulating energy use. Cholecystokinin, a hormone released in the upper intestine that stimulates digestive juices, may work to control meal size.

Insulin is a hormone produced by the pancreas that is necessary for cells to be able to use blood sugar.

Genetics may directly contribute to severe obesity in people with family histories of the problem. Genetic factors such as slow metabolisms may also make people more likely to be overweight. At least seven genetic mutations have been associated with specific and uncommon cases of severe obesity. Some are outlined below.

HOB1 (human obesity 1) is a gene that is linked to a high BMI in women.
Leptin gene variants have been linked to leptin deficiencies and obesity.
Melanocortin-4 receptor is a gene that helps turn off the urge to eat. It may not work properly in those with a family history of obesity.
Researchers have also identified a mutation in a gene for a protein called proopiomelanocortin, which results in a syndrome of obesity, red hair, and deficiencies in stress hormones.
A protein called agouti-related protein increases hunger. About 5% of severely obese people have mutations that over-respond to agouti-related protein.

Genetics also determine the number of fat cells a person has. Some people are simply born with more. It should be noted that even when genetic factors are present, a person can still control their diet.

The Thrifty Gene. Some experts think the existence of a so-called "thrifty" gene regulates changes in hormone levels, to accommodate seasonal changes. Theoretically, it works in the following manner:

In certain populations, hormones are released during seasons when food supplies have traditionally been low. This leads to insulin resistance and increased fat storage.
The process is reversed in seasons when food is readily available.
Because modern industrialization has made high carbohydrate and fatty foods available all year long, the gene no longer serves a useful function. Fat, originally stored for famine situations, is not used.

This theory could explain why the previously nomadic Native American tribes who now have Western dietary habits have such high rates of Type 2 diabetes and obesity. In the past, the traditional low-fat, high-fiber foods tribe members ate may have protected them from obesity and type 2 diabetes. Today, these tribes' diet consists of more Western foods, which are higher in fat. Furthermore, these foods are readily available year-round, and many members of the tribe are sedentary. The result is a very high incidence of Type 2 diabetes and obesity. Although genetic abnormalities may make it harder or easier to lose weight, the occurrence of obesity has dramatically increased over the past two decades, and genes cannot have changed within that short amount of time. Our ability to use the food that we eat evolved so that our body could conserve energy and store fat during times of famine. Most cases of obesity now occur in people with normal body function who live in industrialized nations, where there is more than enough food.

A number of medical conditions may contribute to being overweight, but rarely are they a primary cause of obesity.

Hypothyroidism is sometimes associated with weight gain. But, patients with an underactive thyroid generally show only a moderate weight increase of five to 10 pounds.
Very rare genetic disorders, including Froehlich's syndrome in boys, Laurence-Moon-Biedl, and the Prader-Willi syndromes, cause obesity.
Abnormalities or injury to the hypothalamus gland can cause hypothalamic obesity.
Cushing's disease is a rare condition caused by high levels of steroid hormones. It results in obesity, a moon-shaped face, and muscle wasting.
Obesity is also linked to polycystic ovarian syndrome, a hormonal disorder in women.

Click the icon to see an image of polycystic ovaries.

Some prescription medications contribute to weight gain, usually by increasing appetite. Such drugs include the following:

Corticosteroids
Female hormone treatments, including some oral birth control pills (effect is usually temporary), and certain progestins (such as Megestrol) used to treat cancer
Antidepressants and anti-psychotic drugs, including lithium and valproate
Insulin and insulin-stimulating drugs used to treat diabetes often lead to weight gain, a particularly unfortunate conflict of interest for obese individuals with type 2 diabetes

You should not stop taking any medications without your doctor's knowledge.

Cultural and Emotional Causes

Enough food is produced in the US to supply 3,800 calories every day to each man, woman, and child in the country, far more than the average person needs to sustain life. In a 2002 study, participants carefully recorded everything they ate and drank, and all activities and psychological factors surrounding the eating events. The people who gained weight ate more and their portions were larger than those who did not. This may be an obvious conclusion, but the public press often plays up biologic factors involved with obesity and overlooks the simple notion that Americans eat too much and exercise too little.

Obesity is dramatically increasing not only in American children and adults, but also in every country that has adopted similar cultural habits. The World Health Organization now considers obesity to be a global epidemic and a public health problem as more nations become "Westernized." In spite of the proven health risks of obesity, the government, insurance companies, and the medical profession do not spend nearly enough money to balance the commercial and cultural pressures that are producing millions of overweight people.

In 2007, the Robert Wood Johnson Foundation sounded a positive note with the announcement of a $500 million initiative, aimed at “reversing the childhood obesity epidemic by 2015.” The money will be used for research, education, and activities that promote healthy eating among America’s children.

Perhaps the primary reason for the dramatic rise in obesity is the sedentary (inactive) lives led by most Americans, including children and young people. In a 2003 study comparing modern life to the past, researchers found that labor saving devices had reduced a person's energy use by 111 calories a day -- adding up to an extra 11 pounds a year. Half the difference in energy use was due to less walking. At the same time, according to the U.S. Centers for Disease Control and Prevention, between 1970 and 2000 the typical American man increased his caloric intake by 168 calories a day (good for 17 pounds a year) while the average woman added 335 calories a day.

Regular television watching has been singled as the most hazardous pastime. According to a major 2003 study, for every 2 hours a person spends in front of the TV each day, the risk for obesity increases by 23% and for type 2 diabetes by 14%. In the study, TV watching produced the lowest metabolic rates compared to sewing, playing board games, reading, writing, and driving a car. Just the act of watching TV encourages unhealthy snacks and eating patterns. In addition, the advertising on the television complicates the problem by promoting fast foods, cereal, and snack products that are high in salt, fats, and carbohydrates. Even worse, much of these advertisements are directed at children -- the most vulnerable group.

People are not only eating more food than they did 20 years ago, they are also replacing home cooking with packaged foods, fast food, and dining out. This behavior, according to studies, places people at higher risk for obesity. Fast foods may be more harmful than restaurant cooking. These foods tend to be served in larger portions. They generally contain more calories and unhealthy fats, and less nutritious ingredients, than homemade or restaurant meals. Snack foods and sweet beverages, including juice and soft drinks, are specific problems that add to the increasing rates of obesity. Frequent small, healthy meals (instead of two or three large daily meals) have been associated with lower weights.

People react differently to stress. Some overeat and gain weight and others stop eating and lose weight. People who gain weight in response to stress often overeat foods high in sugar, fats, and salt. A 2003 study on rats suggested that stress hormones increase the pleasure of eating such so-called "comfort foods." Furthermore, the study supported previous research showing that stress-related eating was connected to the unhealthy accumulation of abdominal fat.

Risk Factors

Where you live plays a role in your risk for obesity. Simply living in the United States makes a person more susceptible to obesity. The prevalence of obesity in America has risen dramatically over the past few years and continues to increase.

According to the latest figures available, 32.2% of American adults (aged 20 and older) are obese (BMI over 30) -- up from about 23% in the early 1990s.
The number of Americans aged 20 - 74 who were overweight also increased -- from about 44.8% in 1960 to 65.2% in 2002.
The rate of extreme obesity (BMI > 40) increased from 0.8% in 1960 to 4.9% in 2002.
Obesity has increased in every state, in both men and women, across all age groups, and in every ethnic group, although some groups may face slightly higher risks than others.

Fat tends to settle in certain regions, depending on gender. Women gain fat predominantly in the stomach, hips and thighs, while men tend to gain fat in the belly and waist.

Risk by Age. People of any age are at risk for obesity. More children and adolescents are overweight in America than ever before. Gaining some weight is inevitable with age and adding about 10 pounds to a normal base weight over time is not harmful. The current weight gain in American adults over 50, however, is significant. By age 55, the average American has added nearly 40 pounds of fat during the course of adulthood. This condition is made worse by the fact that muscle and bone mass decrease with age.

Risk by Gender. In men, BMI tends to increase until age 50 and then it levels off. In women, weight tends to increase until age 70 before it plateaus. A 2000 study found that there are three high-risk periods for weight gain in women.

The first is at the onset of menstruation, particularly if it is early. In fact, a study released in March 2007 found that obesity in young girls results in early puberty -- as early as age 9. This, in turn, increases the risk for more weight gain as girls enter puberty.
The second is after pregnancy, with higher risk for women who are already overweight.
Finally, many women gain weight after menopause.

These findings are significant because they may allow women to target high-risk times, and consequently prevent unnecessary weight gain.

Risk by Economic Group. Obesity is more prevalent in lower economic groups. One 2002 study reported that women who reported that they did not have enough food were more likely to be overweight than those who said they had sufficient food. Researchers discovered that the low-income women tended to have fewer fruits and vegetables but were actually taking in more calories a day than higher-income women. However, obesity is increasing in young adults with college education as well as in other groups.

Ethnic Groups. Among ethnic groups in general, African-American women are more overweight than Caucasian women but African-American men are less obese than Caucasian men. (Currently, 80% of African-American women are overweight.) Hispanic men and women tend to weigh more than Caucasians.

US Regions. Regionally, the prevalence of obesity is lowest in the Western states and highest in the South.

