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Marathon Dangers

FitSugar — Tue, 04 Nov 2008 08:00:00 -0800

The New York City Marathon is over now, but many people are still in training for future races such as the Rock 'n' Roll San Antonio Marathon (Nov. 16), the Philadelphia Marathon, (Nov. 23), and the Atlanta Marathon (Nov. 27). There's just something about conquering the distance of 26.2 miles that inspires so many people. Training for a marathon is a healthy aspiration, but if running this distance is on your to-do list, you should know there are some risks involved.

Running extreme distances is not exactly good for your health. As you run, you experience changes in your immune system and kidney function. The consistent stress signals your body to go into emergency-repair response mode. Your adrenal glands and brain produce the stress hormones cortisol and vasopressin. Also, your damaged muscles churn out proteins called cytokines, which trigger the liver to start producing C-reactive protein. The result is inflammation, and all your muscles feel the brunt, including your heart. In extreme cases, death by cardiac arrest has been associated with running this historic distance.

To find out if it's possible to avoid these risks, read more.

How you train plays a huge role in how your body will react on race day. Averaging at least 45 miles a week while training will significantly lower your risk of heart injury. Even though your body suffers damage on your training runs, it also repairs itself and becomes stronger. So on race day, your body is better equipped to handle the struggle. What's also good to know is that for most runners, if they do end up suffering some heart damage, it isn't permanent. Within a month, the heart is functioning normally again.

With all this in mind, some health officials suggest doing all the training for the marathon, but skipping out on the actual race. The thing is, though, most people train for the sole purpose to be able to cross the finish line. It's an amazing sense of accomplishment, and the difficulty of the race and the risks involved add to its appeal. If it wasn't so hard, no one would want to do it.

Fit's Tip: If running a marathon is on your mind, first have your heart checked by a doctor to make sure you're not at risk for heart problems. Then be sure to train long and well (at least four months in advance). Rack up miles and miles so that come race day, your body will be ready.

Source

Are Marathons Bad For You?

FitSugar — Thu, 01 Oct 2009 10:00:57 -0700

With marathon season winding down (NYC marathon is 11/1) there is an ongoing debate in the medical field over the effect the 26-mile race has on the heart. Some scientists are claiming that running a marathon causes long lasting damage to the heart, while others say the damage is only temporary and is brought on by the extreme physical demands of the race.

Last year studies were conducted in Australia, Canada, and Germany measuring the effect running a marathon had on the hearts of elite to novice runners. Tests were given on the participants immediately before and after running a marathon. The end findings were similar across the board - the participants showed marked blood indicators of cardiac damage.

“We measure those same blood markers when someone comes in to the emergency room and we suspect a heart attack,” says Davinder S. Jassal, MD, an assistant professor of cardiology, radiology, and physiology at the University of Manitoba as told to the New York Times. Blood profiles like those displayed by the runners are similar to those in a very mild heart attack.”

Those scientists that oppose the findings, site that the research is premature and the studies were too small. They also say that accurate results cannot be determined since researchers in the original studies did not follow up with any of the participants after the race day. A later second study conducted in Canada seems to support this claim - a week after completing a marathon, researchers followed up with the runners and found none of the initial damage was lasting.

As the debate continues please keep in mind that running long distances is definitely taxing on the heart. Check out our tips to avoid any risks while training and share your own tips with us below.

Melanoma and other skin cancers

FitSugar — Wed, 08 Oct 2008 17:35:01 -0700

In This Report

Highlights
Introduction
Melanoma
Nonmelanoma Skin Cancer
Precancerous Skin Condition...
Causes
Risk Factors
Prevention
Screening
Diagnosis
Staging
Treatment for Melanoma
Treatment for Nonmelanoma S...
Prognosis
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Risk factors

According to a report in the Archives of Dermatology, marathon runners are more likely than the general population to develop skin changes that increase the risk for melanoma.

Prevention

A study published in The Lancet indicates that the best ways to avoid sun damage are to reduce the time you spend in the sun and to wear a hat and clothing to protect as much of your skin as possible. Fabrics that are thick and tightly woven offer the best protection.

The U.S. Food and Drug Administration has approved a new type of sunscreen that may more effectively block UVA than products currently available in the United States. UVA light penetrates the skin deeper than other forms of sunlight. Exposure to UVA is believed to contribute to skin cancers. The new sunscreen, called Anthelios SX, is available over the counter.

Screening

A study published in CANCER has shown that older men are more likely to undergo a whole body skin exam if they understand their personal risk factors for melanoma and know where to go to have such an exam. The study emphasizes the importance of skin cancer awareness and education.

One-time melanoma screening for adults over age 50 seems to be as cost-effective as other nationally recommended cancer screening programs, according to a report in the Archives of Dermatology. The study authors also found that screening brothers and sisters of someone with melanoma every 2 years may also be cost-effective.

Diagnosis

Dermatologists detect melanoma earlier than other health care providers, according to an article in the Archives of Dermatology. The earlier melanoma is diagnosed and treated, the greater your chances of survival.

Introduction

Skin cancer is cancer that starts in the skin. Skin cancers are divided into two major groups:

Nonmelanoma, which includes basal cell cancer and squamous cell cancer
Melanoma, the deadliest form of skin cancer

Different skin cancers start in different layers or cells of the skin. To understand how skin cancer develops, it is useful to know something about the skin.

The Skin. The skin is the largest organ in the body and consists of layers.

The outermost layer of the skin is called the epidermis. It is only about 20 cells deep, roughly as thick as a sheet of paper.
The dermis ranges in thickness from 1 - 4 millimeters (about 1/32 - 1/8 inch). The dermis contains tiny blood and lymph vessels, which increase in number deeper in the skin.

The skin is the largest organ of the body. The skin and its derivatives (hair, nails, sweat, and oil glands) make up the integumentary system. One of the main functions of the skin is protection. It protects the body from external factors, such as bacteria, chemicals, and temperature. The skin contains secretions that can kill bacteria, and the pigment melanin provides a chemical pigment defense against ultraviolet light that can damage skin cells. The skin also helps control body temperature.

Melanocytes. A layer of cells between the epidermis and the dermis, called melanocytes, produces a brown-black skin pigment ( melanin) that determines skin and hair color. Melanin also helps protect against the damaging rays of the sun.

As a person ages, melanocytes often proliferate, forming concentrated clusters that appear on the surface as small, dark, flat, or dome-shaped spots, which are usually harmless moles or liver spots.

When cell proliferation occurs in a controlled and contained manner, the resulting lesion is benign and is commonly referred to as a mole or nevus.
Sometimes, however, pigment cells grow out of control and become a cancerous and life-threatening melanoma.

Click the icon to see an image of melanin.

Melanoma

At first, melanoma cells are found in the epidermis and top layers of the dermis. However, once they grow downward into the dermis, the cancer can come into contact with lymph and blood vessels. The thicker the melanoma, the greater the likelihood that it could spread to distant sites.

Removal of the lesion before it reaches the deeper layers of the skin is important for achieving a cure.

Superficial Spreading Melanoma. Superficial spreading melanoma is the most common and most curable. It is flat, asymmetrical, unevenly colored, and usually grows outward across the surface of the skin.

Nodular Melanoma. Nodular melanoma appears as a fast-growing brown or black lump, and its characteristics do not always fit the definitions described above. It is important to check for this type of melanoma because it is associated with an outbreak of other tumors.

Lentigo Maligna. Lentigo maligna (sometimes called Hutchinson's freckle) usually occurs in elderly people and is marked by flat, mottled, tan-to-brown freckle-like spots with irregular borders. These lesions often appear on the face or other sun-exposed areas and typically enlarge slowly for 5 - 15 years before cancer appears.

Acral Lentiginous Melanoma. Although rare, acral lentiginous melanoma is the most common melanoma among African and Asian populations. It commonly appears as a dark patch on the palms, soles, fingers, toes, under fingernails or toenails, or in mucous membranes.

Melanoma cells usually spread first through the lymph vessels or glands. Melanoma cells can also spread by way of blood vessels to various organs, spreading cancer to the liver, lungs, brain, or other sites.

Melanomas tend to grow in stages:

Most melanomas tend to be flat initially and spread laterally across the skin surface as they grow. At this early stage, which can last 1 - 5 years or longer, removal of the growth has an excellent chance of curing the melanoma. Still, there is a chance that some of these melanomas are invasive, and they should be treated aggressively.
Lesions that become raised or dome-shaped over at least part of their surface indicate that downward growth has occurred. In some cases, this growth is very rapid, occurring over a period of weeks to months.

Any suspicious lesion should be checked immediately, particularly if it has grown quickly or is partially flat and partially raised.

Common sites of melanoma in men include:

Head
Middle of the body (trunk)
Neck

Common sites of melanoma in women include:

Arms
Legs

However, any area of the skin may be affected. You may not notice melanomas if they appear on areas that are difficult to examine, such as the scalp or the back.

Less common sites for melanoma include:

Fingers
Palms
Soles of the feet
Genitals
Lips
Under the fingernails or toenails

The presence of a dark lesion under the nail that runs into the adjoining skin and doesn't heal may signal melanoma.

Rarely, melanomas appear in the mouth, in the iris of the eye, or in the retina at the back of the eye, where they may be detected during dental or eye examinations.

Click the icon to see an image of melanoma.

Nonmelanoma Skin Cancer

The two other types of skin cancers are called basal cell cancer and squamous cell cancer. These are nonmelanoma skin cancers.

Basal cell cancer starts in the lowest part of the epidermis in round cells called basal cells. Basal cell is the most common form of skin cancer. It occurs in about 800,000 - 900,000 people every year.

Basal cell cancer usually develops later in life in areas that have received the most sun exposure, such as the head, neck, back, and especially the nose. However, some basal cell cancers appear in areas not exposed to the sun.

Basal cell cancers have many different appearances:

They usually appear as a round area of thickened skin that does not change color or cause pain or itching.
Very slowly, the lesion spreads out and develops a slightly raised edge, which may be translucent and smooth. Infrequently, basal cell cancers resemble malignant melanomas in color.
Eventually, the center becomes hollowed and covered with a thin skin, which can become sore and open.
A form known as aggressive-growth basal cell cancer resembles a scar with a hard base. This type is more likely to spread and must be treated very aggressively.

Basal cell cancer is a cancerous (malignant) skin tumor involving basal skin cells. Basal cell skin cancers usually occur on areas of skin that are regularly exposed to sunlight or other ultraviolet radiation. Once a suspicious lesion is found, a biopsy is needed to prove the diagnosis of basal cell cancer. Treatment varies depending on the size, depth, and location of the cancer.

Basal cell cancers are sometimes hard to tell from benign skin conditions. For instance, occasionally they arise in unexposed skin, where they may mimic an ordinary mole, cyst, or pimple. They may be particularly difficult to distinguish from benign cysts when they occur near the eyes.

Usually, basal cells grow slowly. They are rarely deadly. Most basal cell cancers need not be treated as an emergency, although late treatment can cause disfigurement, so they should be removed as early as possible.

Basal cell cancers that are most likely to spread include those that are larger than 1 centimeter, scar-like, and those located on the cheek, nose, neck, earlobe, eyelid, or temple.

Some studies have shown that people with basal cell cancer may be at higher risk for second cancers, including melanoma, cancer of the lip, salivary glands, larynx, lung, breast, and kidney, and non-Hodgkin's lymphoma. Those at higher risk for such cancers appear to be men and anyone diagnosed before 60 with basal cell cancer.

Squamous cell cancer develops from flat, scale-like skin cells called keratinocytes, which lie under the top layer of the epidermis. Most squamous cell cancers occur on sun-exposed areas, especially the forehead, temple, ears, neck, and back of the hands. People who have spent considerable time sunbathing may develop them on their lower legs.

Types of squamous cell cancer:

Squamous cell carcinoma in situ (also called Bowen's disease) is the earliest form of this type of cancer. The cancer has not spread. Cancer areas appear as large reddish patches (often over 1 inch) that are scaly and crusted.
Invasive squamous cell carcinoma is highly likely to spread (metastasize). The skin cancer lesions can grown rapidly (over months) or slowly (over years). Eventually they become ulcerated.

Click the icon to see an image of squamous cell cancer.

Prompt treatment is desirable because squamous cell cancers are more likely to spread to local lymph nodes than basal cell cancer. Squamous cell cancers most likely to spread include:

Deep lesions, those larger than 2 cm in diameter, or patches with poorly defined margins
Recurrent lesions
Squamous cell cancer on neck, earlobe, eyelid, lips, or temple
Squamous cell cancer that develops in ulcers
Squamous cell cancer that develops on skin areas that have been previously treated with radiation or exposed to cancer-killing chemicals

People with squamous cell cancers seem to be at higher risk for other cancers, including melanoma, lung cancer, non-Hodgkin's lymphoma, bladder cancer, leukemia, testicular and prostate cancer in men, and breast cancer in women.

Precancerous Skin Conditions

Actinic (Solar) Keratosis. Actinic keratosis (also called solar keratosis) is a precancerous skin lesion caused by too much sun exposure. Such lesions can turn into cancer, but not always.

Actinic keratoses occur after years of sun exposure. They appear predominantly on sun-exposed skin, such as the face, neck, back of the hands and forearms, upper chest, and upper back. Men may develop keratoses along the rim of the ear.

Actinic keratoses have the following characteristics:

Lesions typically occur on the surface of the skin and have a sandpaper-like feel. In fact, they are sometimes more easily felt than seen.
Most lesions are pink and even flesh-colored. Some are red or brown, scaly, and tender. At times, they can resemble melanomas; even dermatologists may have trouble telling the two apart.
They can range in size from microscopic to several inches in diameter.

Keratoacanthomas. Keratoacanthomas closely resemble squamous cell cancers, but they are not malignant. The majority occur in sun-exposed skin, usually on the hands or face. They are typically skin colored or slightly red when they first develop, but their appearance typically changes:

In the early stages, keratoacanthomas are smooth, red, and dome shaped.
Within a few weeks, they can grow rapidly, usually to 1 or 2 centimeters. Some reach the size of a quarter in less than a month and can be rather disfiguring.
They eventually stop growing and become crater-like with a surrounding outer rim of tissue and sometimes have a crusty interior.