A number of dietary habits put people at risk for becoming overweight:

Night-Eating Syndrome. Night-eating syndrome is defined as having no appetite in the morning, insomnia, and consuming more than half of daily food intake after 6:00 PM. It is associated with obesity and is difficult to treat. Stress reduction and relaxation techniques may be helpful.
Binge Eating and Eating Disorders. About 30% of people who are obese are binge eaters who typically consume 5,000 - 15,000 calories in one sitting. To be diagnosed as a binge eater, a person has to binge at least twice a week for 6 months. Many experts believe that binge-eating carbohydrates causes an increase in a natural opiate leading to dependence on carbohydrates. Therefore, this condition should be treated as an addiction. Other eating disorders are bulimia and anorexia. Bulimia is binge eating followed by purging in order to lose weight. Anorexia nervosa is a mental illness in which the person refuses to maintain weight at the normal level. The patient with anorexia has a terrible fear of getting fat, and an abnormal perception of what his or her body looks like. Both conditions pose risks for serious medical problems, and anorexia nervosa can be life-threatening. A combined approach using behavioral therapy and antidepressants may help these individuals. [See In-Depth Report #49: Eating disorders.]
Restrained Eating. Some people, mostly middle-aged women who have normal weight, have a pattern referred to as restrained eating. This pattern requires a high level of conscious control and usually maintains a lower weight. However, such restraint places these individuals at higher risk for loss of control and subsequent overeating.
Infrequent Eating. There is some evidence to suggest that eating small frequent meals uses more calories than infrequent large meals. It should be strongly noted, however, that packaged snack foods add calories and some do not produce a feeling of being full, so that people simply eat more than they should.

Anyone with Sedentary Lifestyles. Office workers, drivers, and anyone whose lifestyle involves sitting for long periods are at higher risk for obesity.

Ex-Smokers. The trend toward weight increase has followed the trend for quitting smoking. Nicotine increases the metabolic rate, and quitting, even without eating more, can cause weight gain, which may be considerable. It is important to note that weight control is not a valid reason to smoke. People in previous centuries did not smoke cigarettes, nor were they usually obese.

Shift-Workers. A recent study found that individuals who work late shifts (between 4 p.m. and 8 a.m.) tend to eat more and take longer naps than day workers and are more likely to gain excess weight.

People with Disabilities. Obesity rates are higher than average in people with physical or mental disabilities. Those with disabilities in the lower part of the body, such as the legs, are at highest risk.

Overweight in children and adolescents is rising at an alarming rate. In 2004, 19% of young children aged 6 - 11 were overweight, an increase of 8% from 1994. Among children aged 25, 13.9% were overweight in 2004, up from 7.2% 10 years earlier.

Definition of Overweight in Children

Children and adolescents are considered to be overweight if their BMI is above 95% of the children in their age and sex categories. Ethnic variations, timing of growth spurts, and higher normal fat levels around puberty can affect these measurements.

Causes and Risk Factors for Overweight in Children

Lifestyle Factors. Without educational or parental guidance, children are extremely vulnerable to the intense cultural pressures that are largely responsible for the obesity epidemic. The following are some specific problems created by the culture:

Excessive television watching plays a critical role in obesity in children. Not only is it a sedentary activity, but television also offers innumerable temptations with its advertisements for fast foods, sugar cereals, and unhealthy snacks. In one study obesity rates were lowest in children who watched television 1 hour or less a day and highest in those who watched 4 or more hours.
Sugar, particularly from soda, other sweetened beverages, and fruit juice, may be the major contributor to childhood obesity. One study reported that drinking soda regularly increases a child's risk for obesity by 60%. The average American adolescent consumes 15 - 20 extra teaspoons of sugar a day just from soda and sugary drinks. (Juice, while better than soda, is still filled with sugar.)
Less physical exercise and greater sedentary activities play another significant role in obesity in children. A high level of physical activity -- not just using up energy -- is important for weight control in young people. Unfortunately, according to one study, the annual distance walked by children has fallen by nearly 30% since 1972, partially because more parents are driving their children to school out of fear of abduction, molestation, and traffic accidents. Schools are also offering fewer opportunities for daily physical activities than in the past.

Neither the media nor the educational system has strong well-financed programs that encourage healthy alternatives, including exercise and healthy foods.

Family History. Parental obesity more than doubles the risk that a young child, whether thin or overweight, will become obese as an adult. In older children and teenagers, obesity in parents starts to count less as a predictor for body weight than their own weight. The risk for obesity may be due to environmental or genetic factors, or both.

Ethnic and Socioeconomic Factors. As in adult populations, children from lower socioeconomic groups and minority populations are at higher risk for obesity. For example, among young Mexican Americans and African-Americans, there has been an increase in overweight prevalence of about 13% to over 23%.

Factors Surrounding Birth. The following factors surrounding birth are associated with a child's weight:

Low birth weight is a risk factor for later obesity and diabetes. One theory is that humans have a "thrifty gene" that produces metabolic changes in infants with low birth weight. Such changes affect insulin and fat accumulation, in order to produce a "catch-up" weight in these young children as quickly as possible. This rapid weight gain in infancy increases the risk for obesity in children and young adults.
In a study of African-American children, having an overweight pregnant mother increased the risk for later weight gain, but low birth weight did not.

Although some small studies have reported protection against obesity from breastfeeding, evidence is weak. In a 2003 study, for example, children who were breast fed for 3 - 5 months had a lower risk for obesity, but prolonged breastfeeding had no effect. Nevertheless, given the healthful effects of breast feeding and the possibility that it may have even a slight impact on childhood obesity, it is highly recommended.

Biological Effect of Childhood Overweight on Adult Weight

Achieving a healthy weight becomes more difficult as children get older. The odds of obesity persisting into adulthood ranges from 20% in 4 year olds to 80% in teenagers. One reason for the persistence is biological. The fat cells change in number or mass depending on a person's age:

Fat cells themselves multiply during two growth periods: early childhood and adolescence. Overeating during those times increases the number of fat cells. Some people are also just born with more fat cells.
After adolescence, fat cells tend to increase in mass rather than quantity, so that adults who overeat and gain weight tend to have larger fat cells, not more of them. This growth in mass may be responsible for the greater risk of persistent obesity among teenagers compared to small children who are overweight. Losing weight after adolescence reduces the size of the fat cells but not their number, so weight loss becomes much more difficult.

Health Consequences of Childhood Overweight

Children and adolescents who are overweight have poorer health than other children. Studies are reporting unhealthy cholesterol levels and high blood pressure in overweight children and adolescents. Of great concern is the dramatic increase in type 2 diabetes in young people, which is largely due to the increase in overweight children. Overweight in children is also linked to asthma, gallbladder problems, sleep apnea, and liver abnormalities. Overweight girls are more likely to enter puberty early, according to a new study, and subsequently be at higher risk for breast cancer.

It is not clear yet how many of these childhood problems persist in people who achieve normal weight as adults. Staying overweight into adulthood certainly carries health risks.

Managing Overweight Children

Childhood obesity is best treated by a non-drug, multidisciplinary approach including diet, behavior modification, and exercise. Evidence suggests that reducing calories by only 200 - 260 per day would prevent weight gain in most overweight children. Here some tips for children who are overweight:

Limit (or avoid, if possible) take out, fast foods, high-sugar snacks, commercial packaged snacks, soda, and sugar-sweetened beverages (including too much juice).
Let children snack but make sure the snacks are healthy. Eating small frequent healthy meals (instead of two or three large ones) has been associated with being thinner and having a better cholesterol profile.
Let children choose their own food portions. One study indicated that children naturally ate 25% less when they chose their own portion size. When they were given larger portions their bite sizes were larger and they ate more.
Do not criticize a child for being overweight. It does not help and such attitudes could put children at risk for eating disorders, which are equal or even greater dangers to their health.
Limit television, video games, and computer use to a few hours a week. This can contribute significantly to weight control, regardless of diet and physical activity.
For young children, try the traffic-light diet. Food is designated with stoplight colors depending on their high caloric content: Green for go (low calories); yellow for "eat with caution" (medium calories); red for "stop" (high calories).
Try a low glycemic index diet. This may be as beneficial, and possibly more, than a standard reduced-fat diet in overweight children. Such a diet focuses on certain carbohydrates (for example, dried beans and soy), which raise blood sugar more slowly than other types of carbohydrates. This diet is sometimes used in diabetes, and as a dietary approach in overweight adults. [See In-Depth Report #42: Diabetes diet.]

Click the icon to see an image about TV watching.

Click the icon to see an image of childhood overweight.

Complications

General Adverse Effects of Obesity. Obesity, defined as a BMI of 30 or over, accounts for nearly 300,000 deaths in the U.S. each year. It is associated with more chronic health problems than smoking, heavy drinking, or poverty. Furthermore, given the current increase in obesity, it will surpass smoking as the most important preventable cause of death in America.

Some studies indicate the following health risks by body mass:

The lowest risks for heart disease, diabetes, and some cancers are in people with BMI values of 21 - 25.
The risks increase slightly when BMI values are between 25 - 27.
The risks are significant in BMIs between 27 - 30.
The same risks are dramatic at BMIs over 30.

Anyone with chronic health problems such as heart or lung disease, stroke, or arthritis, should be concerned about extra weight. This same concern also applies to people with known risk factors for such conditions.

Metabolic Changes. As fat stores increase, the fat cells themselves enlarge and produce chemicals that increase the risk for several diseases. Such diseases may include diabetes, high blood pressure, gallbladder disease, and some cancers.
Increased Mass. The increased body weight itself causes problems that result in injury and diseases, including osteoarthritis and sleep apnea.
Harmful Fat Cell Types. Weight concentrated around the abdomen and in the upper part of the body (the apple shape) poses a higher health risk than fat that settles around the hips and flank (the pear shape). Fat cells in the upper part of the body appear to have different qualities from those found in the lower parts. In fact, studies suggest a higher risk for diabetes in people with the "apple shape" and lower risk in those who are "pear shaped."

Weight gain in the area of and above the waist (apple type) is more dangerous than weight gained around the hips and flank area (pear type). Fat cells in the upper body have different qualities than those found in hips and thighs.

General Adverse Effects of Being Overweight (Not Obese). It is still not clear if being overweight (a BMI of 25 - 29.9) hurts healthy people with no risk factors for serious illnesses.

According to one 2001 study, just being overweight increased the risk for developing diabetes, gallstones, hypertension, heart disease, stroke, and colon cancer. The risk rose according to how much the individuals were overweight. In any case, adults who are overweight in middle age face a poor quality of life as they age, with the quality declining the greater the weight. One study suggested, however, that being over 65 and overweight (but not obese) is not associated with higher mortality rates.

Some experts argue, in fact, that in anyone who is not severely obese, it is the unhealthy diet and sedentary lifestyle that causes harm -- not weight per se. In support of this argument, a British study found that overweight fit individuals had half the death rate of unfit trim individuals.

Being somewhat overweight may also have some benefits under specific circumstances:

In older women, some excess fat may produce extra estrogen that helps slow down bone loss, and insulates bones from fall-related injuries. It should be strongly noted, however, that when older overweight women lose weight they report less pain, improved vitality, and improved physical function. The same positive effect of overweight does not appear to hold in older men.
Conditioned athletes may have high BMIs because of very dense muscle tissue. Being fit in general may protect many overweight people.
Some evidence suggests that Caucasians have the lowest mortality with BMIs of 24.3 - 24.7 while African-Americans are better off in the range of 26.8 - 27.1.
Children may have higher normal fat levels during growth spurts and around puberty.

Individuals with a BMI of at least 30 have a 10 - 50% increased rate of death from all causes, compared with individuals with a BMI of 20 - 25. Mortality rates from many causes are higher in obese people, but heart disease is the primary cause of death. People who are obese have almost three times the risk for heart disease as people with normal weights. Being physically unfit adds to the risk.

Weight concentrated around the abdomen and in the upper part of the body (apple shape) is particularly associated with insulin resistance and diabetes, heart disease, high blood pressure, stroke, and unhealthy cholesterol levels. Fat that settles in a pear shape around the hips and lower body appears to have a lower association with these conditions.

Obesity poses many dangers to the heart and circulatory system.

Damage in the Blood Vessels. As people age, changes in body fat (particularly increasing abdominal fat) seem to cause stiffness in the aorta, the major blood vessel leading from the heart. Studies are finding higher levels of a factor called C-reactive protein (CRP) in people with obesity and abdominal fat. CRP is now considered to be a marker for inflammation and damage in the arteries. (Losing weight reduces CRP levels.)

High Blood Pressure. High blood pressure is the health problem most commonly associated with obesity, and the greater the weight, the greater the risk. High blood pressure carries serious risks of stroke, heart attack, and heart failure. The link between obesity and high blood pressure is complex, and may be a combination of genetic, population, and biological factors. Many studies have reported that modest weight loss is beneficial for reducing existing high blood pressure. [See In-Depth Report #14: High blood pressure.]

Heart Failure. An important 2002 study reported that obesity might account for 11% of heart failure cases in men and 14% in women. This link existed independently of other risk factors, such as high blood pressure, sleep apnea, and diabetes, which are also associated with obesity. The biologic mechanisms involved in obesity that lead specifically to heart failure are not clear. [See In-Depth Report #13: Heart failure.]

Unhealthy Cholesterol Levels and Lipid Levels. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels (the major form of fat storage in the body) are usually high, while HDL levels (the "good" cholesterol) tend to be low. Both conditions are risk factors for heart disease. [See In-Depth Report #23: Cholesterol.]

Click the icon to see an image of coronary artery disease.

Stroke. Obesity is also associated with a higher risk for stroke. [See In-Depth Report #45: Stroke.]

Type 2 Diabetes and Insulin Resistance. Most people with type 2 diabetes are obese and, in fact, studies strongly suggest that weight loss may be the key in controlling the current epidemic of type 2 diabetes. The common factor appears to be insulin resistance. Insulin is a critical hormone in the use of sugar. In type 2 diabetes, different factors cause the body to become insulin resistant -- that is, the body can no longer respond properly to insulin. This has the effect of increasing sugar levels in the blood, the hallmark of diabetes. Both obesity and insulin resistance, at different phases, are marked by high levels of certain chemicals. It is not known yet if the higher levels are simply a product of obesity, or play some role in causing diabetes.

Insulin resistance is also associated with high blood pressure and abnormalities in blood clotting. Some research indicates that obesity, in fact, is the one common element linking insulin resistance, diabetes type 2, and high blood pressure. [See In-Depth Report #60: Diabetes - type 2.]

Metabolic Syndrome. Metabolic syndrome (also called syndrome X) is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. The syndrome consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. A 2002 study estimated that nearly a quarter of the U.S. population now has this condition. Even worse, according to a 2003 study, nearly a million American teenagers have this syndrome. A combination of weight loss and exercise is an effective treatment for this syndrome.

The American Cancer Society released new cancer prevention guidelines in September 2006. The guidelines stress the importance of keeping a healthy weight throughout life. The Society indicates that healthy weight is even more important than eating specific healthy foods, when it comes to cancer prevention.

Obesity has been associated with a higher risk for cancer in general and specific cancers in particular. Studies have also suggested that restricting calories reduces the risk for cancer. Some experts believe that effective weight control for children and adults could reduce cancer rates by 30 - 40%. One way obesity may increase the risk for cancer is its association with high levels of hormones called growth factors, which can trigger rapid cell production leading to cancer.

Uterine Cancers. The risk of uterine cancer in obese women appears to be two or three times higher than in thinner women.

Prostate Cancer. New studies from 2005 and 2006 report that obesity is associated with an increase in prostate cancer mortality, although not with the risk for less aggressive forms of prostate cancer.

Click the icon to see an image of prostate cancer.

Breast Cancer. Studies are mixed on the association between obesity and breast cancer. A number of studies have linked obesity to breast cancer in postmenopausal women, particularly in women who begin to gain weight after age 18.

Click the icon to see an illustrated series detailing a breast cancer surgery (mastectomy).

Gallbladder Cancer. Obese women are at higher risk for gallbladder cancer.

Gastrointestinal Cancers. A number of cancers in the gastrointestinal tract have been associated with obesity:

Cancer of the esophagus may be due to a higher incidence of gastroesophageal reflux disorder (heartburn) in people who are overweight.
Colon cancer has been linked to increased body mass in both men and women.
Pancreatic cancer and obesity have been weakly linked, with one study reporting a lower risk in overweight people who are physically active.

Click the icon to see an illustrated series detailing a colon cancer surgery.

Muscles and Bones

Obesity places stress on bones and muscles. Studies report that the incidence of osteoarthritis is significantly increased in people who are overweight. People who are obese are also at higher risk for carpal tunnel syndrome and other problems involving nerves in their wrists and hands. It should be noted that some weight may be protective against osteoporosis (loss of bone thickness).

Obesity increases the risk for the following mouth and eye disorders:

Gum disease
Cataracts
Maculopathy, an eye disease related to aging

Infertility. Abnormal amounts of body fat, either 10 - 15% too high or too low, can contribute to infertility in women. Obesity is specially related to certain infertility problems, such as uterine fibroids or menstrual irregularities. In men, obesity can contribute to reduced testosterone levels.

Effect on Pregnancy. Obesity has many dangerous effects on pregnancy. These include high blood pressure, gestational diabetes (diabetes, usually temporary, that occurs during pregnancy), urinary tract infections, blood clots, prolonged labor, and higher fetal death rate in late stages of pregnancy. Obesity is also associated with increased rates of cesarean delivery. Infants of women who are obese are also at higher risk for neural tube birth defects, which affect the brain or spine. Folic acid supplements, ordinarily effective in preventing these conditions, may not be as protective in overweight women.

Obesity is thought to be a risk factor for symptoms of adult-onset asthma. Though there is evidence that obesity causes wheezing and shortness of breath, it does not appear to be strongly associated with the disease mechanisms in the lungs that cause true asthma.

Obesity also puts people at risk for hypoxia, a condition in which there is not enough oxygen to meet the body's needs. Obese people need to work harder to breathe. They tend to have breathing muscles and lungs that do not work as well as those in thinner people.

The Pickwickian syndrome, named for an overweight character in a Dickens novel, occurs in severe obesity when lack of oxygen produces intense and chronic sleepiness and, eventually, heart failure.

Nonalcoholic Fatty Liver Disease. People with obesity, particularly if they also have type 2 diabetes, are at higher risk for a condition called nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH). This condition causes liver damage that is similar to liver injury seen in alcoholism. In some cases, it can be very serious and require liver transplantation. It occurs in about half of people with diabetes, and 20 - 50% of obese people, depending on how severe their obesity is. NASH can also occur in overweight children.

Gallstones. The incidence of gallstones is significantly higher in obese women and men. The risk for stone formation is also high if a person loses weight too quickly. In people on ultra-low calorie diets, gallstones may be prevented by taking ursodeoxycholic acid (Actigall).