Most will spontaneously get better within 1 year, but they almost always scar after healing. Also about 25% develop into squamous cell cancers, most frequently in older people and in sun-exposed areas. Removal by surgery (sometimes by radiation) is recommended. They may also be treated with 5-fluorouracil, either as a cream or injections.

Causes

You cannot overestimate the role of the sun as the most important cause of prematurely aging skin (called photoaging ) and skin cancers.

Long-term repetitive and cumulative exposure to sunlight appears to be responsible for the vast majority of undesirable consequences of aging skin, including basal cell and squamous cell cancers.

Melanoma is more likely to be caused by intense exposure to sunlight in early life.

UVA and UVB Radiation. When sunlight penetrates the top layers of the skin, ultraviolet (UVA or UVB) radiation strikes the DNA inside the skin cells and damages it.

UVB is the main type of radiation responsible for sunburns. It primarily affects the outer skin layers. This type of ultraviolet light is most intense at midday when sunlight is brightest.
UVA penetrates more deeply and efficiently. Unlike UVB, window glass does not filter out UVA rays.

Damaging Effects of UV Radiation. Both UVA and UVB rays cause damage, including genetic injury, wrinkles, lower immunity against infection, aging skin disorders, and cancer, although the mechanisms are not yet fully clear. The following are some ways in which cancer may develop and some defensive actions that the skin uses to defend itself against DNA damage.

Oxidation and Antioxidants. The effects of UV radiation are implicated in the production of oxidants, also called free radicals. Free radicals are unstable molecules produced by normal chemical processes in the body that, in excess, can damage the body's cells and even alter the DNA. This contributes to the aging process and sometimes to cancer.
Defective DNA Repair and Protective Enzymes. Some skin cancers are caused by a breakdown in the body's mechanisms that help repair DNA damage. For example, xeroderma pigmentosum (XP) is a rare genetic disease in which the body cannot repair damage caused by ultraviolet light. Normally, a number of enzymes in the skin help protect against this damage.
Breakdown of Immune Protection. Specific immune factors protect the skin, including white blood cells called T lymphocytes and specialized skin cells called Langerhans cells. These immune system cells attack developing cancer cells at the very earliest stages. However, certain substances in the skin, particularly a chemical called urocanic acid, can suppress such immune factors when exposed to sunlight.

Defective Cell Death (Apoptosis). Apoptosis is the last defense of the immune system. It is a natural process of cell-suicide, which occurs when cells are very severely damaged. Apoptosis in the skin kills off cells harmed by UVA so that they do not turn cancerous. The peeling after sunburn is the result of these dead skin cells. However, some gene defects or other factors interfere with apoptosis. If this occurs, damaged cells can continue to spread, resulting in skin cancer.

A number of genetic factors are being investigated for their role in melanomas, including inherited genes and genetic defects that are acquired from environmental assaults (particularly sunlight).

Mutations in Genes that Regulate Cell Growth. Noninherited mutations in a number of genes that block tumor growth or other cell-protecting properties may account for cancerous changes in moles and for aggressive melanomas. The following are some examples.

Important studies have now identified a mutation in the BRAF gene that appears to be the most common event in the process that leads to melanoma. Some researchers have observed mutations in 66% of malignant melanomas. Researchers hope that agents that block this gene may be a viable treatment path.
P16 is a tumor suppressive gene that may be abnormal in some melanoma cases.
Genetic mutations that regulate Ku70 and Ku80 proteins may disrupt processes that repair strands of DNA.
Researchers are also studying mutations in a gene that encodes for a substance called epidermal growth factor (EGF). EGF plays a role in skin cell growth and wound healing, and may account for many sporadic (non-inherited) cases of melanoma.
Of further interest are mutations in genes that regulate Fas proteins, which are involved in apoptosis, a natural process of cell self-destruction. When apoptosis goes awry in melanoma cells, proliferation can become rampant.

CDKN2A Mutations. Mutations in a gene regulator called CDKN2A are the most common causes of inherited melanoma, which is still very uncommon. Mutations in this gene also appear in non-inherited cases of melanoma. Genetic tests are being developed for CDKN2A, although it is not clear if knowing the results of the test would benefit people carrying the gene.

Variations in the Melanocortin-1 Receptor Gene. One study found that the greater the number of variations from normal in a gene called the melanocortin-1 receptor gene, the greater the risk for melanoma. The gene plays an important role in determining if a person has red hair, fair skin, and sensitivity to UV radiation. Interestingly, people who had olive and darker skin and who carried one or more variations of the gene had a higher than average risk for melanoma.

Aging may weaken the body's ability to fend off impending cancers, including melanomas. As a person ages, they lose Langerhans cells that help fight off early skin cancers. The number of these immune cells decreases with age, possibly setting the stage for skin cancers in later life.

Risk Factors

In the United States, the rate of melanoma is rising more rapidly than any other cancer. According to the American Cancer Society, about 59,940 persons will be diagnosed with melanoma in 2007. More than 8,000 people will die from the cancer.

Survival rates have been improving, however, and the increase in melanomas has occurred principally with thin, less aggressive forms of the disease. Some experts believe this is due to the increased awareness from effective public programs and earlier diagnosis.

A risk factor is anything that increases your chance of getting a disease. The following factors increase your risk for skin cancer:

Age over 40
Being male
Fair skin
Too much exposure to sunlight and ultraviolet radiation
Personal history of skin cancer
Family history of skin cancer
Smoking
Certain chronic or severe skin problems
Certain medical conditions or treatments that affect your immune system
Exposure to chemicals or radiation

Melanoma in Adults. Melanoma is most common in people over 40, and the incidence increases significantly as people get older. Before age 40, melanomas are slightly more common in women than men, but after age 40 men are more often affected. Men are also more likely to have invasive and fatal melanoma than are women, although some research suggests that the higher rates are only because men fail to seek a diagnosis of suspicious skin changes before they become dangerous. The rate in women levels off somewhat between age 45 and 60; researchers speculate that menopause could have some sort of protective effect during those years.

Melanoma in Children. Melanoma is rare in children under age 10. Among children ages 10 - 14 the incidence is only 0.3 per 100,000. Between ages 14 - 19, it is still very rare, 1.3 per 100,000. Parents, then, should not be unduly alarmed by every minor skin imperfection in their children. Nevertheless, melanoma is as serious in children as in adults, and early detection is still critical.

Skin cancer is associated with both duration and intensity of sun exposure. Risk of melanoma increases with excessive sun exposure during the first 10 - 18 years of life. Sunburns are also dangerous, with five or more sunburns doubling the risk of developing cancer. Cancer typically arises many years later.

Marathon runners are more likely than the general population to develop skin changes that increase your risk for melanoma. That's because marathon runners spend a lot of time outdoors. The study findings are published in the Archives of Dermatology.

Tanning Devices. Tanning beds and sunlamps increase the risk for developing melanoma, according to a 2005 review of epidemiologic studies. Previous findings have suggested that women who use tanning devices more than once a month significantly increase their melanoma risk. Women in their 20s, as well as blondes and redheads, are especially at risk.

Ethnic Groups and Complexion. People with light skin, blue, gray, or green eyes, red or blond hair, and lots of freckles are at highest risk for developing melanoma. The risk increases for those who are easily sunburned and rarely tan, particularly if they live close to the equator where sunlight is most intense. Darker ethnic groups or those with swarthy complexions are not immune, however.

Experts have devised a classification system for skin phototypes (SPTs) based on the sensitivity to sunlight. It ranges from SPT I (lightest skin plus other factors) to IV (darkest skin). Tanning and Sunburn Risk People with skin types I and II are at highest risk for photoaging skin diseases, including cancer. It should be noted, however, that premature aging from sunlight can affect people of all skin shades.


Skin Type	Tanning and Burning Risk
I	Always burns, never tans, sensitive to sun exposure.
II	Burns easily, tans minimally.
III	Burns moderately, tans gradually to light brown.
IV	Burns minimally, always tans well to moderately brown.
V	Rarely burns, tans profusely to dark.
VI	Never burns, deeply pigmented, least sensitive.

Australia has the highest melanoma rate in the world. In the United States the rate is highest in California, Florida, and Texas. The disease is by no means limited to such sunny states and countries, however. In general, the risks are highest in regions where the population tends to be blonde and fair-skinned. Norway, for example, has had the highest rate of melanoma in Europe, and rates are soaring in the UK, particularly among men, perhaps because Britons are increasingly vacationing in sunny climates.

Melanoma. Individuals who have been diagnosed with melanoma are at increased risk for a second primary melanoma. According to one 2003 study, the risk over time for developing a second melanoma is 1% in the first year after diagnosis, 2.1% at 5 years, 3.2% at 10 years, and 5.3% at 20 years. The risk is especially higher in older men and in those with first melanomas on the upper body and face.

People with family members who have or had melanoma should also be considered at high risk and examined on a regular basis.

Nonmelanoma Skin Cancers. Nonmelanoma skin cancers, including basal and squamous cell carcinomas, increase the risk of dying from other cancers, including melanoma itself, lung cancer, non-Hodgkin's lymphoma, bladder cancer, and leukemia as well as testicular and prostate cancers (in men) and breast cancer (in women).

Psoriasis. Psoriasis increases the risk for squamous cell carcinoma, but studies conflict on whether it has any effect on melanoma. One study, in fact, reported a lower risk. Nevertheless, there is some evidence that long-term treatment for psoriasis using UVA radiation (PUVA) may increase the risk for melanoma. In one study, there was a significantly higher risk even with relatively few treatments. In one study, invasive melanoma had occurred in 2.8% of patients 15 or more years after the initial treatment.

Moles (Nevi) and Other Dark Blemishes. Certain moles and dark blemishes increase the risk for skin cancer. Any mole ( nevus) or other blemish that seems new, changing, or unusual in any way should be evaluated by a health care professional.

Some specific moles or dark blemishes that are risk factors for melanoma include:

Freckles. Freckles typically appear in children on sun-exposed areas and are usually evenly brown or tan. The more freckles a person develops as a child, the greater the risk for melanoma in adulthood.
Dysplastic (or Atypical) Nevi. About 30% of the population has moles called dysplastic nevi, or atypical moles. They are larger than ordinary moles (most are 5 mm across, about the size of a pencil eraser, or larger), have irregular borders, and are various shades or colors. Individuals who have dysplastic nevi plus a family history of melanoma (a syndrome known as FAMM) are at a high risk for developing melanoma at an early age (younger than 40). The risk for those with atypical moles and no family history of melanoma is less clear.
Large birthmarks (giant congenital nevi). Very large birthmarks more than 8 inches across are major risk factors for melanoma. In such cases, cancer usually appears by age 10. Medium-sized congenital nevi do not appear to increase the risk for melanoma. Whenever possible, very large birthmarks should be removed during infancy. Experts disagree, however, about whether small birthmarks need to be removed. Parents should watch any birthmark for changes.

The more moles one has the higher the risk that one of them will become cancerous, although the danger is still very small. A 2003 study estimated that the risk for a single mole to develop into melanoma by age 80 is 1 in 3,164 in men and 1 in 10,800 for women.

The risk is higher, however, with atypical moles. One study of people with melanoma indicated that the presence of even one atypical mole doubled the normal risk.

Some skin blemishes can look like -- but are not -- melanoma. Noncancerous moles typically have the following characteristics:

They generally remain small with clearly defined, regular borders, and uniform coloration. Some have a regular stippled or net-like pattern of pigmentation, however, and may even resemble early melanoma.
They typically first appear during childhood, puberty, or young adulthood. They may naturally grow, darken, or increase in number at certain times of life, such as adolescence or pregnancy.

Examples of moles or blemishes that may resemble skin cancer include:

Blue nevus. A benign mole that may easily be mistaken for melanoma. It is a blue-black, smooth, raised nodule and commonly occurs on the buttocks, hands, or feet.

Liver Spots. Liver spots are usually evenly brown or tan sun-induced lesions that are universal signs of aging. Occurring most noticeably on the hands and face, these harmless blemishes tend to enlarge and darken over time.

Spindle Cell (Spitz) Nevus. Children may develop a benign lesion called a spindle cell (or Spitz) nevus. The mole is firm, raised, and pink or reddish-brown. It may be smooth or scaly and usually appears on the face, particularly the cheeks. It is not harmful, but it may be difficult to differentiate from a melanoma, even for experts.

Non-Hodgkin's Lymphoma. Survivors of either non-Hodgkin's lymphoma or melanoma face a higher risk for the other malignancy. These may have common causes, such as exposure to UV radiation or shared genetic factors.

Human papillomavirus (HPV). Genital warts (human papillomavirus, or HPV) may also increase the risk of squamous cell cancer in the genital and anal areas and around fingernails.

Immunosuppression. Skin cancer risk is increased in persons whose immune systems are suppressed because of certain medications, organ transplantation, or medical conditions such as AIDS. Melanoma has also developed in patients who received heart transplants from donors who had the disease. Immune-suppressing drugs used to treat autoimmune disorders may also increase the risk of skin cancer. Potential skin cancer risks have been associated with the eczema drugs pimecrolimus (Elidel) and tacrolimus (Protopic).

Rheumatoid arthritis. Despite previous concerns, the rheumatoid arthritis drug etanercept (Enbrel) does not raise the risk for developing squamous cell skin cancer. The findings are reported in the Archives of Dermatology. Etanercept works by blocking tumor necrosis factor (TNF), an immune system chemical messenger that is involved in inflammatory processes and diseases.

Occupational exposure to radiation, such as in health care or industrial settings, may increase the risk for melanoma. Airline pilots, too, are at increased risk for melanoma. It is uncertain, however, whether this higher risk is from excessive exposure to ionizing radiation at high altitudes or because they have more opportunity to spend time in sunny regions. Experts disagree over whether frequent flyers are also at increased jeopardy.

Prevention

The best way to lower the risk your risk of skin cancer is to protect your skin from the sun and UV light.

Wear sunscreen. The use of sunscreens is complex, and everyone should understand how and when to use them. Follow instructions closely and reapply as directed after swimming or sweating. The bottom line is not that people should avoid sunscreens or sunblocks, but that they should always use them in combination with other sun-protective measures.

Many parents are now taking effective steps to protect their children, although experts worry that they are relying too much on sunscreen and less on other protective measures. Adolescents are at special risk for sun-related cancers because, according to a 2002 study, most of them do not take protective measures when out in the sun. According to the study, boys are less likely to use sunscreen than girls, but girls are more likely to get sunburn and use tanning salons more often.

The best way to prevent skin damage in any case is to avoid episodes of excessive sun exposure. The following are some specific guidelines:

Use sunscreens that block out both UVA and UVB radiation. Do not rely on sunscreen alone for sun protection. Also wear protective clothing and sunglasses.
Avoid exposure particularly during the hours of 10 a.m. to 4 p.m., when UV rays are the strongest.
Clouds and haze do not protect you from the sun and in some cases may intensify UVB rays.
Avoid reflective surfaces such as water, sand, concrete, and white-painted areas.
UV intensity depends on the angle of the sun, not heat or brightness. The dangers are greater the closer to the start of summer.
Skin burns faster at higher altitudes. One study suggested that an average complexioned person burns in 6 minutes at 11,000 feet at noon compared to 25 minutes at sea level.
Avoid sun lamps, tanning beds, and tanning salons. The machines use mostly high-output UVA rays. Some experts believe that 15 - 30 minutes at a tanning salon are as dangerous as a day spent in the sun. People should not be misled by advertising claims of "safe" tanning.

Wear protective clothing, sunglasses, and a hat to shield your face from the sun's rays. Special clothing can block out UV rays and is rated using sun protection factor (SPF) ratings or a system called the UPF (ultraviolet protection factor) index, with 50 UPF being the highest. (According to one study, this is a very reliable indicator of protection.) The clothing is expensive, however.

Everyone, including children, should wear hats with wide brims. (Even wearing a hat, however, may not be fully protective against skin cancers on the head and neck.)
People should look for loosely fitted, unbleached, tightly woven fabrics. The tighter the weave the more protective the garment.
Washing clothes over and over improves UPF by drawing fabrics together during shrinkage. An easy way to assess protection is simply to hold the garment up to a window or lamp and see how much light comes through. The less the better.
Everyone over age 1 should wear sunglasses that block all UVA and UVB rays when in the sun.

Click the icon to see a depiction of sun protection.

When choosing a sunscreen, look at the ingredients. Preparations that help block UV radiation are sometimes classified as sunscreens or sunblocks, according to the substances they contain. In general, sunscreens contain organic formulas and sunblocks inorganic formulas. However, the term sunblock is used less and less as sunscreens increasingly contain both kinds of ingredients:

Organic formulas contain UV-filtering chemicals such as octocrylene, octyl salicylate, homosalate, and octyl methoxycinnamate (block UVB), avobenzone-Parsol 1789 (blocks UVA), cinoxate, ethylhexyl p-methoxycinnamate (blocks UVB and small amounts of UVA), oxybenzone, and benzophenone-3 (blocks UVA/UVB). People should look for a wide-spectrum sunscreen that contains combinations of these ingredients and filter both UVA and UVB. Of note: para-amino benzoic acid (PABA), once a popular ingredient, is now used infrequently. PABA may actually break down in the presence of UV exposure and release harmful oxidants. And many people have an allergic reaction to it. Some products contain PABA derivatives, such as padimate O or octyl dimethyl PABA.
Inorganic formulas contain the UV-blocking pigments zinc oxide or titanium dioxide. Zinc and titanium oxides lie on top of the skin and are not absorbed. They prevent nearly all UVA and UVB rays from reaching the skin. Older sunblocks are white, pasty, and unattractive, but current products use so-called microfine oxides, either zinc (Z-Cote) or titanium. They are transparent and nearly as protective as the older types. Microfine zinc oxide may be more protective and less pasty-colored than microfine titanium oxide.

Inexpensive products work as well as expensive ones with the same ingredients. Unfortunately, there are still no standards for sunscreens, and even those claiming UVA protection may offer very little.

Organic formulas and inorganic microfine oxides do not protect against visible light, which is a problem for people who have light-sensitive skin conditions, including actinic prurigo, porphyria, and chronic actinic dermatitis.

Calculating the SPF. SPF is a ratio based on the amount of UVB radiation needed to turn sunscreen- or sunblock-treated skin red compared to non-treated skin. For instance, people who sunburn in 5 minutes and who want to stay in the sun for 150 minutes might use an SPF 30. The formula would be: 30 (the SPF number) times 5 (minutes to burn) = 150 minutes in the sun.

Protection offered by sunscreens may be classified as follows:

Minimal: SPF 2 to 11
Moderate: SPF 12 through 29
High: 30+

Although some sunscreens claim SPFs higher than 30, the added protection at such higher levels is insignificant.

SPF Levels by Age Group. Although sunscreens are safe in most toddlers and children, they should not be the first and only lines of defense. All young children should be well-covered with clothing, sunglasses, and hats. Children should be kept out of the sun during peak sunlight periods. Do not use sunscreens on babies younger than 6 months without consulting a doctor.

Older children and adults (even those with darker skin) benefit from using SPFs of 15 and over. Some experts recommend that most people should use SPF 30 on the face and 15 on the body.

Adults who burn easily instead of tanning and anyone with risk factors for skin cancer should use at least SPF 30.

Timing and Amount of Application. Apply sunscreen or sunblock liberally as follows:

Adults should include sunscreen every day, even if going outdoors for only a short time.
Apply a large amount to all exposed areas, including ears and feet. To achieve protection as indicated by the sunscreen's SPF, experts recommend half a teaspoon each for the head, neck, and each arm and a teaspoon each for the chest area, the back, and each leg.
Apply initially 30 minutes before venturing outdoors for best results. This allows time for the sunscreen to be absorbed. Then reapply every 15 - 30 minutes while being in the sunlight.
Also reapply each time after exercise or swimming. Choose a waterproof or water-resistant formula even if activities don't include swimming. Waterproof formulas last for about 40 minutes in the water, whereas water-resistant formulas last half as long.
Insect repellents reduce sunscreen SPFs by up to one-third. Use higher SPFs and very liberal application when applying both.

Possible Hazards of Sunscreens, Sun Avoidance, or Both. When used generously and appropriately, sunscreen products and sun avoidance help reduce the severity of many aging skin disorders, including squamous cell cancers. There are certain concerns, however. Sunscreens do not appear to provide protection against melanoma and some basal cell cancers. In fact, some studies have reported a higher association with sunscreen use and these skin malignancies, though not all studies report such negative results.

The reasons for this possible increased risk are unclear, though some theories include:

Until recently, many sunscreens blocked only or predominantly blocked UVB rays and not UVA, the more deeply penetrating rays now known to be especially dangerous. Studies then may not have reflected the effects of the broad-spectrum sunscreens now available, which block both UVA and UVB.
People who apply sunscreens may stay out too long during peak sunlight hours. Even if a person doesn't sunburn, UVA rays can still penetrate the skin and do harm.
People may not put on enough sunscreen. A 2002 study found that people generally apply only 20 - 60% of the recommended amount, which can provide significantly less protection than the given SPF. A later study reported that when applied at the recommended amount, a broad-screen sunscreen prevents DNA damage from UV exposure.

Underexposure to sunlight. There is some major concern that underexposure to sunlight, due to the use of sunscreens or sun-avoidance measures, may produce other health problems such as:

Vitamin D deficiency. The body makes vitamin D through a chemical reaction to UVB sunlight. Too many sun-protection measures may increase the risk for developing vitamin D deficiency. Vitamin D helps prevent rickets, osteoporosis, and some cancers, including melanoma. People who need to avoid sunlight and whose diet is low in foods that contain vitamin D should check with their doctor about taking supplements. (Warning: Vitamin D is poisonous when taken in high doses.) People with darker skin are at higher risk for deficiencies from sun protection than those with whiter skin.
Other Cancers. Although sunlight is implicated in skin cancers, it is also associated with lower risks for breast, prostate, ovarian, and colon cancers. Some protection against these cancers may be related to vitamin D production by sunlight.
Depression. Many people suffer from seasonal affective disorder (SAD), a form of depression that generally occurs in winter and is associated with exposure to less sunlight.

The bottom line is that some sunlight is important and even necessary.

A study published in 1994 in the New England Journal of Medicine found that persons with a history of nonmelanoma skin cancer who ate a low-fat diet were much less likely to develop actinic keratosis, a precancerous skin condition.

However, the low-fat diet did not appear to have any effect on the development of basal cell cancer.

Chemoprevention is the use of a substance to prevent or reduce your risk of cancer. Certain drugs have been used to help block the development of skin cancers, including melanoma. For example, a medicine called imiquimod is approved to prevent skin cancer in certain individuals. This medicine prompts the immune system to fight off foreign substances, including cancer cells. Chemopreventive agents under investigation and showing promise for skin cancer include:

Nonsteroidal anti-inflammatory drugs
Difluoromethylornithine (DFMO)
Catechins (phytochemicals found in certain foods)
Anti-aging drugs called retinoids (vitamin A derivatives)

Retinoids have been shown to prevent nonmelanoma skin cancer in patients with basal cell nevus syndrome, xeroderma pigmentosum, and transplanted organs. Oral retinoids include isotretinoin and acitretin. They may also prevent the development of squamous cell carcinoma in patients who are taking such medicines to treat psoriasis.

Early animal studies had suggested that cholesterol-lowering statins or fibrates may reduce the risk of skin cancer, but human studies have produced inconsistent results. A review of several studies has concluded that such drugs do not decrease your risk of melanoma. The findings are published in the Journal of the National Cancer Institute.

Researchers are also studying chemopreventative compounds that target genetic mechanisms in the skin. They may prove to be beneficial ingredients in creams or lotions used to prevent skin cancers on a molecular level. They include cytokine interleukin-12 and T4 endonuclease 5 (T4N5).

Studies have shown that mice with round-the-clock access to an exercise wheel developed skin cancer more slowly when exposed to UVB. Their tumors were also fewer in number and smaller. Analysis of the data suggested that exercise might trigger the death of the developing cancer cells faster than they can grow. Exercise also made the mice lose weight, and the number of tumors decreased as fat disappeared.

Antioxidants are chemicals or drugs that help prevent cell damage from unstable molecules called free radicals. Antioxidants promote to protect the skin include vitamins C and E, and coenzyme Q10 (CoQ10).

Studies suggest that vitamin E creams, particularly those made from a type of Vitamin E called alpha tocopherol, decreased skin roughness, length of facial lines, and wrinkle depth. Studies on mice have also shown that such creams reduce UV-related skin cancer.

Vitamin C is a very potent antioxidant. It is also called ascorbic acid. Most studies on the effects of antioxidants on the skin have used this vitamin. In laboratory studies, large amounts reduced skin swelling and protected immune factors from sunlight.

Selenium in the form of L-selenomethionine has protected against sun damage and even delayed skin cancer in animal studies. It is not known if such benefits apply to people.

Click the icon to read about the antioxidant selenium.

Antioxidant Skin Creams. There are wide claims about the benefits of antioxidants for wrinkles when used in skin creams. However, to date, only vitamin E, C, and selenium-based skin products have been shown to help reduce sun damage to the skin. However, most available brands contain very low concentrations of these antioxidants. In addition, the antioxidants are also not well absorbed by the skin, so the effect may be short-term.

Antioxidant Pills. One small study found that taking a combination of vitamins C and E supplements by mouth may help reduce sunburn reactions, although the protection is much less than from sunscreens. Taking the vitamins alone does not appear to have the same effect.

Other Natural Substances. The following natural substances have antioxidant properties and are being tried for sun-protection:

Both green and black tea appear to have properties that may provide some protection against skin cancers and photoaging. A 2001 study using extracts of topical green tea suggested that it might protect against ultraviolet damage. Green tea skin care products are now available, but their quality is unregulated.
Ginger also appears to have some sun protective qualities.
Silymarin, a substance found in the milk thistle family (which includes artichokes), may prevent UVB-promoted cancers in animals.
Garlic has been shown to protect animals against UVB damage. Whether these results may be applied to humans, and what quantities of garlic might be beneficial, is still unknown.

Warning Note: A wide range of herbal products may contribute to dermatological problems. Some Chinese herbal creams have been found to contain corticosteroids. Mercury or arsenic contaminants have been found in some Ayurvedic therapies. In addition, several oral herbal remedies used for medical or emotional conditions may produce irritation in reaction to sunlight (photosensitivity). They include, but are not limited to, St. John's wort, kava, and yohimbe.

Screening

Education and prevention programs have led to improved screening for skin cancer, which in turn has improved diagnosis and survival rates for melanoma. For example, a study published in CANCER has shown that older men are more likely to undergo a whole body skin exam if they were aware of personal risk factors and where they could go to have an exam performed.

Skin cancers may have many different appearances. They can be small, shiny, or waxy, scaly and rough, firm and red, crusty or bleeding, or have other features. Itching, tenderness, scaling, bleeding, crusting, or sores can signal potentially cancerous changes in any mole.

A mnemonic device, ABCDE, is used to describe several features that help to distinguish skin cancer from noncancerous growths.

Asymmetry (A). Skin cancers usually grow in an irregular, asymmetric fashion. That means one half of the abnormal skin area is different than the other half.
Border Irregularity (B). Noncancerous lesions generally have clearly defined borders. Melanoma lesions often have notched or indistinct borders that may signal ongoing growth and spread of the cancer.
Color Variation (C). One of the earliest signs of melanoma may be the appearance of various colors within the lesion. Because melanomas arise within pigment-forming cells, they are often varicolored lesions of tan, dark brown, or black, reflecting the production of melanin pigment at different depths within the skin. Occasionally, lesions are flesh colored or surrounded by redness or lighter areas of depigmentation.
- Pink or red areas may result from inflammation of blood vessels within the skin.
- Blue areas reflect pigment in the deeper layers of the skin.
- White areas can arise from dead cancerous tissue.
Diameter (D). A diameter of 6 millimeters or larger (about the size of a pencil eraser) is worrisome. Melanomas start out small; by the time a lesion has grown this large, other abnormalities will most likely be present. A doctor should examine any suspicious lesion, no matter what size it is.
Evolution (E). A lesion that is growing or changing deserves evaluation.