Click the icon to see an image of gallstones.

People who are obese and nap tend to fall asleep faster and sleep longer during the day. At night, however, it takes them longer to fall asleep, and they sleep less than people with normal weights. In an apparent vicious circle, studies have suggested that obesity not only interferes with sleep but that sleep problems may actually contribute to obesity.

Sleep Apnea. Obesity, particularly the apple shape, is strongly associated with sleep apnea, which occurs when the upper throat relaxes and collapses from time to time during sleep. This collapse temporarily blocks the passage of air. Sleep apnea is increasingly being viewed as a potentially serious health problem, which may lead to complications such as heart disease and stroke. Some studies suggest that among overweight people, those who have sleep apnea have a greater risk of heart disease than those without it. In one study, the more obese a person with sleep apnea was, the higher the pressure on the airway, and therefore the greater the obstruction of the airway. Obstructive sleep apnea may also add to obesity, however, as sleepy people tend to be sedentary. Some studies indicate that treating sleep apnea may help people lose abdominal fat.

Narcolepsy. A small European study found a link between narcolepsy (a sleep disorder characterized by excessive daytime sleepiness with frequent daily sleep attacks) and high BMI.

Depression. A number of studies have reported an association between depression and obesity, particularly in obese women. There may be a number of factors to explain the link. In some cases of atypical depression, people overeat and may gain weight. Overweight people may also become depressed because of social problems and a poor self-image. In these cases, depression usually disappears when people lose weight.

There is evidence, however, that obesity itself may impair levels of tryptophan -- a chemical needed to make serotonin, a brain chemical associated with mental well-being. In one study, even after people lost weight, tryptophan levels were lower than normal.

There does not appear to be any association between depression and obesity in men.

Social Problems. One long-term study reported that overweight young women completed fewer years of school, were 20% less likely to be married, and had 10% higher rates of household poverty than their thinner peer. Obese young men were also less likely to be married, and their incomes were lower than their thinner peers. Nevertheless, studies consistently show that overweight males (both boys and men) are not as severely emotionally affected as females of any age. Women and girls tend to blame themselves for being heavy, while males tend to blame being overweight on outside factors.

Weight Loss and Maintenance

Even modest weight loss can reduce the risk factors for heart disease and diabetes. The simplest (but still difficult) approach to weight loss is reducing calories and exercising at least 150 minutes a week. Behavioral and mental changes in eating habits, physical activity, and attitudes about food and weight are also essential to weight management. For people who are very overweight and cannot lose weight through lifestyle changes, a number of effective weight-loss medications are available. For those with severe obesity, surgical procedures are proving to be very beneficial.

Some Tips for Losing Weight. The following are some general suggestions for dieters:

Start with realistic goals. Diet failure is extremely common, and the odds of significant weight loss are low, particularly in people with the highest weights. People who are able to restrict calories, engage in an exercise program, and get help in making behavioral changes can expect to lose between 5 - 10% of their current body weight. That is generally all that is needed to achieve meaningful health changes. Certainly, the distorted image of a super-thin female shape should not be anyone's goal.
Maintain a regular exercise program, assuming you have no health problems that will stop you. Choose a program that you enjoy. Check with your doctor about any health considerations. [See In-Depth Report #29: Exercise.]
Do not use hunger pangs as cues to eat. A stomach that has been stretched by large meals will continue to signal hunger for large amounts of food until its size reduces over time with smaller meals.
Be honest about how much you eat and start by recording all calories in writing. Studies suggest that when many people report their own calories intake they significantly underestimate their consumption of high-calorie and over-estimate the low-calorie foods. People who do not carefully note everything they eat tend to take in too many calories when they believe they are dieting.
Observe weekend eating. People tend to eat more on the weekends. If it is difficult to monitor all meals during the week, it be may be useful to at least track eating habits during the weekends.
Once the pounds are lost, do your best to keep the healthier weight. Make daily, even hourly, conscious decisions about eating and exercising activities. Such thinking, in many cases, can become automatic and not painful.
Don't give up, even after repeated weight loss failures. Most studies indicate that yo-yo dieting or weight cycling have no bad psychological or physical effects. Repeated dieting also does not harm the body's ability to burn calories efficiently.
Weight loss, in any case, should not be the only or even the primary goal for people concerned about their health. The success of weight loss efforts should be evaluated according to improvements in disease risk factors or symptoms, and by the adoption of healthy lifestyle habits, not just by the number of pounds lost.


Lifestyle	Reduce rate of eating. Keep food records. Eliminate environmental triggers to eating. Identify high-risk situations for overeating. Separate eating from other activities.
Exercise	Face up to emotional barriers to exercise. Understand the link between exercise and weight control. Establish reasonable exercise goals. Develop a plan for regular activity. Add increased activity into daily lifestyle.
Attitudes	Develop reasonable weight-loss goals. Avoid "all or none" thinking. Focus attention away from the scale and toward behavior. Uncouple weight from self-esteem. If you "fall off the wagon," take steps to ensure the situation does not repeat (recover from lapses with constructive action).
Relationships	Understand the key role of social support to health. Identify supportive others. Match personal style to support-seeking activities. Be specific in making support requests. Be assertive but reinforcing in drawing help from others.
Nutrition	Resist the temptation of popular fad diets. Eat with your health in mind; do not concentrate on what should be "off-limits." Eat with moderation in mind. Maximize fiber. Develop a tailored plan.
From Brownell KD. The LEARN Program for Weight Control. 7th ed. Dallas, Tex: American Health Publishing Company; 1998.

Weight Management

There are many approaches to dieting and many claims for great success with various fad diets. To date, although many diets achieve effective immediate weight loss, none has emerged as an effective tool for maintaining healthy weight. The only definite recommendation that can be made about any diet plan is to be sure it includes an exercise program, assuming there are no health problems to forbid it.

The original food pyramid, with four food groups, has been replaced with an updated food guide called "My Pyramid." This illustrates the relative proportions of different foods that make up a nutritious, well-balanced diet and includes exercise.

Calorie restriction has been the cornerstone of obesity treatment. The standard dietary recommendations for losing weight are the following:

As a rough rule of thumb, one pound of fat equals about 3,500 calories. A person could lose a pound a week by reducing daily caloric intake by about 500 calories a day. Naturally, the more severe the daily calorie restriction, the faster the weight loss. Very-low calorie diets have also been associated with better success, but extreme diets can have some serious health consequences.
To determine your daily calories requirements, multiply the number of pounds of ideal weight by 12 - 15 calories. The number of calories per pound depends on gender, age, and activity levels. For instance, a 50-year old woman who wants to maintain a weight of 135 pounds and is mildly active might require only 12 calories per pound (1,620 calories a day). A 25-year old female athlete who wants to maintain the same weight might require 25 calories per pound 2,025 (calories a day).
Fat intake should be no more than 30% of total calories. Most fats should be in the form of monounsaturated fats (such as olive oil). Saturated fats (found in animal products) should be avoided.

Extreme diets of less than 1,100 calories carry health risks. They are also often followed by bingeing or overeating, and a return to the obese state. Such diets often do not have enough vitamins and minerals, which must then be taken as supplements. Most of the initial weight loss is in fluids. Later, fat is lost, but so is muscle, which can account for more than 30% of the weight loss. No one should be on severe diets for longer than 16 weeks, or fast for more than 2 or 3 days. Severe dieting has unpleasant side effects including fatigue, intolerance to cold, hair loss, gallstone formation, and menstrual irregularities. There have been rare reports of death from heart arrhythmias when liquid formulas did not have sufficient nutrients. Pregnant women who excessively diet during the first trimester put their unborn children at risk for birth defects. Of note, those whose diets include a high intake of fluids and much reduced protein and sodium are at risk for hyponatremia, which can cause fatigue, confusion, dizziness, and in extreme cases, coma and death.

This dietary approach requires counting only grams of fat with the goal of achieving 30% or fewer calories from fat. One gram of fat contains nine calories, while one gram of carbohydrates or protein has only four calories. Fat in your diet converts more readily to fat in the body, compared with carbohydrates or proteins. Simply switching to low-fat or skimmed dairy products may be enough for some people.

There are possible drawbacks to this approach:

Some people who reduce their fat intake may not get enough basic nutrients, including vitamins A and E, folic acid, calcium, iron, and zinc. People on low-fat diets should eat a wide variety of foods and take a multivitamin supplement, if appropriate. Calcium deficiencies may be particularly harmful in women at risk for osteoporosis.
Many people start eating foods with too many carbohydrates, believing that they are not adding calories. No one should use a low-fat diet as an excuse for eating too many carbohydrates, particularly starchy foods and sugar. A high-calorie diet from any source will add pounds.
A small study in Norway found that a diet low in fat and high in carbohydrates ("carbs") increases symptoms of psychological distress, such as depression and anger. The study compared three different diets that had varying amounts of fat and carbohydrates in each. The diets contained the same amount of calories, but differed in the percentage and type of fat. People on the low-fat, high-carbohydrate diet reported more anger and depression compared with the other two diets.
Replacing fatty foods, such as cakes, cookies, and chips, with their commercial "low-fat" counterparts does not constitute a low-fat diet. These foods generally contain more sugar and hence calories, not to mention other ingredients, which have virtually no nutritional value. In fact, a 2002 study suggested that increasing sugar may, over time, reduce levels of HDL ("good") cholesterol.
Very low-fat diets may increase the risk for stroke from hemorrhage in the brain.

Some fat in a diet is essential. It should come from plant oils and fish, however, and not from animal products or hardened oils, such as margarine. Trans-fatty acids, found in hardened oils, are actually more of a risk factor for obesity than saturated fats from animal products, although both should be avoided.

Fiber and Complex Carbohydrates. In all cases, complex carbohydrates found in whole grains and vegetables are preferred over those found in starch-heavy foods, such as pastas, white-flour products, and potatoes. Fiber is an important component of many complex carbohydrates. Fiber is almost always found only in plants, particularly vegetables, fruits, whole grains, nuts, and legumes (beans and peas). One exception is chitosan, a dietary fiber made from shellfish skeletons. Fiber cannot be digested but passes through the intestines, drawing water with it, and is eliminated as part of feces content. The following are specific advantages from high-fiber diets (up to 55 grams a day):

Insoluble fiber (found in wheat bran, whole grains, seeds, nuts, and fruit and vegetable peels) has been associated with weight loss. Studies also suggest that diets rich in fiber from whole grains reduce the risk for type 2 diabetes.
Soluble fiber (found in dried beans, oat bran, barley, apples, citrus fruits, and potatoes) has important benefits for the heart, particularly for achieving healthy cholesterol levels and possibly benefiting blood pressure as well. Simply adding breakfast cereal to a diet appears to reduce cholesterol levels. People who increase their levels of soluble fiber should also increase water and fluid intake.

High-protein, low carbohydrate diets, such as the Atkins and South Beach diets, have been touted as effective ways to produce short-term weight loss. Because of their emphasis on fats and proteins, many experts are concerned about long-term health problems. A report in the March 2006 Lancet linked the Atkins diet to life-threatening complications that caused the death of one woman. The 40-year-old woman had a deadly buildup of acids called ketones in her blood, a condition called ketoacidosis. Ketoacidosis can cause coma and death. Ketones are a known by-product of high protein, low carbohydrate diets. At low levels they can cause nausea, lightheadedness, and bad breath.

The long-term effects of these diets are still unknown. For example, the Atkins diet restricts some vegetables and most fruits, which are known to protect against serious diseases such as heart problems and cancer. The diet may also cause too much calcium to build up in the urine. This can increase the risk for kidney stones and osteoporosis. In addition, high-protein intake, particularly from meat, can be harmful in people with kidney problems. Individuals at risk for kidney stones, or those who have other kidney problems, should not go on high-protein diets without talking to their doctor first. Unfortunately, many people with diabetes are at risk of kidney problems, which could reverse any possible benefits a high-protein diet may bring them. Eating a lot of meat has also been associated with certain common cancers, notably prostate and colon cancers. A 2002 study suggested that such diets during pregnancy may increase the risk for high blood pressure in the child.

Still, significant studies say that such diets improve cholesterol and blood sugar levels. Studies in 2002 and 2003 have indicated that these diets lower blood glucose levels, which can be important in people who are diabetic. The diets also reduce triglyceride levels (unhealthy fat molecules) and increases HDL (" good") cholesterol levels. High triglyceride and low HDL levels are important risk factors for heart disease, and are common in people with type 2 diabetes. Studies are mixed on whether this type of diet reduces overall cholesterol or LDL ("bad") cholesterol levels.

Experts that promote the low carbohydrate approach argue that heart problems from obesity are due to insulin disturbances from sugar imbalances. Therefore, they believe that restricting carbohydrates is the best approach for obesity -- especially for overweight people with diabetes. More research is needed, however, to determine the long-term impact of such diets on health.

High-protein, low-carbohydrate diets include Atkins, Protein Power, Sugar Busters, and Dr. Stillman. The Atkins diet is one of the most popular and has a four-phase program:

Induction. For the first 2 weeks, individuals consume no more than 20 grams of carbohydrates a day. The diet consists of pure protein and fats. There is no fruit, bread, grains, starchy vegetables, or dairy products other than cheese, cream, or butter. This phase is not suitable for children, pregnant women, or anyone with kidney disease.
On-going Weight Loss. After the first phase, individuals continue to lose weight while they increase carbohydrate levels by five grams each day.
Premaintenance. When individuals get close to their weight goal, they add another 10 grams of carbohydrates per day as long as they do not begin to gain weight. Weight loss is very slow at this time, but the individual is now getting used to maintenance.
Maintenance. Lifetime maintenance is usually between 40 and 100 grams of carbohydrates a day, depending on steady weight level.

Anyone who chooses this diet should prefer fish or soy products to meat as protein sources. Fish may reduce leptin, a hormone associated with fat storage and heart diseases, and would be the best protein source. People on this diet should also choose monounsaturated fats (as in olive oil) over saturated fats or trans-fatty acids fat. Patients often need supplements, at least a multivitamin and possibly calcium, chromium, omega-3 fatty acids (found in fish oil), and other supplements.

The South Beach and Zone diets encourage healthy fats. They also allow certain carbohydrates. For example the Zone uses healthy carbohydrates (vegetables and dried beans) and unsaturated fats. The South Beach diet uses carbohydrates that have a lower impact on blood sugar levels. This is called a low-glycemic index. Low-glycemic foods include barley, dried bean and peas, milk, strawberries, and apples. High-glycemic foods include refined grains, white bread, white potatoes, and bananas and other tropical fruits. The glycemic index was developed for use in diabetes -- not for weight loss. Nevertheless, there is some evidence that foods with low glycemic indexes may produce a feeling of fullness and so discourage further eating. As with any high-protein diets, people at risk for kidney stones, or those who have other kidney problems, should avoid these plans.

Replacing fats and sugars with substitutes may help many people who have trouble maintaining weight. In fact, in one 2003 study, people with type 2 diabetes used the artificial sweetener sucralose and a beta-glucan fat substitute (derived from oats) as part of a low-calorie diet. At the end of the 4 weeks, they achieved better weight, glucose control, and HDL levels than those on a standard diabetic diet.

Fat Substitutes. Fat substitutes added to commercial foods or used in baking deliver some of the desirable qualities of fat, but do not add as many calories. It should be stressed that eliminating all fats from a diet can be harmful to general health.

Fat substitutes include the following:

Stanols. Stanols are plant compounds used in margarines (Benecol, Take Control). Benecol is derived from pine bark and Take Control from soybeans. Two servings a day of either brand, as part of a low-fat, diet can lower LDL and total cholesterol by impairing its absorption in the intestinal tract. Some studies have reported that the use of stanols can allow lower doses of statins (cholesterol lowering medications). Stanols do not appear to block absorption of fat-soluble nutrients or vitamins, as olestra does.
Olestra (Olean) passes through the body without leaving behind any calories from fat. Studies suggest that it improves cholesterol levels and helps people lose weight when it is used to replace a third of normal dietary fats. (Note that simply adding snacks containing olestra does not appear to have any effect on cholesterol or weight loss.) Early reports of cramps and diarrhea after eating food containing olestra have not proven to be significant. Of greater concern is the fact that even small amounts of olestra deplete the body of certain vitamins and nutrients that may help protect against serious diseases, including cancer. The FDA requires that the missing vitamins be added back to olestra products, but not other nutrients. The side health effects, if any, are unknown.
Beta-glucan is a soluble fiber found in oats and barley. Products using this substance (e.g., Nu-Trim) may reduce cholesterol and have additional health benefits.

A number of other fat-substitutes are also available. Although studies to date are not showing any significant side effects, these products' effect on weight control is uncertain, since many of the products containing them may be high in sugar.

Artificial Sweeteners. Many artificial or low-calories sweeteners are available. A 2002 study confirmed that people who consumed artificial sweeteners and reduced their sugar intake weighed less over time than those who took in similar types and amounts of drinks and food containing sugar. It should be noted that using these artificial sweeteners should not give dieters a license to increase their fat intake. Studies indicate that consuming some sugar is not a significant contributor to weight gain, as long as the total amount of calories in the diet is under control. There is some public concern about chemicals used to produce many of these sweeteners, and the side effects seen in studies using rats. Natural low-calories sweeteners are available that may be more acceptable to many people.

Saccharin (Sugar Twin, Sweet n' Low, Sucaryl, and Featherweight). Saccharin has been used for years. Some studies found that large amounts of saccharin cause bladder cancer in rats. However, the rats were fed huge amounts that do not apply to human diets. Currently there is no evidence that saccharin causes cancer in humans.
Aspartame (Nutra-Sweet, Equal, NutraTase). Aspartame has come under scrutiny because of rare reports of nervous system disorders, including headaches or dizziness, associated with its use. People with phenylketonuria (PKU), a genetic condition, should not use it. Studies have not reported any serious health dangers, but some people may be sensitive to it.
Sucralose (Splenda). Sucralose has no bitter aftertaste and works well in baking, unlike other artificial sweeteners. It is made from real sugar by replacing part of the sugar with chlorine. Some people are concerned because chlorinated molecules used in major industrial chemicals have been associated with cancer and birth defects. Over 100 studies have been conducted on sucralose over a 20-year period, with no reports of such risks.
Acesulfame-potassium (Sweet One, SwissSweet, Sunette). It has been used in the U.S. since 1988 with no reported side effects.
Neotame (Neotame). Neotame is a synthetic variation of aspartame, but was developed to avoid its side effects. The association with aspartame has raised some concerns. Studies to date have reported no effects that would cause alarm, and it appears to be safe for general consumption.
D-tagatose (Tagatose). This reduced-calorie sweetener is made from lactose, which is the sugar found in dairy products and other foods. It may be especially beneficial for people with type 2 diabetes. It may also have additional benefits that help the intestinal tract.
Alitame (Aclame) is formed from amino acids, the building blocks of proteins. It has the potential to be used in all products that contain sugar, including baked goods.
Stevioside (Stevia). This is a natural sweetener derived from a South American plant. It is available in health food stores. People with diabetes should avoid alcohol-based forms. It has not been carefully tested.