The ABCDE plan is a general guide. It will not help detect the early stages of nodular melanoma and may also miss amelanotic melanoma, which is not pigmented.

You should keep in mind that the most important warning sign of melanoma is a new or changing skin lesion, regardless of size or color. Changes that occur over a short period of time (particularly over a few weeks) are most worrisome.

Anyone with risk factors for skin cancer should check the entire body about once a month. People who regularly check moles on their skin may have a lower risk of developing advanced melanoma.

Experts suggest drawing a map of the body, indicating locations of moles, areas of discoloration, lumps, or other blemishes. Whenever a person conducts a self-examination, they should compare their body to the map to check for new lesions, lumps, or moles and for changes in shape, color, and size.

Some experts have defined three specific body areas to look for skin cancers, including melanomas:

Areas visible to anyone, such as the arms or face -- about 60% of melanomas are found on such areas.
Areas usually covered with clothing and visible only to the patients or their partners -- about 34% of melanomas are detected in these areas.
Hidden areas such as the scalp, buttock folds, and mouth -- about 6% of melanomas, usually more advanced, are found here.

Ask a partner to help you check these areas. Turn on a hair dryer to separate hair and examine the scalp.

Some experts recommend that everyone, especially those with a high risk of developing melanoma, have a dermatologist perform a whole body skin exam. Dermatologists detect melanoma earlier than other health care providers, according to an article in the Archives of Dermatology.

High-risk people include those with a personal or family history of melanoma and individuals with atypical nevi (irregular moles that are also larger than normal).

Such people should protect themselves from overexposure to sunlight and have a medical examination of the entire skin surface every 3 - 12 months, with the frequency depending on risk factors. Doctors may take photographs of any moles at each visit and compare them with previous photos for any changes.

Examinations for Patients Previously Treated for Melanoma. People who have had melanoma and have been treated successfully are at risk for recurrence or a second primary melanoma. Based on recurrence rates by cancer stage, a team of researchers suggested the following guidelines for being reexamined by the doctor after treatment:

Stage I patients: Yearly exam
Stage II patients: Every 6 months for years 1 and 2 and annually thereafter
Stage III patients: Every 3 months for the first year, every 4 months for year 2, and every 6 months for years 3 to 5

All patients should be checked annually after year 5. These are guidelines only and may be changed, depending on individual patient characteristics.

Some studies also suggest that regular screening of family members of people with melanoma could prevent a number of serious cases. A 2007 report in the Archives of Dermatology has called for expanded melanoma screening programs. The study found that one-time melanoma screening for adults over age 50 seems to be as cost-effective as other recommended cancer screenings. The study authors also found that screening brothers and sisters of someone with melanoma every 2 years may also be cost-effective.

Diagnosis

An experienced doctor should first rule out benign conditions that resemble melanoma, such as a noncancerous mole called a melanocytic nevi.

In rare instances, a melanoma will be difficult to detect. For example, an uncommon form, called a myxoid melanoma, may be mistaken for a benign skin disorder known as a myxoid fibrohistiocytic lesion. Other opinions from a second pathologist, computerized image processing or advanced staining techniques, may help to confirm the diagnosis.

A study published in the Archives of Internal Medicine has found that melanoma tends to be diagnosed at a later stage in persons who are not light-skinned. The study involved nearly 50,000 patients with melanoma, and included Caucasians, Hispanics, Asian/Pacific Islanders, African-Americans, and American Indians.

Some doctors now use dermoscopy (also called dermatoscopy or epiluminescence microscopy). This technique uses a handheld scope-like device that enhances the suspected lesion. It is still not clear if such devices are any better than the naked eye of a trained professional. Of interest, however, was a 2002 study suggesting that it was very useful in identifying possible melanomas in suspicious nail abnormalities and therefore avoiding many painful biopsies in this area. A 2004 study confirmed that adding dermoscopy to conventional naked-eye examination leads to fewer biopsies than using naked-eye examination alone.

A recently developed Australian device (the Solarscan) may improve detection. It is shaped like a hair dryer and takes an image of the suspicious lesion; it then reads the image and compares it with a databank of melanoma images to help determine if it is cancerous. It can also store the image of the lesion and compare it for changes with later images taken at subsequent check ups. The device is not yet used in the United States. It still requires FDA approval. Testing is under way to confirm its accuracy.

A skin biopsy is the removal of skin tissue for examination under a microscope. The exact type of biopsy depends on how deep the lesion has penetrated the skin.

Shave biopsy uses a thin surgical blade to shave off the top layers of skin. The doctor may use this type of biopsy to diagnose basal cell cancer.
Punch biopsy uses a round, cookie-cutter-like tool. It is used to take a deeper sample skin.
Incisional and excisional biopsies remove tumors that have grown deep into the skin. An incisional biopsy cuts out part of the tumor. An excisional biopsy removes the entire tumor. These biopsies are used to diagnose melanoma.

All of the above-mentioned biopsies can be done using local anesthesia.

A lymph node biopsy helps the doctor determine whether cancer has spread to one or more lymph nodes.

A procedure called sentinel lymph node (SLN) biopsy is now recommended for cancers that are thicker than 1 millimeter and generally unnecessary for those thinner than 0.75 millimeter, unless they are ulcerated. Although some evidence suggests this procedure may improve survival, no clinical trials have proven to date that this procedure improves the outlook in persons with melanoma.

Sentinel node biopsy is a technique that helps determine if a cancer has spread. When a cancer has been detected, often the next step is to find the lymph node closest to the tumor site and retrieve it for analysis. The concept of the "sentinel" node, or the first node to drain the area of the cancer, allows a more accurate staging of the cancer, and leaves unaffected nodes behind to continue the important job of draining fluids. The procedure involves the injection of a dye (sometimes mildly radioactive) to pinpoint the lymph node which is closest to the cancer site. Sentinel node biopsy is used to stage many kinds of cancer, including melanoma.

This procedure involves the following:

A tiny amount of a tracer, either a radioactively labeled substance (radioisotope) or a blue dye, is injected into the tumor site.
These substances then flow through the lymph system into the sentinel node, the first lymph node to which any cancer would spread.
The sentinel lymph node and possibly one or two others are then removed and biopsied.

The results of the biopsy can help doctors decide whether or not to remove other lymph nodes:

If the sentinel node and others shows signs of cancer then the nearby lymph nodes are removed.
If they do not, then the remainder of the lymph nodes will likely be cancer-free, and further surgery is not needed.

If melanoma has been diagnosed, the doctor will perform other tests to see if the cancer has spread, such as a chest x-ray.

Blood tests that show high levels of lactate dehydrogenase suggest that the cancer has spread. Blood tests to assess liver function and other factors to help determine specific sites where the cancer may appear.

Advanced imaging techniques, such as computed tomography (CT) or positron emission tomography (PET), may also be used. PET is particularly accurate. One study reported that PET was able to diagnose melanoma that had spread even when other tests, including CT, did not. PET can also be very accurate for identifying recurrent melanomas.

Biomarkers are specific substances that are linked to cancer. Blood tests to detect biomarkers may be used to identify microscopic cancers if sentinel node biopsy results are uncertain. Researchers are continually investigating other biomarkers that may indicate whether the cancer had spread or how severe it is, which would help determine whether treatments should be more or less aggressive.

A number of proteins and other factors detected in blood tests are showing promise as markers for microscopic metastasis. Examples include antibodies to MART-1, Melan-A, tyrosinase, and microphthalmia transcription factor (Mitf). Combinations of some of these factors may improve detection rates.

Staging

Staging is the process used to determine the size of the tumor and where and how far it has spread. When a cancer spreads, it’s said to have metastasized. Staging helps the health care team plan for appropriate treatment.

Basal cell cancer is rarely staged, because it doesn't usually spread to other organs. However, it may be staged if it's very, very large.
Squamous cell cancer may be staged in persons who have a high risk of the cancer spreading.
Melanoma is always staged.

Health professionals have come up with various methods for staging the cancer. This report uses the TNM staging system recommended by American Joint Committee on Cancer.

T = tumor. T is followed by a number to indicate thickness.
N = node. N is followed by numbers to indicate the number of lymph nodes involved.
M = metastasis. Metastasis is the spread of cancer to far away sites.

In addition a stage will include whether the melanoma is ulcerated or not, an indication of severity. Ulceration is determined if skin layers over the tumor appear indistinct under the microscope.

In general, the thicker the lesion and the farther the cancer has spread, the higher the assigned stage. The higher the stage, the worse the long-term outlook.

The earliest melanomas, which do not penetrate beneath the surface of the skin and are known as melanoma in situ, are highly curable and are called stage 0 or not given a stage.
Melanomas less than 4 mm thick suggest Stage I or II cancers, and the next step is to attempt to determine if they have spread or are likely to spread to the lymph nodes.
Melanomas that are over 4 mm thick indicated later stages. In such cases, the lymph nodes are sometimes removed to attempt to prevent the cancer from spreading, although about 70% of these melanomas have already spread.

Specific stages are as follows:

Stage I. Cure rates are excellent with surgical removal, since they are least likely to have spread.

Stage 1A. Tumor has not spread to the nodes. It is less than 1 mm and is not ulcerated.
Stage IB. Tumor has not spread to the nodes. It is less than 1 mm, but is ulcerated, or the tumor is between 1.01 and 2 mm but is not ulcerated.

Stage II. Melanomas can be cured, but the success rate lags behind that of Stage I because a small number of cancer cells may have spread to distant sites. In addition to surgery, other forms of therapy may be recommended.

Stage IIA. Tumor has not spread to the nodes. It is between 1.01 and 2 mm and is ulcerated, or it is 2.01 to 4 mm without ulceration.
Stage IIB. Tumor has not spread to the nodes. It is between 2.01 and 4 mm and is ulcerated or greater than 4 mm without ulceration.

Stage III. Survival rate is lower than earlier stages.

Stage IIIA. Tumor has spread to 1 node and it is up to 4 mm without ulceration. Sentinel biopsy has detected microscopic evidence of tumor cells in the node (micrometastasis).
Stage IIIB. Tumor is up to 4 mm without ulceration and has spread to one node or there is evidence of micrometastasis in two nodes.
Stage IIIC. Tumor is any thickness and ulceration may or may not be present. It has spread to 2 or 3 nodes. Additional "satellite" melanomas on the skin more than 2 cm (about an inch) from the original lesion may be present; these are sometimes called "metastases in transit."

Treatment for Melanoma

Treatment for melanoma depends on various factors, including:

The site of the original lesion
The stage of the cancer
The patient's age and general health

Treatment options include:

Surgery to remove the melanoma cancer cells
Chemotherapy
Immunotherapy
Radiation therapy
Palliative therapy

Surgery is the primary treatment for all stages of melanoma. Some or all of the melanoma is often removed during the diagnosis biopsy. If cancerous tissue still remains after such a biopsy, a surgeon will cut away additional tissue from the surrounding area to remove any stray cancer cells.

Mohs micrographic surgery is a technique used to remove very thin layers of skin one at a time. Each layer is examined immediately under a microscope. When the layers are shown to be cancer-free, the surgery is complete.

The amount of tissue removed depends on the size, depth, and degree of invasion:

Stage I lesions that are less than 1 mm deep require the smallest surgical cuts, usually about 1 cm off each side and downward from the original lesion.
For melanomas that are 2 mm or thicker, a margin of 3 cm is important for reducing the risk of recurrence.
Thicker lesions require wider surgical cuts.

It used to be customary to remove a large area, regardless of the stage of cancer. This potentially disfiguring approach has been abandoned because studies have shown that excising wider margins does not improve survival. Nevertheless, sometimes skin grafts may need to be taken from other body sites to help cover the wound.

Lymph Node Removal. If there is evidence that melanoma has spread to nearby lymph nodes but has not spread beyond, removing them may reduce the chance of recurrence and help patients live longer.

Surgery for Metastatic Melanoma. In some cases, surgical removal of distant tumors may be possible and prolong survival, since often in melanoma the cancer spreads first only to a single site, such as the lung or the brain.

Cryosurgery. Cryosurgery freezes skin tissue and destroys it. This procedure is not useful for most melanomas, but it might have some value in specific situations. For example, it may be effective for smaller melanomas in the eye, a location that is difficult to treat with traditional surgery. It may be useful to eliminate residual cancer cells after standard surgery for lentigo maligna melanomas, an atypical form of melanoma that has a wide surface and is difficult to treat.

Recurrence rates are very high with lentigo maligna after conservative surgery. Although this is a very slowly progressive condition, lentigo maligna can develop into melanoma. Most of these lesions appear on the face and neck, so extensive surgery can be disfiguring. Patients should discuss with their doctor carefully staged surgery to remove all diseased tissue with as little cosmetic harm as possible.

Chemotherapy is often used to treat recurrent or metastatic melanomas. This type of therapy is not intended as a cure but can prolong life and improve its quality.

Drugs Used. The following are some of the chemotherapy drugs used to treat melanoma. They may be used alone or in combination under specific situations.

Methylating agents impair the ability of cancer cells to divide. Dacarbazine (DTIC) and temozolomide (Temodar) are the ones most often used.
Nitrosoureas, which include carmustine (BCNU) and lomustine (CCNU) are often used.
Taxanes, such as docetaxel (Taxotere) and paclitaxel (Taxol), are showing some low-level activity against melanoma.

Researchers continue to investigate other chemotherapy drugs and combinations of drugs to see which works best.

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

Common side effects include the following:

Nausea and vomiting
Diarrhea
Temporary hair loss
Weight loss
Fatigue
Anemia
Depression

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

Increased chance for infection from suppression of the immune system.
Severe drops in white blood cells (neutropenia). Certain agents, such as taxanes, pose a higher risk for this than other chemotherapeutic drugs. White blood cell count may be improved with the addition of a drug called granulocyte colony-stimulating factor (either filgrastim or lenograstim).
Liver and kidney damage.
Abnormal blood clotting (thrombocytopenia).
Allergic reaction.
Menstrual abnormalities and infertility in women. A natural hormone medication called a gonadotropin-releasing hormone analogue that puts women in a temporary pre-pubescent state during chemotherapy may preserve fertility in some women.
Rarely, secondary cancers such as leukemia.
Problems in concentration, motor function, and memory, which may be long-term.