Other sugar substitutes being investigated include glycyrrhizin (derived from licorice) and dihycrochalcone (derived from citrus fruits).

Some studies have reported good success with meal replacement beverages (Slim-Fast, Sweet Success). They contain major nutrients needed for daily requirements. Each serving typically contains between 200 - 250 calories and replaces one meal. (Note: Using them for all meals reduces calories to a severe extent and can be harmful.)

One study reported that most subjects who had undergone a 12-week weight loss program and then used Ultra Slim Fast supplements as directed for maintenance kept off more than half their weight loss after more than 3 years. A quarter of the subjects were still losing weight.

Medical evidence suggests that a diet rich in magnesium could reduce a person's risk of metabolic syndrome, a cluster of problems including obesity, high blood pressure, and high cholesterol. Metabolic syndrome can lead to diabetes and heart disease. A long-term study of thousands of Americans found that the risk for metabolic syndrome decreased in those who consumed the most magnesium from meals. The findings were published in the journal Circulation.

Commercial and Non-Profit Support Programs for Weight Loss. There are many different types of weight-loss program. (This report cannot address all of the many commercial and nonprofit weight-loss programs currently available, nor can it assess their claims.)

Taking off Pounds Sensibly (TOPS), a nonprofit support organization with many local chapters, is one of the least expensive programs, costing $20 a year.

Most of the commercial programs such as Weight Watchers, Jenny Craig, and NutriSystem offer individual or group support, lifestyle changes and packaged meals. These programs tend to be expensive. There are few well-conducted studies on these programs. One 2003 study reported modest weight loss over 2 years with Weight Watchers compared to a self-help program. There were no differences in heart risk factors.

Cognitive Behavioral Approaches. Most support programs use some form of cognitive-behavioral methods to change the daily patterns associated with eating. They are very useful for preventing relapse after initial weight loss. The following is a typical approach:

The patient first records in a diary all activity related to eating patterns, including the times of day, length of meal, emotional states, companions, and, of course, the kind and amounts of food eaten. Most people -- even professional dieticians, according to one study -- tend to underreport their daily calorie intake. However, writing it down is still a good method for increasing a person's awareness of eating patterns. (One patient said that recording circumstances surrounding relapses was a particularly valuable guide for understanding the stresses leading to her own eating behaviors.)
The patient reviews the diary with a therapist or group to set realistic goals and identify patterns that the patient can change. For instance, if food is normally eaten while watching television, then the patient may be advised to eat in another room instead.
Good eating habits are reinforced by rewards. These rewards are other pleasures that substitute the high calorie consumption and sedentary activities.

Behavioral modification has been shown to be helpful particularly for people who have an overly strong response to the taste, smell, and appearance of food. It also may be useful for binge eaters.

Stress-Reduction Techniques. Stress reduction and relaxation techniques may be helpful for some people with obesity, such as those whose weight is related to night-eating syndrome. [See In-Depth Report #31: Stress.]

Changing Sedentary Habits. Making even small changes in physical activity can expend energy. For example, simply getting up to turn the TV on and off instead of using the remote, and standing (instead of sitting) while talking on the phone may help a person lose up to five pounds a year. Other suggestions include cooking one's own food (instead of eating take-out or fast food), walking to as many places as possible, using stairs instead of escalators or elevators, and gardening. Even fidgeting may be helpful in keeping pounds off, and, in one study, chewing gum increased energy expenditure.

No one should rely on such mild activities, however, for serious weight loss. Only high levels of physical activity -- not just using up energy -- help prevent obesity.

Approach to Exercise. Exercise, which replaces fat with muscle, is the critical companion for any weight control program. In a one-year study, women who regularly averaged 3.5 days (176 minutes) of exercise each week lost significantly more weight than women who did not exercise regularly. Women who exercised more than 195 minutes a week lost nearly 7% of their abdominal fat.

People who exercise are more apt to stay on a diet plan. Exercise improves psychological well-being and replaces sedentary habits that usually lead to snacking. Exercise may even act as a mild appetite suppressant. Moreover, exercise improves overall health even with modest weight loss. In support of this, a British study found that overweight fit individuals had half the death rate of unfit trim individuals.

Be aware, however, that the pounds won't melt off magically. Losing significant weight requires both intensive exercise and calorie restriction. In addition, if a person exercises but doesn't diet, any actual pounds lost may be minimal, because denser and heavier muscle mass replaces fat. Nonetheless, regardless of weight loss, a fit body will look more toned and be healthier. In addition, exercise benefits the heart even with modest weight loss.

The following are some suggestions and observations on exercise and weight loss:

The more strenuous the exercise, the better the chances for short-term and long-term success. With intense exercise, the metabolism continues to burn calories before returning to its resting level. This state of elevated metabolism can last for as little as a few minutes after light exercise to as long as several hours after prolonged or heavy exercise.
Of the standard aerobic machines, the treadmill burns the most calories. It may be particularly effective when used in short multiple bouts during the day. In fact, frequent exercise sessions as short as 10 minutes in duration (about four times a day) may be the most successful exercise program for obese people.
Resistance, or strength, training is excellent for replacing fat with muscles. It should be performed two or three times a week.
As people slim down, their initial level of physical activity becomes easier and they burn fewer calories per mile of walking or jogging. The rate of weight loss slows down, sometimes discouragingly so, after an initial dramatic head start using diet and exercise combinations. People should be aware of this phenomenon and keep adding to their daily exercise program.
As people age, they also need to exercise more to keep off the same amount of weight.
Changes in fat and muscle distribution may differ between men and women as they exercise. Men tend to lose abdominal fat (which lowers their risk for heart disease faster than reducing general body fat). Exercise, however, does not appear to have the same effect on weight distribution in women. In one interesting study, women in aerobic and strength training programs lost fat in their arms and trunk, but did not gain muscle tissue in these regions.

Warning Note. Because obesity is one of the risk factors for heart disease and diabetes, anyone who is overweight must discuss their exercise program with a doctor before starting. Sudden demanding exercise, in such cases, can be very dangerous. [See In-Depth Report #29: Exercise.]

Medications

There are several different drugs used for weight loss. Unless specifically instructed by a doctor, people should use non-drug methods for losing weight. Except under rare circumstances, pregnant or nursing women should never take diet medications of any sort, including herbal and over-the-counter remedies.

A 2001 study reported that 7% of American adults use nonprescription weight-loss products. People must be cautious when using any weight-loss medications, including over-the counter diet pills and herbal or so-called natural remedies. Buying unverified products over the Internet can be particularly dangerous.

Green tea. Perhaps the best alternative advice for people who are overweight is to drink tea. Studies have indicated that regular tea drinking is associated with lower weight, particularly in people who drink it for years. Green tea specifically has been associated with increased energy expenditure. One study reported that people who took a green tea extract (Exolise) lost weight and reduced their waist size. Better evidence is needed to confirm the results on this supplement.

Thermogenic Approach to Weight Loss. An approach to weight loss called thermogenic (also hepatothermic) therapy is based on the idea that certain natural compounds have properties that enable the liver to increase energy in the cells and stimulate the metabolism. Theoretically, the result would be fat loss. Among the natural substances used in such products are EPA-rich fish oil, sesamin, hydroxycitrate, pantethine, L-carnitine, pyruvate, aloe vera, aspartate, chromium, coenzyme Q10, green tea polyphenols, aloe vera, DHEA derivatives, cilostazol, diazoxide, and fibrate drugs.

Nearly all the current over-the-counter dietary aids contain some combination of these ingredients. There is no evidence that any of these ingredients can produce weight loss, and some may even have harmful effects.

Chromium is a common ingredient in many diet supplements (e.g., Xenadrine, Dexatrim, Acutrim Natural, Twinlab Diet Fuel). It is claimed to specifically promote fat loss, rather than lean muscle loss. Some evidence suggests that niacin-bound chromium may improve insulin sensitivity. On the negative side, animal studies have suggested that chromium may have damaging effects on genetic materials in cells. This could cause sterility.

Ephedra, Ephedrine, and Ma Huang. The FDA does not allow the sale of drugs that contain ephedrine. In May 2004, the FDA banned the sale of dietary supplements that contain ephedra (also called Ma Huang). Ephedra has been linked to serious side effects, including strokes and heart attacks.

Brazilian Diet Pill. The US Food and Drug Administration (FDA) is warning consumers not to buy a product known as the "Brazilian diet pill." This product is labeled as a dietary supplement, but contains several chemicals found in powerful prescription drugs. The products are also known as Emagrece Sim and Herbathin dietary supplements.

Conjugated Linoleic Acid (CLA). Conjugated linoleic acid is found in many dietary products (e.g., Biosculpt Liquid, Body Success, GNC Optibolic Body Answers Dietary Formula). There is no evidence that it produces weight loss. Furthermore, there is some concern that CLA might increase insulin resistance and a dangerous inflammatory response in people with obesity.