Treating Side Effects

Drugs known as serotonin antagonists, especially ondansetron (Zofran), can relieve nausea and vomiting in nearly all patients given moderate drugs and most patients who take more powerful drugs.

Erythropoietin stimulates red blood cell production and can help reduce or prevent anemia related to chemotherapy. It is available as epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp). Aranesp persists longer in the blood than epoetin alfa and so requires fewer injections.

Benefits of Chemotherapy. About 20% of cancers shrink in response to one or more of these drugs, but the effects last only 3 - 6 months. If the tumors completely disappear, the cancer may stay in remission much longer, but in virtually all cases it returns.

Chemotherapeutic regional perfusion (also called isolated limb perfusion) is a technique used to give a person very high-dose chemotherapy. It is often used effectively for metastasized or recurrent melanoma that occurs on the arm or leg. It does not appear to be useful for preventing metastasis after a first occurrence of melanoma in one of these locations.

This technique involves the following:

The blood supply to the limb with melanoma is temporarily interrupted using a tourniquet and then rechanneled through a heart-lung machine.
Anticancer drugs are added to the blood in doses up to 10 times the standard doses.
The blood is then heated to enhance the drug's potency.
The chemo-infused blood is then sent directly to the melanoma site, minimizing the likelihood of drug toxicity.
Adverse effects occur in less than 1% of cases and include severe problems in the treated limb (rarely leading to amputation) and drug leakage into the bloodstream. This can severely reduce white blood cells and lead to serious infection.

In addition to arms and legs, perfusion techniques have been tested for the pelvis, head, neck, skin of the breast, and even the abdomen.

Immunotherapy uses drugs to boost the patient's own immune system. Immunotherapy after surgery may help prevent recurrence in certain persons with melanoma.

Cytokines. Cytokines are small proteins that play an important role in the body's immune response. Certain cytokines called interferons are used as a therapy for metastatic melanoma. These medicines are usually given along with chemotherapy or other immunotherapies, or both.

A number of cytokines and combinations are being investigated. They include:

Interferon alpha-2b (Intron) is the only FDA approved immunotherapy for late stage melanoma. The most common side effects are fatigue, depression, and flu-like symptoms, which can be severe. Starting an antidepressant, such as paroxetine (Paxil), several weeks before interferon therapy may help prevent depression.
Pegylated interferon and natural human interferon are long-acting forms are under investigation. One study showed that low-dose natural interferon after chemotherapy increased the 5-year relapse-free survival rate.
Interleukin-2 (Proleukin) is a hormone-like substance that stimulates the growth of cancer-fighting white blood cells. High-dose interleukin-2 has been shown to help patients with metastatic melanoma. The drug can cause significant side effects, including very low blood pressure, heart rhythm abnormalities, severe infections, and shortness of breath. The side effects are manageable and nearly always reversible.
Granulocyte-macrophage colony stimulating factor (GM-CSF, Leukine, Sargramostim) is an injectable cytokine under study. The drug boosts production of immune cells in the blood and bone marrow. An inhaled form of the drug is being tested for melanoma that has spread to the lungs.
T-cell therapy uses white blood cells, called tumor-infiltrating lymphocytes (TIL), that taken from the patient. The cells are modified so they better fight cancer and are then reinjected back into the patient. T-cell therapy is showing promising results, especially for patients with advanced melanoma who have failed to respond to other treatments.

A chemical called histamine is a powerful inhibitor of reactive oxygen species, ROS, which may inactivate immune cells that fight cancer. Researchers are investigating to see if it can be used along with interleukin-2 cytokine therapy. In one study, the added benefits of histamine were modest except in patients with liver metastatic; in these patients, survival improved by 129 days, which was significant.

Vaccine Immunotherapy. Vaccine immunotherapy is the use of a specific vaccine to treat an existing cancer. In this case, the vaccine targets one or more proteins that are uniquely expressed by melanoma cells.

Many therapeutic melanoma vaccines are in advanced stages of development, but none is approved for use in the United States.

There are two basic types of therapeutic vaccines:

Autologous vaccines
Allogenic vaccines

Sometimes a combination of the two are used. In this case, it's called a hybrid.

Autologous vaccines are made from the patient's own cancer cells. This produces a very specific immune response that can target the patient's cancer precisely. Oncophage (HSPPC-96) and M-Vax are autologous vaccines for melanoma that have shown promise in early clinical trials. One problem with the autologous approach is that there is no way to scientifically assess outcome or even guarantee repeated success since each vaccine is unique to the individual patient. This approach is also appropriate only for select patients.

Allogenic vaccines are made in a laboratory using cells from someone other than the patient. They may be made from proteins from tumor cells, genetic material, or even bacteria. One such vaccine is Canvaxin. Early studies showed this vaccine increased survival rates in some patients with Stage 3 melanoma. However, a later trial was halted because the vaccine did not appear to improve make such patients live any longer.

Vaccine immunotherapy requires the body to build up its own defenses. It can take months before beneficial effects occur, but when they do, tumor reduction is much more lasting than with chemotherapy. Vaccines also seem to have fewer side effects than interleukin and interferon.

Antisense Compounds. Antisense compounds can prevent defective cancer genes from being translated into proteins that cause abnormal cell proliferation.

Monoclonal Antibodies (MAb). Antibodies are natural substances produced by immune cells that home in and destroy cancer cells. Scientists are identifying specific antibodies that may attack melanoma cells and cloning them to create monoclonal antibodies. MAbs have shown promise for other cancers and are now being tested for melanoma, often in combination with vaccines and other forms of immunotherapy.

In general, radiation is used to help relieve pain and discomfort caused by cancer that has spread or recurred. Radiation is not used as often for treating melanoma as it is for other forms of cancer because melanoma cells tend to be more resistant to its effects. It may be useful in some cases, however.

In some patients with tumors less than 3 cm deep, however, radiation may help slow down metastasis when combined with a super-heating process using microwaves.
Brachytherapy, in which radioactive seeds are implanted close to the tumor, has also been used with success for melanoma of the eye.
Lentigo maligna may sometimes be treated successfully with specific radiation treatments called soft, or Grenz, x-rays.
Radiotherapy using a so-called gamma knife (very focused gamma radiation) is also effective for cancer that has metastasized to the brain, in some cases halting the growth and, in rare situations, even eliminating it.

The goal of palliative therapy is to improve the patient's quality of life and relieve symptoms. It is not a cure. Advanced melanoma that has spread to distant sites often cannot be cured, although surgical removal of metastatic tumors may provide some benefit by easing pain, increasing the general quality of life, and lengthening survival.

Patients should ask their doctor's about clinical trials, studies that examine new immunotherapies (vaccines, cytokines), gene therapies, chemotherapy combinations, or other treatments.

Tetracyclines. Chemically modified tetracyclines, a common antibiotic, have been shown to modify metalloproteinase, an enzyme in the skin that promotes skin cancers, including melanoma.

Anti-Angiogenesis Agents. An anti-angiogenesis drug is one that blocks the formation of new blood vessels. The growth of new blood vessels helps cancer cells grow and spread. The anti-angiogenesis drug thalidomide (Thalomid) is approved for treatment of melanoma but requires special prescribing precautions. This drug had gained notoriety in the 1960s because of devastating birth defects in the children of women who took it during pregnancy. Scientists are investigating drugs that are chemically similar to thalidomide but have fewer side effects.

Curcumin. The yellow spice found in turmeric and curry powders may contain cancer-fighting properties. In a preliminary laboratory study, curcumin stopped the growth of melanoma cells. It is far too early, however, to recommend curcumin for clinical use.

Treatment for Nonmelanoma Skin Cancer

A number of options are available for treating nonmelanoma skin cancer, including surgery, cryosurgery, phototherapy, radiation, and topical 5-fluorouracil.

For any skin cancer and for some keratoses that require removal, surgery is the first treatment. It is usually one of the following:

Excisional Surgery. This is the surgical removal of the cancerous lesion.

Curettage and Electrodesiccation. This procedure involves scraping away of the cancerous tissue followed by electric cauterization to stop the bleeding.

Mohs Micrographic Surgery. Mohs surgery is a meticulous procedure used for skin cancers at high risk for recurrence or becoming invasive. The technique removes very thin layers of skin one at a time. Each layer is examined immediately under a microscope. When the layers are shown to be cancer-free, the surgery is complete. A human skin substitute (Apligraf) is applied to the surgical area. It helps speed up wound healing to achieve a better cosmetic effect.

Good candidates for Mohs surgery include:

Persons with squamous cell cancer
Persons with basal cell cancer greater than 1 cm (about half an inch)
Persons with basal cell cancer on the face, ear, or neck
Young people with skin cancer

Mohs surgery saves more healthy tissue than other procedures and is highly effective. It results in a 99% cure rate for primary tumors and a 95% cure rate for recurrent ones. It can be safely performed in the doctor's office. Complications are uncommon but can include bleeding and infection.

Lasers. Laser surgery may be useful for certain basal cells and for keratoses that appear on the lips, although it is not clear whether lasers offer any advantages over other surgical treatments. Lasers do not appear to be very effective for thick or tough squamous cell cancers.

Cryosurgery removes skin cancer cells or actinic keratoses by freezing the affected tissue with liquid nitrogen. Studies have shown that cyrosurgery can be used to remove even wide areas of actinic keratoses and that it may be more successful over the long term than treatment with 5-fluorouracil, the standard drug. Cryosurgery also appears to reduce the risk for squamous cell cancer in these patients.

A head-to-head comparison of a freezing technique with Mohs micrographic surgery in patients with basal cell cancer reported similar recurrence rates with each approach. Over 85% of the patients with the freezing technique were satisfied with the appearance of the area afterwards. Five-year recurrence rates were only 2.1%.

Cryotherapy achieves good cosmetic results for many patients. However, it may cause blistering and ulceration, leading to pain and infection, as well as harmless, but undesirable, skin-color changes.

In unusual cases where the skin cancer may be in an inoperable position (such as the eyelid or the tip of the nose) or if cancer has recurred multiple times, radiation therapy may be indicated. Radiation is directed at the tumor. It may take 1 - 4 weeks with treatments performed several times a week. One technique being investigated for basal and squamous cell cancer uses radiation implants (brachytherapy) and custom-made molds to specifically target the radiation to the cancer site. Studies suggest that this treatment is very effective with few complications.

Topical phototherapy with the drug aminolevulinic acid (ALA) is a nonsurgical method that is proving to be a good choice for treating actinic keratoses and nonmelanoma skin cancers. The technique involves shining blue light onto the cancer area after that patient has taken ALA. ALA accumulates in the skin cells. When the cells are exposed to intense light, the chemical causes them to die. This approach allows precise targeting of one or more lesions, leaving healthy skin unaffected.

It does not penetrate deeper than the epidermis (the top layer of the skin), so it does not produce scarring or changes in skin color, as cryotherapy or other more invasive treatments do.

It can cause pain and irritation, including stinging, itching, and burning, but in one study only 3% of patients stopped using it for these reasons. In a 2002 study, the procedure was more painful for patients with actinic keratoses than for those with nonmelanoma skin cancers. It was also painful when large areas were affected, and men experienced more pain than women.

ALA Phototherapy for Actinic Keratoses. Phototherapy works best on flat lesions performed in two treatments, and is more effective for clearing lesions on the face than those on the scalp. Phototherapy can also treat multiple lesions at the same time instead of sequentially, as in cryotherapy. Studies suggest that it may work as well as cryotherapy and achieve better cosmetic results. (More patients report burning and itching with phototherapy, however.) Phototherapy is also equal to topical 5-fluorouracil in effectiveness and achieving a satisfactory appearance.

ALA Phototherapy for Nonmelanoma Skin Cancers. In patients with squamous cell cancer-in-situ and basal cell cancer, phototherapy has been equal to cryotherapy, with superior healing and appearance afterward. A 2003 study reported that it was more effective than topical 5-fluorouracil for patients with Bowen's disease, and there were fewer side effects.

Some studies have shown that about 10% of patients using phototherapy have a recurrence within 1 year. These recurrence rates are higher than with surgery and other standard treatments. Longer-term studies are required before ALA phototherapy can be recommended for most patients with nonmelanoma skin cancers.

Chemical peeling, or exfoliation, is useful for solar keratoses on the face, especially in people with fair, dry skin. Alpha-hydroxy acids, for example, are being investigated for keratoses. Dermabrasion, which "sands" the skin, may also be effective, although scarring is possible. A 2002 study found laser resurfacing to treat severe sun damage on the face; however, it may not prevent nonmelanoma skin cancers.

A number of medications are being used for keratoses and some may be helpful for skin cancers as well. Besides cryotherapy, 5-fluorouracil is the other most commonly used treatment for actinic keratoses. Other medications are also available.


Medication	Skin Conditions Affected	Oral or Topical		Comments
5-Fluorouracil	Actinic keratoses, Bowen's disease and small nonmelanoma skin cancers.		Topical cream (Efudex, Fluoroplex) or injected gel containing 5-FU and epinephrine (AccuSite).	5-Fluorouracil (5-FU) removes actinic keratoses and is useful for some patients with a large number of lesions. It requires twice daily application for 3 - 4 weeks. It can cause significant redness, irritation, swelling, and crusting, which takes 2 - 4 weeks to heal. Newer preparations are reducing these side effects. It is still unclear if this medication protects against recurrent keratoses or future skin cancer. Of concern is the possibility that (5-FU) will clear the top of a skin cancer and obscure the rest of the cancer that lies beneath the surface of the skin. A 10-year 2003 study of patients with Bowen's disease reported that 5-FU was safe and effective, with only 2 out of 26 cancers recurring.
Diclofenac and hyaluronan (Solaraze)	Actinic keratoses (approved). Investigated for basal cell.		Topical gel applied twice a day.	Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). When used to treat actinic keratoses, it is delivered to the skin with hyaluronan, a water-seeking molecule that helps maintain skin tension. It has modest effects and when healing occurs, it may not be evident for at least a month after treatment ends. However, it causes less irritation than 5-FU and may be useful for some people.
Imiquimod (Aldara)	FDA approved for the treatment of superficial basal cell cancer. Previously approved for treating actinic keratoses. Investigated for Bowen's disease and squamous cell cancer.		Imiquimod is a topical cream.	Imiquimod triggers the production of immune factors that help fight cell proliferation. Aldara should be used only when surgery for basal cell cancer is inappropriate. It is not approved for use on the face.
Alpha-Interferons	Basal cell cancer, squamous cell cancer.		Require injections administered three times a week.	Interferons are immune factors that are being used to treat a number of serious conditions. Alpha-interferon injections may be effective against skin cancers that are hard to treat using conventional surgical measures. Cosmetic results reported to be good or very good by 83% of patients.