Tiratricol. Over-the-counter products containing tiratricol, a thyroid hormone, have been sold for weight loss. Such products may increase the risk for thyroid disorders, heart attack, and stroke.

Laxative Actions in Natural Substances. Many dietary herbal teas contain laxatives, which can cause gastrointestinal distress, and, if overused, may lead to chronic pain, constipation, and dependency. In rare cases, dehydration and death have occurred. Some laxative substances found in teas include senna, aloe, buckthorn, rhubarb root, cascara, and castor oil.

Guar Gum. Some fiber supplements containing guar gum have also caused obstruction of the gastrointestinal tract.

Chitosan. Chitosan, a dietary fiber from shellfish, prevents a small amount of fat from being absorbed in the intestine. Well-conducted studies, however, have not found it to be effective. Products containing it include Cheat & Lean Fat Blocker, Natrol, Chroma Slim, and Enforma. People who are allergic to shellfish should not take these supplements.

Plantain. Dietary remedies that list the ingredient plantain may contain digitalis, a powerful chemical that affects the heart. NOTE: This substance should not be confused with the harmless banana-like plant also called plantain.

Orlistat (Xenical) can help about one-third of obese patients with modest weight loss, and can assist in long-term maintenance of weight loss. It works by slowing the absorption of fat (by about 30%) in the intestine. Studies indicate that between 50 - 80% of patients can achieve weight loss of 5% or greater, depending on other lifestyle changes. However, many people regain a significant portion of this weight back within 2 years. It does not work for all patients, however. In one survey of patients who took it, 10% gained weight or did not lose any, and 43% lost less than 5%. Nevertheless, orlistat may delay or even prevent the onset or progression of diabetes and improve cholesterol levels, regardless of weight loss.

The drug can cause gastrointestinal problems and may interfere with absorption of the fat-soluble vitamins A, D, and E and other important nutrients. The most unpleasant side effect is oily leakage of feces from the anus. Restricting fats can reduce this effect. People with bowel disease should probably avoid it. In spite of these side effects, most patients are able to tolerate this agent.

In February 2007, the FDA approved an over-the-counter (OTC) version of orlistat. It will be sold under the name alli, and will be available at half the prescription strength of Xenical. Those eager to use the new pill should consider its cost and modest benefits compared with its side effects, most commonly oily diarrhea. This pill, which prevents fat absorption from food, also increases the risk of not absorbing important nutrients from food while using it. The FDA recommends taking a daily multivitamin supplement when using alli.

Sibutramine (Meridia) helps balance the brain chemicals serotonin and norepinephrine. This helps increase metabolism, causes a feeling of fullness, and increases energy levels. It may be particularly useful for binge-eaters. Studies indicate that sibutramine is effective in achieving weight loss, although the weight loss slows considerably after the first 3 months. The drug also appears to improve cholesterol and lipid (fat) levels, and may have other effects that benefit the heart.

Side effects of sibutramine are common. They include dry mouth, constipation, and insomnia. In one study, almost half the patients dropped out as a result of these side effects. There have been reports of increases in heart rate and blood pressure while taking this medication, although a 2001 study indicates that blood pressure stabilizes over time.

At this time, people who have a history of high blood pressure, stroke, heart disease, or arrhythmias should not take this drug. People taking decongestants, bronchodilators (such as for asthma), monoamine oxidase inhibitors, or serotonin reuptake inhibitors should also avoid sibutramine.

Phentermine and Other Sympathomimetics. Sympathomimetics are drugs that act like the stress hormone (and chemical messenger) norepinephrine. These medications act as stimulants in the brain. Some are approved for treating obesity, but only for short-term use. They include:

Phentermine (Ionamin, Adipex-P, Fastin)
Benzphetamine (Didrex)
Phendimetrazine (Adipost, Bontril, Melfiat, Plegine, Prelu-2, Statobex)

Phentermine is the most commonly prescribed appetite suppressant, and is less expensive than orlistat or sibutramine. Its effects are not long lasting, however. It can also raise blood pressure. In addition, phentermine is associated with depression, which is already a problem in many cases of obesity. A combination (Phen-Pro) containing phentermine and the antidepressant fluoxetine (Prozac) is being investigated to help reduce this problem. Note: Neither phentermine nor such combinations are associated with the heart problems linked to the previous phentermine combination known as Fen-Phen (phentermine and fenfluramine).

Amphetamines. The amphetamines dextroamphetamine (Dexedrine), methamphetamine (Desoxyn), and phenmetrazine (Pleudin) are powerful stimulants. They were used most often in the past but are no longer prescribed for weight loss. These drugs improve mood and produce some modest weight loss over the short term, but carry serious risks of addiction, agitation, and insomnia.

Rimonabant. Rimonabant (Accompli) belongs to a new class of drugs called selective CB1 blockers. The drug is designed to block receptors in the brain associated with the regulation of eating. Rimonabant also targets receptors in fat tissue. The Rimonabant in Obesity-Lipids (RIO-Lipids) study looked at how rimonabant affected metabolic risk factors in high-risk overweight or obese patients with blood fat disorders. The study involved more than 1,000 participants. The findings, published in the November 2005 New England Journal of Medicine, said that people who took the drug significantly reduced their body weight and size of their waist.

Earlier studies involving the drug reported that obese patients treated with 20 mg of rimonabant lost significantly more weight and inches from their waist than patients who received placebo. The drug also appeared to have beneficial effects on raising HDL ("good") cholesterol levels.

Note: Fake rimonabant has been found for sale on several web sites. Patients should be aware that this drug is still experimental, and rimonabant is not available for sale. Buying and taking counterfeit drugs can have serious health consequences. In addition, an FDA advisory panel in April 2007 rejected the drug, citing fears it may cause psychiatric problems and seizures in some patients.

Axokine. Axokine is a type of drug called a ciliary neurotrophic factor. It signals the brain to suppress one's appetite. It is proving to be effective in achieving weight loss, and also improves cholesterol, lipid, and glucose levels regardless of food intake. It could be particularly helpful for people with type 2 diabetes. Early study results found that severely obese patient who took the drug lost more weight than those who took a dummy pill (placebo). Nearly half (46%) of patients who took the drug lost at least 10 pounds, compared to 5% of those who received the placebo. Study participants tolerated the drug well. There were no reports of serious side effects.

Zonisamide. Zonisamide (Zonegran) is an anti-seizure medication that is also being investigated for weight loss. In one study, patients who took it lost more weight than those on placebo. Zonisamide increases the risk for kidney stones, which can be reduced with increased fluid intake and citrate. It has also been associated with reduced sweating and a sudden rise in body temperature, especially in hot weather. Other side effects include dizziness, forgetfulness, headache, and nausea.

Topiramate. Topiramate (Topamax) is another anti-seizure medication being investigated for weight reduction. Three clinical trials have reported that patients given topiramate lost more weight than those receiving placebo. Weight loss was sustained for up to 1 year. The drug is also being studied for binge-eating disorders associated with obesity.

Other Treatments

Surgical procedures for obesity may be appropriate for some dangerously obese people, and may reduce heart problems and many of the risks associated with obesity. These risks include high blood pressure, sleep apnea, and diabetes. In fact, some evidence suggests that surgery may provide much greater control of weight and diabetes than nonsurgical weight-loss methods. Studies are reporting significant reductions in diabetes, and the need for diabetic medications, after surgery. Other medical conditions that often improve after surgery include heartburn, arthritis, and other joint and circulation problems.

Bariatric surgeries produce weight loss through one of two approaches:

Restrictive Banding Procedures. These procedures restrict the amount of food by closing off parts of the stomach with bands.
Malabsorptive Bypass Procedures. This approach restricts the amount of food and also reduces absorption by using a bypass of parts of the intestine.

The malabsorptive procedures are more successful in achieving weight loss than the banding approach, but they carry a greater risk for nutritional deficiencies.

Most people who have bariatric surgery lose about two-thirds of excess weight within 2 years. In addition, diseases associated with obesity (such as diabetes, high blood pressure, sleep apnea, joint pain, and incontinence) often improve.

Researchers at the Mayo Clinic looked at records from patients who had the surgery between 1990 and 2003. They found that those who had bariatric surgery reduced their risk of cardiovascular events such as a heart attack much more than those who lost weight without surgery. The findings were published in the September 2005 Mayo Clinic Proceedings.

Other studies have shown that even though most patients maintain significant weight loss, the majority regain about to 10% of their weight. Patients must still develop a healthy life style and be calorie conscious after the operation. Follow-up must be life-long.

Any surgical candidate must have failed consistently in losing weight through less invasive methods. Experts recommend bariatric surgery only for the following:

Those whose BMI is above 40 (about 100 pounds overweight)
Those with BMIs of over 35 who have type 2 diabetes or serious obesity-related medical problems
Those with severe obesity that interfered with employment, normal physical activity (e.g., walking), and important relationship

About a third of people who undergo these procedures achieve normal weight, and 80% experience some weigh loss. They are less successful than the bypass procedures, but carry a lower risk of nutritional deficiencies.

Vertical Banded Gastroplasty. Vertical banded gastroplasty (VBG) was the most common restrictive procedure. It involves creating a hole through both stomach walls and sealing the edges with a staple. This narrows the stomach, similar to a funnel, and allows only small amounts of food to pass through.