Prognosis

Virtually all basal and squamous type skin cancers can be cured if treated early.

The outlook for melanoma depends on when it is diagnosed.

If melanoma is detected in its earliest form, the 5-year survival rate is 99%. Other localized forms of melanoma have very favorable outlooks.

If the cancer is found after the melanoma has spread, the 5-year survival rate drops.

If melanoma spreads to nearby areas (regional metastatic), the rate is 65%.
If melanoma has spread to distant areas of the body, the survival rate is 15%.

In general, after patients are treated for melanoma, the longer they remain free of cancer recurrence following treatment the better the chance of remaining disease-free. However, relapses are not uncommon in those whose initial melanoma was large.

Anyone who has recovered from melanoma should be especially strict about adhering to preventive guidelines and remain vigilant for suspicious lesions, since the risk for developing a new melanoma is increased even if the first one was successfully cured. Such relapses may occur years after the original diagnosis.

Resources

www.aad.org -- American Academy of Dermatology
www.cancer.org -- American Cancer Society
www.asds.net -- American Society for Dermatologic Surgery
www.mpip.org -- Melanoma Patients' Information Page
www.cancer.gov -- National Cancer Institute
www.nccn.org -- National Comprehensive Cancer Network
www.skincancer.org -- The Skin Cancer Foundation
www.epa.gov/sunwise/uvindex.html -- UV index information

References

Ambros-Rudolph CM, Hofmann-Wellenhof R, Richtig E, et al. Malignant melanoma in marathon runners. Arch Dermatol. 2006;142:1471-1474.

American Cancer Society. Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.

Chemotherapy for Inoperable Liver Metastases from Ocular Melanoma. NCI Cancer Bulletin. November 30, 2004;1(46):7.

Dale KM, Coleman CI, Henyan NN et al. Statins and Cancer Risk: A Meta-Analysis. JAMA. 2006;295:74-80.

Delavalle RP. Melanoma chemoprevention. Program presented at: Annual meeting of the American Academy of Dermatology. March 3, 2006; San Diego, CA.

Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357.

Early Detection and Surgery for Melanoma in Lymph Nodes May Increase Survival. NCI Cancer Bulletin. May 17, 2005;2(20):2.

Freeman SR, Drake AL, Heilig LF, et al. Statins, Fibrates, and Melanoma Risk: a Systematic Review and Meta-analysis. J Natl Cancer Inst. 2006;98:1538-46.

Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2005;14(3):562-566.

Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. The Lancet [early online publication]. May 3, 2007.

Lebwohl M. Cutaneous oncology. Program presented at: Annual meeting of the American Academy of Dermatology; March 7, 2006; San Diego, CA.

Michna L, Wagner GC, Lou YR, XE JG, Peng QY, Lin Y, Carlson K, Shih WJ, Conney AH, Lu XP. Inhibitory effects of voluntary running wheel exercise on UVB-induced skin carcinogenesis in SKH-1 mice. Carcinogenesis. May 2006.

Pennie M, Soon S, Risser J, et al. Melanoma outcomes for medicare patients. Arch Dermatol. 2007; 143:488-494.

Response to Immunotherapy for Melanoma Tied to Autoimmunity. NCI Cancer Bulletin. February 21, 2006;3(: 4.

Siwak DR, Shishodia S, Aggarwal BB, Kurzrock R. Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IkappaB kinase and nuclear factor kappaB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway. Cancer. 2005;104(4):879-890.

Treatment for Metastatic Ocular Melanoma. NCI Cancer Bulletin. March 7, 2006;3(10):8.

Veierod MB, Weiderpass E, Thorn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95(20):1530-1538.

Weinstock MA. Cutaneous melanoma: public health approach to early detection. Dermatologic Therapy. 2006;19(1):26-31.

Review Date:
6/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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adam.com

Infertility in women

FitSugar — Wed, 08 Oct 2008 17:35:02 -0700

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

New At-Home Fertility Test for Couples

Fertell is a new at-home fertility test kit for couples. It screens for sperm motility concentrations and follicle-stimulating hormone (FSH) levels. Fertell may be helpful as an initial test for infertility, but for a definitive diagnosis it is important to consult a doctor. Infertility can be due to many different factors.

Intracytoplasmic Sperm Injection Overused for Female Infertility

The assisted reproductive technology intracytoplasmic sperm injection (ICSI) is being increasingly used in combination with in vitro fertilization (IVF), even for couples who do not have problems with male infertility, suggests a 2007 study in the New England Journal of Medicine. Researchers found that use of ICSI has increased 5-fold in the past decade. Some doctors are now recommending ICSI for women who have failed prior IVF cycles or who have few or poor-quality eggs. Doctors caution that ICSI should be used only to improve pregnancy chances for couples with male-factor infertility.

Clomiphene Best for PCOS-Associated Infertility

The infertility drug clomiphene (Clomid) works better than the diabetes drug metformin (Glucophage) for treating infertility resulting from polycystic ovarian syndrome (PCOS), indicates a 2007 study in the New England Journal of Medicine.

Fertility Drugs and Breast Cancer

Fertility drugs such as clomiphene and gonadotropins do not increase the risk for breast cancer, indicate several studies. In fact, according to a 2006 study in the Archives of Internal Medicine, clomiphene may decrease breast cancer risk.

Iron Deficiency and Female Infertility

Iron deficiency may increase the risk for ovulatory infertility, suggests a 2006 study in Obstetrics and Gynecology. Researchers found that women who took daily iron supplements were 40% less likely to be infertile than women who did not take supplements. Some experts recommend screening for iron deficiency as part of the clinical evaluation for infertility.

Introduction

Infertility is the failure of a couple to become pregnant after one year of regular, unprotected intercourse. In both men and women the fertility process is complex.

About 10% of couples who wish to have a baby are still unable to after a year of unprotected sex. About half of these couples can achieve pregnancy within 2 years after appropriate treatment of the woman, the man, or both. Even under ideal circumstances, the probability that a woman will get pregnant during a single menstrual cycle is only about 30%. And, when conception does occur, only 50 - 60% of pregnancies advance beyond the 20th week. (The inability of a woman to produce a live birth because of abnormalities that cause miscarriages is called infecundity and is not discussed in detail in this report.)

Males and females each account for 40% of infertility. In the remaining 20%, either both partners are responsible or the cause is unclear. Although this report specifically addresses infertility in women, it is equally important for the male partner to be tested at the same time. [See In-Depth Report #67: Infertility in men.]

The Reproductive System

The Primary Organs and Structures in the Reproductive System. The primary structures in the reproductive system are:

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, 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 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.

Reproductive Hormones. The hypothalamus (an area in the brain) and the pituitary gland regulate the reproductive hormones.

Click the icon to see an image of the hypothalamus and pituitary gland.

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).

Click the icon to see an image of the pituitary gland.

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.

Ovulation. The process leading to fertility is very intricate. It depends on the healthy interaction of two sets of organs and hormone systems in both the male and female. In addition, reproduction is limited by the phases of female fertility. Nevertheless, this astonishing process results in conception within a year for about 80% of couples. Only 15% conceive within a month of their first attempts, however, and about 60% succeed after 6 months.

A woman's ability to produce children occurs after she enters puberty and begins to menstruate. The process of conception is complex:

With the start of each menstrual cycle, follicle-stimulating hormone (FSH) stimulates several follicles to mature over a 2-week period until their eggs nearly triple in size. Only one follicle becomes dominant, however, during a cycle.
FSH signals this dominant follicle to produce estrogen, which enters the bloodstream and reaches the uterus. There, estrogen stimulates the cells in the uterine lining to reproduce, therefore thickening the walls.
Estrogen levels reach their peak around the 14th day of the cycle (counting days beginning with the first day of a period). At that time, they trigger a surge of luteinizing hormone (LH).

LH serves two important roles:

First, the LH surge around the 14th cycle day stimulates ovulation. It does this by causing the dominant follicle to burst and release its egg into one of the two fallopian tubes. Once in the fallopian tube, the egg is in place for fertilization.
Next, LH causes the ruptured follicle to develop into the corpus luteum. The corpus luteum provides a source of estrogen and progesterone during pregnancy.

Click the icon to see an image of the corpus luteum.

Fertilization. The so-called "fertile window" is 6 days long and starts 5 days before ovulation and ends the day of ovulation. Fertilization occurs as follows:

The sperm can survive for up to 3 days once it enters the fallopian tube. The egg survives 12 - 24 hours unless it is fertilized by a sperm.
If the egg is fertilized, about 2 - 4 days later it moves from the fallopian tube into the uterus where it is implanted in the uterine lining and begins its 9-month incubation.
The placenta forms at the site of the implantation. The placenta is a thick blanket of blood vessels that nourishes the fertilized egg as it develops.

Click the icon to see an image of the placenta.

The corpus luteum (the yellow tissue formed from the ruptured follicle) continues to produce estrogen and progesterone during pregnancy.

If the egg is not fertilized, the corpus luteum degenerates into a form called the corpus albicans, and estrogen and progesterone levels drop. Finally, the endometrial lining sloughs off and is shed during menstruation.


Menstrual Phases	Typical No. of Days	Hormonal Actions
Follicular (Proliferative) Phase	Cycle Days 1 - 6: Beginning of menstruation to end of blood flow.	Estrogen and progesterone start out at their lowest levels. FSH levels rise to stimulate maturity of follicles. Ovaries start producing estrogen and levels rise, while progesterone remains low.
	Cycle Days 7 - 13: The endometrium (the inner lining of the uterus) thickens to prepare for the egg implantation.
Ovulation	Cycle Day 14:	Surge in LH. Largest follicle bursts and releases egg into fallopian tube.
Luteal (Secretory) Phase, also known as the Premenstrual Phase	Cycle Days 15 - 28:	Ruptured follicle develops into corpus luteum, which produces progesterone. Progesterone and estrogen stimulate blanket of blood vessels to prepare for egg implantation.
	If fertilization occurs:	Fertilized egg attaches to blanket of blood vessels that supplies nutrients for the developing placenta. Corpus luteum continues to produce estrogen and progesterone.
	If fertilization does not occur:	Corpus luteum deteriorates. Estrogen and progesterone levels drop. The blood vessel lining sloughs off and menstruation begins.

Onset of Menstruation (Menarche). Previous evidence had set the onset of menstruation, called the menarche, at an average age of 12 or 13. Recent studies, however, set the time of onset earlier by about 1 year in Caucasian girls and 2 years in African-American girls. Currently, the youngest possible age for normal puberty is 7 years old for Caucasians and 6 years old for African-Americans, down from a previous low of 8 years for both.

Evidence is pointing to the increasing incidence of childhood obesity as a major cause of the trend in earlier menarche onset. (Obesity is also highly associated with hormonal disorders in girls entering puberty at young ages.) Environmental estrogens found in chemicals and pesticides are also suspects.

Length of Monthly Cycle. The menstrual cycle can be very irregular for the first 1 - 2 years, usually being longer than the average of 28 days. The length then generally stabilizes to an average of 28 days, although the cycle length may range from 20 - 45 days and still be considered normal. A variation of 10 days or more -- either more or fewer days -- may have an impact on fertility, however. When a woman reaches her 40s the cycle lengthens, reaching an average of 31 days by age 49. Several factors can affect cycle length at any age.


Risk Factors for Shorter Cycles	Risk Factors for Longer Cycles
Regular alcohol use	Being under 21 and over 44
Stressful jobs	Being very thin (also at risk for short bleeding periods)
	Competitive athletics (also at risk for short bleeding periods)

Length of Periods. Periods average 6.6 days in young girls. By the age of 21, menstrual bleeding averages 6 days until women approach menopause. However, about 5% of healthy women menstruate less than 4 days, and 5% menstruate more than 8 days.

Normal Absence of Menstruation. Normal absence of periods can occur in any woman under the following circumstances:

Menstruation stops during the duration of pregnancy. Some women continue to have irregular bleeding during the first trimester. This bleeding may indicate a threatened miscarriage and requires immediate attention by the doctor.
When women breastfeed they are unlikely to ovulate. After that time, menstruation usually resumes, and they are fertile again.
Perimenopause starts when the intervals between periods begin to lengthen, and it ends with menopause itself (the complete cessation of menstruation). Menopause usually occurs at about age 51, although smokers often go through menopause earlier.

Risk Factors

In the U.S., an estimated 10.2% of women ages 15 - 44, or about 6.1 million women, have impaired fertility, and the incidence is increasing. About 25% of women experience some period of infertility during their reproductive years.

As a woman ages, her chances for fertility decline. Infertility in older women appears to be mostly due to a higher risk for chromosomal abnormalities that occur in her eggs as they age. Older women are also more likely to have health problems that may interfere with fertility. If fertilization occurs, older, healthy women can usually successfully bear a fetus to term, although they have a higher risk for miscarriage. Using population studies, experts have come up with estimated odds for pregnancy at different ages, given no fertility intervention. One analysis of pregnancy rates based on conception on the day of ovulation suggested that women ages 19 - 26 have twice the pregnancy rates as those ages 35 - 39.


Age	Fertility %
Up until age 34	90%
By age 40	Declining to 67%
By age 45	Declining to 15%

Although most of a woman's estrogen is manufactured in her ovaries, 30% is produced in fat cells by a process that transforms circulating adrenal male hormones into estrogen. Because a normal hormonal balance is essential for the process of conception, it is not surprising that extreme weight levels, either high or low, can contribute to infertility.