Laparoscopic Gastric Banding. Laparoscopic gastric banding (the Lap-Band) usually does not require a major incision and avoids some of the major complications of gastric bypass:

It employs an adjustable silicone band that is placed around the upper part of the stomach.
A small balloon-like reservoir attached to the band under the abdominal skin contains saline, which can be added or removed to tighten or loosen the band.
The procedure restricts the amount of food a person can eat and gives the feeling of fullness.

The band is removable, if necessary. Studies to date indicate that the intestinal tract returns to normal afterward. Studies, including those done in the elderly, have reported significant weight loss and improved quality of life with the procedure.

Malabsorptive procedures produce greater weight loss than restrictive procedures. Patients generally achieve about two-thirds of their weight loss within 2 years. Furthermore, in a 2003 study, after standard bypass surgery, 83% of patients with type 2 diabetes experienced normal blood glucose levels and the rest had significant reductions.

Roux-en-Y Gastric Bypass Procedure. This is the most common and successful malabsorptive surgery in the United States. It involves creating a small stomach pouch that serves as a reservoir and restricts food intake. The pouch eventually holds up to 3 ounces of food and has a small outlet that delays emptying and causes a feeling of fullness. Then the surgeon creates a Y-shaped section in the small intestine that attaches to the pouch. This section allows food to bypass the lower stomach and upper part of the intestine. One 2003 study reported that this procedure was associated with significant weight loss, and 80% of patients with type 2 diabetes were able to reduce their medications. A more recent study, published in the March 14, 2006, issue of Archives of Surgery, found that gastric bypass surgery also helps lower the blood pressure of very obese patients.

The procedure produces greater and more sustained weight loss than banding procedures, but it is also more complicated, and carries a higher risk of nutritional deficiencies. Laparoscopy techniques, which are less invasive, are now preferred over open surgery. They achieve equally good results with fewer complications.

Biliopancreatic Diversion. This procedure is more complicated and removes portions of the stomach. The pouch that is created attaches directly to the lower part of the small intestine. It poses a higher risk for nutritional deficiencies than other procedures and is not used as often.

Click the icon to see an image of gastric bypass surgery.

General Side Effects and Complications. Side effects and complications of bariatric procedures are common, and up to 25% of patients require corrective or repeat procedures. After any of these procedures people must chew all their food carefully, and they cannot eat large amounts of food at one time. If patients do not follow these guidelines, they will experience nausea, abdominal distress, or both.

Complications from any bariatric procedure includes the following:

Vomiting: This is the most common complication, and it is most common with banding procedures.
Nutritional deficiencies: There is a strong risk of nutritional deficiencies, particularly with malabsorptive operations. This complication can lead to anemia and increase the risk of bone loss and osteoporosis. Taking enough mineral and vitamin supplements is important after bariatric surgery.
Deep-vein thrombosis: There is a significant risk for deep-vein thrombosis (blood clots in the veins).
Abdominal hernia: This is another common complication. Newer, laparoscopic techniques do not carry this risk, but not all individuals are candidates for this less-invasive approach.
Rapid weight loss after surgery: This complication puts people at high risk for gallstones.
Women who wish to be pregnant should wait until their weight has stabilized. Rapid weight loss and nutritional deficiencies can harm the fetus.

People at highest risk for complications are those with heart or lung problems, severe obesity, and a history of abdominal surgeries. The mortality rate from bariatric surgeries is 0.2%, which is lower than the morality rates from severe obesity itself. Other surgical variations and less invasive techniques using laparoscopy have been developed.

Specific Complications of Restrictive Banding Procedures. Nausea, vomiting, or both occurs in half the patients, and severe heartburn occurs in a third. Device-related complications include band slippage, pouch dilation (widening), or both in nearly a quarter of patients, and obstruction in 12% of patients. Very serious complications are rare, but include blood clots, bleeding, infection, pneumonia, and perforation (tearing) of the stomach.

Specific Complications of Malabsorptive Bypass Procedures. Vomiting often occurs. Nutritional deficiencies occur more often in these procedures. The so-called dumping syndrome is a common unpleasant side effect, which occurs when food waste moves too quickly through the intestine. Symptoms include nausea, weakness, sweating, and faintness (particularly after eating sweets).

Spot Exercising. Anyone seeking to lose weight must expect that the results may not be as cosmetically satisfying as one would wish. Spot exercising (training particular areas of the body) is ineffective in reducing fat in specific locations because exercise draws on fat stores throughout the body. Gimmicky devices such as bust developers, vacuum pants, and exercise belts do absolutely nothing to reduce fat or add bulk in specific locations. Electrical pads wrapped around the waist, arms, or thighs were reported to cause burns and fires.

Cellulite-Removal Creams. Many women try to reduce fat in their thighs (cellulite) with creams that contain aminophylline (Skinny Dip, Thermojetics Body Toning Cream, Smooth Contours). Studies provide no evidence that these creams are effective. Their apparent effect on fat may simply be from narrowing blood vessels and forcing water from the skin, which could be dangerous for people with blood flow problems.

Endermologie. Endermologie uses motorized rollers and regulated suction to smooth out cellulite. In one study, about 28.6% of patients reported improved appearance after using it.

Liposuction. Liposuction eliminates fat in specific areas, such as the abdomen, thighs, buttocks, or knees. Special instruments are inserted through the skin into the pockets and suction is used to move the fat, break it up, and remove it. Small tubes may be used to drain blood and fluid during the first few days. The pain after the operation can be severe and often the skin does not contract, resulting in a flabby look. Complications can include burns from the vibrators, bruising, blood clots, and bleeding. Weight gain generally tends to develop in other locations after the operation. Some doctors are using this procedure in overweight people with diabetes to remove abdominal fat. Although there is no proof that it has an effect on diabetes, some experts believe the procedure deserves attention.

Liposuction is not recommended for major weight loss.

Resources

www.healthierus.gov/dietaryguidelines -- Dietary Guidelines for Americans 2005
www.naaso.org -- North American Association for the Study of Obesity
www.eatright.org -- American Dietetic Association
www.nutrition.gov. -- Nutrition.gov
www.asbs.org -- American Society for Bariatric Surgery
www.cnpp.usda.gov -- Center for Nutrition Policy and Promotion
http://fnic.nal.usda.gov -- Food and Nutrition Information Center
www.americanheart.org -- American Heart Association
www.nationaleatingdisorders.org -- National Eating Disorders Organization
www.aabt.org -- Association for Advancement of Behavior Therapy
www.fda.gov -- Food and Drug Administration
http://win.niddk.nih.gov -- Weight-Control Information Network

References

US Food and Drug Administration FDA Approves Orlistat for Over-the-Counter Use. Rockville, MD: National Press Office; February 7, 2007.

Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 1999-2004. Journal of the American Medical Association. 2006; 295:1549-1555.

National Center for Health Statistics. Chartbook on Trends in the Health of Americans. Health, United States, 2005. Hyattsville, MD: Public Health Service. 2005

National Institute of Diabetes and Digestive and Kidney Diseases - Weight-control Information Network. Statistics Related to Overweight and Obesity. Available online.

National Center for Health Statistics. Prevalence of Overweight Among Children and Adolescents: United States, 2003-2004.

Morino M, Toppino M, Bonnet G, Rosa R, et al. Laparoscopic vertical banded gastroplasty for morbid obesity. Assessment of efficacy. Surg Endosc. 2002 Nov;16(11):1566-72.

Brethauer SA, Schauer PR, Chand B. Risks and benefits of bariatric surgery: Current evidence. Cleveland Clinic Journal Of Medicine. 2006 Nov; 73(11): 993-1007.

Rosenthal RJ, Szomstein S, Kennedy CI, et al. Laparoscopic surgery for morbid obesity: 1,001 consecutive bariatric operations performed at The Bariatric Institute, Cleveland Clinic Florida. Obes Surg. 2006 Feb;16(2):119-24.

He K, Liu K, Daviglus ML, et al. Magnesium Intake and Incidence of Metabolic Syndrome Among Young Adults. Circulation. 2006: Published online before print. March 27, 2006.

Chen TY, Smith W, Rosenstock JL, Lessnau KD. A life-threatening complication of Atkins diet. Lancet. 2006 Mar 18;367(9514):958.

Lopez-Jimenez F, Bhatia S, Collazo-Clavell ML, Sarr MG, Somers VK. Safety and efficacy of bariatric surgery in patients with coronary artery disease. Mayo Clin Proc. 2005 Sep;80(9):1157-62.

Sidhaye A, Cheskin LJ. Pharmacologic treatment of obesity. Adv Psychosom Med. 2006;27:42-52.

Fernstrom JD, Courcoulas AP, Houck PR, Fernstrom MH. Long-term changes in blood pressure in extremely obese patients who have undergone bariatric surgery. Arch Surg. 2006 Mar;141(3):276-83.

Despres JP, Golay A, Sjostrom L; Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005 Nov 17;353(20):2121-34.

Lanningham-Foster L, Nysse LJ, Levine JA. Labor saved, calories lost: the energetic impact of domestic labor-saving devices. Obes Res. 2003 Oct;11(10):1178-81.

Review Date:
6/14/2007
Reviewed By:
A.D.A.M. Editorial Team: Greg Juhn, M.T.P.W., David R. Eltz, Kelli A. Stacy. Previously reviewed by Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital (4/30/2007).

A.D.A.M. Copyright

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