Being Overweight. Being overweight or obese (fat levels that are 10 - 15% above normal) can contribute to infertility in various ways. Obesity is highly associated with polycystic ovarian syndrome (PCOS), which is the cause of infertility in some cases. In one study, overweight women without PCOS were classified in one of five grades, depending on the severity of the obesity. The risk for irregular or absent periods increased two-fold by each increase in grade. In this group, amenorrhea (absent periods) was also highly associated with type 2 diabetes and blood sugar abnormalities.

Being Underweight. Body fat levels 10 - 15% below normal can completely shut down the reproductive process. Women at risk include:

Women with eating disorders, such as anorexia or bulimia.
Women on very low-calorie or restrictive diets are at risk, especially if their periods are irregular.
Strict vegetarians might have difficulties if they lack important nutrients, such as vitamin B12, zinc, iron, and folic acid.
Marathon runners, dancers, and others who exercise very intensely. (Lower body fat contributes to menstrual irregularities in competitive athletes, but other mechanisms are also involved.)

Exposure to environmental hazards (herbicides, pesticides, industrial solvents) may affect fertility. Estrogen-like hormone-disrupting chemicals are of particular concern for infertility in men and for effects on offspring of women.

Phthalates, chemicals used to soften plastics, are under particular scrutiny for their ability to disrupt hormones. Specific phthalates of special concern include dibutyl phthalate (DBP) and others found in many products, including cosmetics and clay products sold to children (Fimo, Sculpey). Animals exposed to phthalates have significantly impaired sperm count and abnormalities in reproductive structures, such as the testes. In addition, there is some concern that exposure in pregnant women may affect the offspring.

Neurotransmitters (chemical messengers) act in the hypothalamus gland, which controls both reproductive and stress hormones. Severely elevated levels of stress hormone can, in fact, shut down menstruation. Whether stress has any significant effect on fertility or fertility treatments is unclear. One 2005 study found that psychological stress does not affect the success or failure of in vitro fertilization.

Click the icon to see an image of the hypothalamus.

Causes

Causes of infertility can be found in about 90% of infertility cases but, despite extensive tests, about 10% of couples will never know why they cannot conceive. Between 10 - 30% of cases of infertility have more than one cause. Male or female infertility each account for about 30 - 40% of cases. In men, sperm defects (their quality and quantity) are usually responsible. Female infertility is more complex.

Pelvic inflammatory disease (PID) is the major cause of female infertility worldwide. PID comprises a variety of infections caused by different bacteria that affect the reproductive organs, appendix, and parts of the intestine that lie in the pelvic area. The sites of infection most often implicated in infertility are in the fallopian tubes, a specific condition referred to as salpingitis.

Causes of PID. PID may result from many different conditions that cause infections. Among them are:

Sexually transmitted diseases (cause of most PIDs). Chlamydia trachomatis is an infectious organism that causes 75% of infertility in the fallopian tubes. Gonorrhea is responsible for most of the remaining cases.
Pelvic tuberculosis (a growing global problem as tuberculosis cases increase)
Nonsterile abortions
Ruptured appendix
Herpes virus (suggested for some cases, but not confirmed as a cause).

Symptoms of PID. The infection may be subclinical (occurring without any symptoms), or there may be fever, chills, or pelvic pain indicating inflammation of the entire pelvic area.

Effects of PID. Severe or frequent attacks of PID can eventually cause scarring, abscess formation, and tubal damage that result in infertility. About 20% of women who develop symptomatic PID become infertile. PID also significantly increases the risk of ectopic pregnancy (fertilization in the fallopian tubes). The severity of the infection, not the number of the infections, appears to pose the greater risk for infertility.

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. Endometriosis rarely causes an absolute inability to conceive, but, nevertheless, it can contribute to it both directly and indirectly.

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.

Direct Effect of Endometrial Cysts. Endometrial cysts may directly cause infertility in several 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 may also cause the infertility associated with endometriosis. Even in early stage endometriosis, investigators have observed increased immune system activity.

Other Conditions Linking Endometriosis and Infertility. Researchers have sometimes 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.

Polycystic ovarian syndrome (PCOS) is a condition in which the ovaries produce high amounts of androgens (male hormones), particularly testosterone. PCOS occurs in about 6% of women, and amenorrhea or oligomenorrhea (infrequent menses) is quite common. According to one study, nearly 30% of obese women with PCOS had amenorrhea. (The rate was lower -- 4.7% -- in women with normal weight.)

Click the icon to see an image of polycystic ovarian syndrome.

In PCOS, increased androgen production produces high luteinizing hormone (LH) levels and low follicle-stimulating hormone (FSH) levels, so that follicles are prevented from producing a mature egg. Without egg production, the follicles swell with fluid and form into cysts. Every time an egg is trapped within the follicle, another cyst forms, so the ovary swells, sometimes reaching the size of a grapefruit. Without ovulation, progesterone is no longer produced, whereas estrogen levels remain normal.

The elevated levels of androgens (hyperandrogenism) can cause obesity, facial hair, and acne, although not all women with PCOS have such symptoms. Other male characteristics, such as deepening voice and clitoral enlargement, are rare.

PCOS also poses a high risk for insulin resistance, particularly in women who are also obese. Insulin resistance is associated with diabetes type 2, in which insulin levels are normal or high but the body cannot use this hormone efficiently. About half of PCOS patients, in fact, also have diabetes.

Premature ovarian failure is the early depletion of follicles before age 40, which, in most cases, leads to premature menopause. It affects about 1% of women and is typically preceded by irregular periods, which might continue for years. In this condition, follicle-stimulating hormone (FSH) levels are elevated, as they are during perimenopause. Premature ovarian failure is a significant cause of infertility, and women who have this condition have only a 5 - 10% chance to conceive without fertility treatments.

Causes of Premature Ovarian Failure. There are numerous causes of premature ovarian failure. Often the cause of this disorder or other causes of premature ovarian failure is unknown. In some cases, premature ovarian failure may represent an acceleration of the aging process.

The following conditions may produce premature ovarian failure:

Adrenal, pituitary, or thyroid gland deficiencies.
Genetic factors related to the X chromosome. A woman needs two functioning X chromosomes for normal reproduction. When one is abnormal, ovarian function fails. The most severe example is Turner syndrome, a genetic condition, in which one of the two X-chromosomes is missing or malfunctioning. Milder cases of ovarian failure can occur in fragile X syndrome and other rare inherited conditions that cause partial X-chromosome abnormalities.
Cancer treatments (radiation, chemotherapy, or both). Women who are undergoing cancer treatments and who want to become pregnant should see a reproductive specialist to discuss their options. According to the American Society of Clinical Oncology's 2006 guidelines, the fertility preservation method with the best chance of success is embryo cryopreservation. This procedure involves harvesting a woman's eggs (oocytes), followed by in vitro fertilization and freezing of embryos for later use. Other treatments under investigation include egg preservation, collecting and freezing unfertilized eggs, removing and freezing a part of the ovary for later reimplantation, and using hormone therapy to protect the ovaries during chemotherapy. Women may be able to access these investigational approaches through enrolling in clinical trials.
Autoimmunity. Autoimmune diseases -- including type 1 diabetes, systemic lupus erythematosus, autoimmune hypothyroidism, and autoimmune Addison's disease -- are associated with a higher risk for early menopause. Autoimmunity, however, may also play a role in some cases of premature ovarian failure without the presence of specific autoimmune diseases. In such cases, antibodies specifically attack the cells that secrete reproductive hormones thus causing ovarian failure.
Other causes of premature ovarian failure include sarcoidosis, mumps, some sexually transmitted diseases, and tuberculosis. Women with epilepsy are at higher risk for premature ovarian failure.

Idiopathic hypogonadotropic hypogonadism is a rare condition in which follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are underproduced, preventing the development of functional ovaries. There are no other abnormalities in the hypothalamus-pituitary axis (such as tumors or abnormal stress hormones or prolactin). In most cases, the causes of hypergonadotropic hypogonadism are unknown. Genetic factors, including Kallman syndrome, have been identified in about 20% of these cases.

Functional hypothalamic amenorrhea (FHA) is the absence of menstruation due to disturbances in the thyroid gland and hypothalamus-pituitary-adrenal (HPA) system, which regulates reproduction and other important functions. The eating disorders anorexia and bulimia are most often associated with FHA. FHA may be due to other different factors, most unknown.

Luteal phase defect is a general term referring to problems in the corpus luteum that result in inadequate production of progesterone. Because progesterone is necessary for thickening and preparing the uterine lining, the ovum fails to successfully implant in the endometrium. Between 25 - 60% of women who have recurrent miscarriages may have a luteal phase defect. A luteal phase defect, however, can also occur in fertile women, so other factors may be responsible for implantation failure.

Benign fibroid tumors in the uterus are extremely common in women in their 30s. The effect of fibroids on fertility is controversial. One analysis suggested that they may account for infertility in only 1 - 2.4% of women who are having trouble conceiving.

Large fibroids may cause infertility impairing the uterine lining, by blocking the fallopian tube, or by distorting the shape of the uterine cavity or altering the position of the cervix.

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.

Click the icon to see an image of uterine fibroids.

Prolactin is a hormone produced in the pituitary gland that stimulates breast development and milk production in association with pregnancy. High levels of prolactin (hyperprolactinemia) reduce gonadotropin hormones and inhibit ovulation. Hyperprolactinemia in women who are not pregnant or nursing can be caused by hypothyroidism or pituitary adenomas. (These are benign tumors that secrete prolactin. They can cause headache and visual problems as well as breast secretions.) Some drugs, including oral contraceptives and some antipsychotic drugs, can also elevate levels of prolactin.

Secretions from the breast not related to pregnancy or nursing (called galactorrhea) are a telltale symptom of high prolactin levels and should be investigated.

Inborn Abnormalities. Inborn genital tract abnormalities may cause infertility. Mullerian agenesis is a specific malformation in which no vagina or uterus develops. Even in these cases, some women can become mothers by undergoing in vitro fertilization and having the fertilized egg implanted in another woman who is willing and able to carry the pregnancy (a surrogate mother).

Uterine or Abdominal Scarring. Bands of scar tissue that bind together after abdominal or pelvic surgery or infection (called adhesions) can restrict the movement of ovaries and fallopian tubes and may cause infertility. Asherman syndrome, for example, is scarring in the uterus that can cause obstructions and secondary amenorrhea. It may be caused by surgery, repeated injury, or unknown factors. Laparoscopic surgery is less likely to cause adhesions than standard open surgery.

In some of these cases, surgery may be helpful. One technique, called pressure lavage under ultrasound guidance (PLUG), may prove to be useful for treating some cases of mild scarring in the uterus (intrauterine adhesions). This technique is based on transvaginal sonohysterography, which uses ultrasound along with saline infused into the uterus to enhance visualization. Continuous accumulation of saline in the procedure is used to break up the scars.

Ectopic Pregnancies. Ectopic pregnancies increase the risk for infertility, although subsequent pregnancy rates are quite variable. Ectopic pregnancies that terminate without treatment appear to pose a lower risk for future infertility. Even a ruptured tube does not appear to reduce the chance for a future pregnancy in most women. Such an event however can be dangerous and even life threatening for the woman. Laparoscopic surgery to remove a fallopian tube affected by an ectopic pregnancy may preserve fertility better than traditional abdominal surgery.

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

Medications. Among the medications that can cause temporary infertility are those used to treat chronic disorders, as well as antidepressants, hormones, painkillers, and antipsychotic drugs.

Inflammatory Bowel Disease. Inflammatory bowel disease (particularly Crohn's disease or surgery for ulcerative colitis) can affect fertility.

Click the icon to see an image of Crohn's disease.

Celiac Sprue. Celiac sprue is a disease in which the patient cannot tolerate gluten, a common food chemical. The disorder is also highly associated with infertility in men and women, possibly through multiple effects on nutrition, immune factors, and hormones. The mechanisms are not altogether clear, but infertility is usually reversible with strict dietary control.

Click the icon to see an image of celiac sprue.

Iron Intake. Nutritional iron deficiency may contribute to female infertility. According to a 2006 study, women who take iron supplements are 40% less likely to experience ovulatory infertility than women who do not take iron supplements. Some researchers suggest that screening for iron deficiency should be part of the standard work-up of infertility tests.

Epilepsy. In one study of women with epilepsy, fertility rates were 33% lower than among women in the general population, perhaps due to certain antiepileptic drugs that increase the risk for birth defects. The social effects of epilepsy may also lead to marriage at an older age, which can be associated with delayed attempts to get pregnant and thereby affect fertility.

Thyroid Problems. Thyroid problems, either too much thyroid hormone (hyperthyroidism) or too little (hypothyroidism), can interrupt cycles.

Click the icon to see an image of hyperthyroidism.

Click the icon to see an image of hypothyroidism.

Metabolic Syndrome (also Called Syndrome X). Doctors diagnose this condition when at least three of the following abnormalities are present:

Abdominal obesity
Low HDL (good) cholesterol levels
High triglyceride levels
High blood pressure
Insulin resistance

Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease. One study reported that, as with polycystic ovarian syndrome, women with metabolic syndrome have higher levels of male hormones and are therefore at risk for infertility. Another study estimated that 24% of the population now has this condition.

Other Medical Conditions. Medical conditions associated with delayed puberty and amenorrhea (absence of periods) include Cushing's disease, sickle cell disease, HIV, kidney disease, and diabetes. Genetic mutations that affect luteinizing hormone may also be responsible for some cases of light or absent menstruation. Other rare genetic disorders, such as Kallman syndrome, cause abnormalities in the hypothalamus of the brain.

Diagnosis

In any fertility work-up, both male and female partners are tested if pregnancy fails to occur after a year of regular unprotected sexual intercourse. Fertility testing should be done earlier if a woman is over 35 years old or if either partner has known risk factors for infertility. An analysis of the man's semen should be performed before the female partner undergoes any invasive testing.

The first step in any infertility work up is a complete medical history and physical examination. Sexual technique and timing, menstrual history, lifestyle issues (such as smoking and drug, alcohol, and caffeine consumption), any medications being taken, and a profile of the patient's general medical and emotional health can help the doctor decide on appropriate tests.

Before embarking on an expensive fertility work-up, the following steps are free or low-cost and can be helpful:

Monitor basal body temperature. This is accurate in determining if ovulation is actually taking place.
Test the consistency of your cervical mucus. Collect some mucus between your two fingers and stretch it apart. If you are near the time of ovulation, the mucus will stretch more than 1 inch before it breaks. As an alternative, at-home kits can test saliva as substitute for checking cervical mucus.
Take an over-the-counter urine test for detecting luteinizing hormone (LH) surges. This helps determine the day of ovulation.
Fertell is the first at-home test kit for couples that is approved by the Food and Drug Administration. Women can test their urine for levels of follicle-stimulating hormone (FSH), while men can test their semen for sperm motility (ability of sperm to move). Fertell became available online and in some pharmacies in June 2007.

Several laboratory tests may be used to detect the cause of infertility and monitor treatments:

Hormonal Levels. Blood and urine tests are taken to evaluate hormone levels. Hormonal tests for ovarian reserve (the number of follicles and quality of the eggs) are especially important for older women.

Examples of possible results include:

High follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels and low estrogen levels suggest premature ovarian failure or hypogonadotropic hypogonadism.
High LH and low FSH may suggest polycystic ovary syndrome or luteal phase defect.
High FSH and high estrogen levels on the third day of the cycle predicts poor success rates in older women trying fertility treatments.
LH surges indicate ovulation.
Blood tests for prolactin levels and thyroid function are also measured. These are hormones that may indirectly affect fertility.

Clomiphene Challenge Test. Clomiphene citrate (Clomid, Serophene), a standard fertility drug, may be used to test for ovarian reserve. With this test, the doctor measures FSH on day 3 of the cycle. The woman takes clomiphene orally on days 5 and 9 of the cycle. The doctor measures FSH on the tenth day. High levels of FSH either on day 3 or day 10 indicate a poor chance for a successful outcome.

Tissue Samples. To rule out luteal phase defect, premature ovarian failure, and absence of ovulation, the doctor may take tissue samples of the uterus 1 - 2 days before a period to determine if the corpus luteum is adequately producing progesterone. Tissue samples taken from the cervix may be cultured to rule out infection.

Tests for Autoimmune Disease. Tests for autoimmune disease, such as hypothyroidism and diabetes, should be considered in women with recent ovarian failure that is not caused by genetic abnormalities.

If an initial fertility work-up does not reveal abnormalities, as happens in about 40% of cases, more extensive tests will reveal abnormal tubal or uterine findings. The three major approaches for examining the uterus are ultrasound (particularly a variation called saline-infusion sonohysterography), hysterosalpingography, and hysteroscopy. Although combinations of these diagnostic approaches are often used to confirm diagnoses, one study indicated that with the introduction of saline-infusion sonohysterography, all are equally accurate and combinations do not increase accuracy. Furthermore, the ultrasound procedure is significantly less painful than the other two, suggesting that this should be the procedure of choice, if available.

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. It is currently the gold standard for diagnosing polycystic ovaries.

Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) gives a better image of any fibroids that might be causing bleeding, but it is expensive and not usually necessary.

Hysteroscopy. Hysteroscopy is a procedure that may be used to detect the presence of endometriosis, fibroids, polyps, pelvic scar tissue, and blockage at the ends of the fallopian tubes. Some of these conditions can be corrected during the procedure by cutting away any scar tissue that may be binding organs together or by destroying endometrial implants. (It may miss cases of uterine cancer, however, and is not a substitute for more invasive procedures, such as dilation and curettage ( D&C) or endometrial biopsy, if cancer is suspected.)

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 frequently causes cramping.

There are small risks of bleeding, infection, and reactions to anesthesia. Many patients experience temporary discomfort in the shoulders after the operation due to residual carbon dioxide that puts pressure on the diaphragm. The wound itself is minimally painful.

Hysterosalpingography. Hysterosalpingography is performed to discover possible blockage in the fallopian tubes and abnormalities in the uterus:

The doctor inserts a tube into the cervix through which a special dye is injected. (The patient may experience some cramping and discomfort.)
The dye passes into the uterus and up through the fallopian tubes.
An x-ray is taken of the dye-filled uterus and tubes.
If the dye is seen emerging from the end of the tube, no blockage is present. (In some cases, hysterosalpingography may even restore fertility by clearing away tiny tubal blockages.)
If results show blockage or abnormalities, the test may need to be repeated. In case of blockage, hysterosalpingography may reveal a number of conditions, including endometrial polyps, fibroid tumors, or structural abnormalities of the uterus and tubes.

The test has significant rates of false diagnoses, both positive and negative. There is a small risk of pelvic infection, and antibiotics may be prescribed prior to the procedure. One study suggested that flushing the tubes with an oil-based fluid (lipiodol) during this procedure may improve fertility rates in women with infertility of unknown causes.

As women age, the number of follicles (and therefore their egg supply) declines. Researchers are developing tests that may help determine how many are left. Such tests include the following:

Calculating the volume of the ovaries. In general, the smaller the ovaries, the fewer the remaining eggs.
Counting antral follicles. Antral follicles are those that develop but do not become dominant follicles. Instead, they form a fluid-filled space called an antrum. Women who have fewer than three to five antral follicles appear to have a poor chance of fertility.
Measuring inhibin B. Inhibin B is a growth factor produced in the ovaries. Low levels suggest fewer eggs.

Eventually these markers may be useful for determining which women need more aggressive treatments.

Genetic testing may be warranted in cases of male infertility or when genetic factors may be causing pregnancy failure in the woman. If genetic abnormalities are suspected in either partner, counseling is recommended.

A technique called preimplantation genetic diagnosis (PGD) is now available in some centers that can examine all the chromosomes in a human embryo. It helps identify abnormalities that increase the risk for infertility, treatment failures, or genetic defects in the offspring.

Treatment

Some doctors recommend that if a couple fails to conceive after 1 - 2 years of frequent unprotected sex, they should consult a fertility expert. Women who are 35 or older, however, may want to begin exploring their options if they do not become pregnant within 6 months to a year.

Several approaches can treat infertility, depending on the cause:

Lifestyle measures (healthy lifestyle, planning sexual activity with ovulation cycle, managing stress and emotions)
Treatments for endometriosis, fibroids, or menstrual disorders
Use of anti-estrogen drugs, such as clomiphene, to induce ovulation in women with ovarian dysfunction
Surgery (standard or laparoscopic) to unblock fallopian tubes
Use of hormone treatments (clomiphene or progestins) for luteal phase defect
Assisted reproductive technologies (ART) such as in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)

Choosing a good fertility clinic is important. Those offering assisted reproductive techniques are not always regulated by the government, and abuses have been reported, including lack of informed consent, unauthorized use of embryos, and failure to routinely screen donors for disease.

The clinic should always provide the following information:

The live-birth rate (not just pregnancy success rate) for other couples with similar infertility problems. (Multiple births, such as twins or triplets, are counted as one live birth.)
Such statistics should include high-risk women, such as those who are older or fail to produce eggs. (Some disreputable clinics give success percentages that exclude high-risk women from their total, thereby making the percentage of success much higher.)

Advanced fertility procedures and medications are extremely expensive and often not covered by insurance. Couples should be cautious about offers of rebates in the event of failure; the clinics offering them are often significantly more expensive than those that don't offer such gimmicks.


Causes of Infertility	Treatments
Endometriosis	Conservative surgery (typically laparoscopy) is the appropriate approach for restoring fertility. GnRH agonists or progestins, used to treat endometriosis itself, have no effect on fertility. Possible exceptions are GnRH agonists used after surgery. In one study, this treatment helped improve conception rates in women who subsequently underwent assisted reproductive techniques. Assisted reproductive technologies (ART). (Fertility drugs alone have no effect.) It is not clear, in any case, whether either laparoscopy for removing endometrial implants or ART has additional advantages in many of these women compared to simply trying to become pregnant through non-aggressive means.
Hyperprolactinemia	Dopamine agonists, including bromocriptine (Parlodel) or cabergoline (Dostinex). Surgery in some cases.
Luteal phase defect	Clomiphene or superovulation drugs (FSH drugs or hMG).
Hyperprolactinemia (elevated prolactin)	Bromocriptine, cabergoline to shrink tumors that result in over secretion of prolactin. Cabergoline is more effective, but bromocriptine has been used longer. Once ovulation starts, women who want to become pregnant should stop cabergoline one month before attempting conception. Surgery may be needed for women who do not respond to medications or who have large tumors.
Hypogonadotropic Hypogonadism	Fertility drugs (hMG preferable to FSH alone) with or without assisted reproductive technologies.
Pelvic Inflammatory Disease	Screening high-risk women for the presence of Chlamydia trachomatis and treating the organism before it causes symptoms could reduce the risk of PID by almost 60%. If any sexually transmitted infection is detected, both partners should receive antibiotics, even if there are no symptoms. If PID symptoms develop, particularly lower abdominal pain, fertility can be preserved if women receive antibiotics within 2 days. A delay significantly increases the risk for scarring.
Polycystic Ovarian Syndrome	Lifestyle changes (weight loss and exercise in women who are overweight.) Clomiphene is the standard first-line treatment for polycystic ovarian syndrome (PCOS)-related infertility. Although some research has indicated that the diabetes drug metformin (Glucophage) might help treat infertility in women with PCOS, a 2007 study in the New England Journal of Medicine indicated that clomiphene is much more effective.
Premature Ovarian Failure	Assisted reproductive technologies with donor eggs.
Preserving fertility after cancer treatments	Removal and freezing (called cryopreservation) of ovarian tissue containing embryos or freezing immature and unfertilized eggs to use for later reimplantation. (Freezing before cancer treatment appears to offer the best chance.) Under investigation: Ovarian transplantation procedures and gonadotropin-releasing hormone analogues, which put women in a temporary pre-pubescent state during chemotherapy and may preserve fertility.
Fallopian tubal blockage	Surgical procedures (laparoscopy or salpingostomy) to clear the tubes. (Average pregnancy rate after salpingostomy is about 30%, but they can vary widely.) Flushing the tubes with an oil-based fluid (lipiodol) during hysterosalpingography (investigative). In a 2002 study, this procedure improved pregnancy rates in women with infertility of unknown causes. Assisted reproductive technologies.
Unexplained infertility	Lifestyle measures. Fertility drugs. Assisted reproductive technologies.

Lifestyle Changes

Although there are no dietary or nutritional cures for infertility, a healthy lifestyle is important. Ovulatory problems are reversible by changing behavioral patterns. Such conditions include:

Maintain a healthy weight. Women who are either over- or underweight are at risk for fertility failure, including a lower chance for achieving success with fertility procedures. Everyone should have a diet rich in fresh fruits and vegetables and whole grains and low in saturated fats.
Stop smoking. Smoking increases the risk for infertility in both men and women, and poses a future health risk for the mother and infant. Everyone should quit.
Avoid caffeine and alcohol.
Avoid excessive exercise if it causes menstrual irregularity. However, moderate and regular exercise is essential for good health. Few women exercise to the extent that their periods are affected. For those who do, one study found that simply adding calories can restore menstruation in many cases.
Don't use electric blankets. In one study, a 74% higher incidence of spontaneous abortion was associated with using an electric blanket during the month of conception. There was no association with heated waterbeds or electromagnetic waves.
Avoid any unnecessary medications.

There is no evidence of harm to a developing fetus from low exposure to microwaves or electromagnetic waves. Women who remain anxious may derive comfort by avoiding some of these devices (such as cellular phones or electric blankets) and remaining a foot or so away from others (such as computers or microwave ovens).

Both male and female hormone levels fluctuate according to the time of day, and they vary from day to day and month to month. Some timing tips might be helpful.

Male Hormone Levels and Sexual Activity. Male hormone levels are highest in the morning. (Sexual interest also tends to be higher in the morning.) In one study of men, their sexual activity was highest in October, when conception rates were also high.

Fertility and Seasonal Changes. Different studies have reported higher sperm counts in the winter than in the summer. For women, fertility rates as measured by treatment success are highest in months when days are longest.

Monitoring Basal Body Temperature. To determine the most likely time of ovulation and therefore the time of fertility, a woman is instructed to take her body temperature, called her basal body temperature. This is the body's temperature as it rises and falls in accord with hormonal fluctuations.

Each morning before rising, the woman takes her temperature with a specialized basal body thermometer and marks the result on a graph-paper chart.
The woman also notes the days of menstruation and sexual activity.
The so-called "fertile window" is 6 days long, starts 5 days before ovulation, and ends the day of ovulation.
The chances for fertility are considered to be highest between days 10 and 17 in the menstrual cycle (with day 1 being the first day of the period, and ovulation occurring about 2 weeks later). However, cycles vary from woman to woman. Researchers suggest that women track the length of their cycles, which can run anywhere from between 19 and 60 days. A long cycle, for example, suggests a delayed ovulation date.
Immediately after ovulation the body temperature increases sharply in about 80% of cases. (Some women can be ovulating normally yet not show this temperature pattern.)

By studying the temperature patterns after a few months, couples can begin to anticipate ovulation and plan their sexual activity accordingly. Couples must try to avoid becoming fixated on the chart, however, in scheduling their sexual activity. Spontaneity can be lost, and the stress on the relationship can be quite severe.

Hormone Monitoring Systems. A device called a saliva fertility monitor (Fertility Tracker) uses a microscope to view slides containing saliva and monitors estrogen levels. Home test kits that monitor reproductive hormone levels in the urine (ClearBlue) are also available. They are less costly than the saliva test but are messier. Monitoring hormones levels helps to determine when a woman is ovulating.

Frequency of Intercourse. The question of how often a couple should have intercourse is in debate. Some doctors say that having sex more than 2 days a week adds no benefits. Moreover, frequent sexual activity lowers sperm count per ejaculation. Other studies have indicated, however, that having intercourse every day, or even several times a day, before and during ovulation, improves pregnancy rates. Although sperm count per ejaculation is low, a constantly replenished semen supply is more likely to result in a fertilized egg.

The fertility process is a roller coaster of emotions that are present throughout and in both failure and success. There are almost no sure ways to predict which couples will eventually conceive. Some couples with multiple problems will overcome great odds, while other, seemingly fertile, couples fail to conceive. Many of the new treatments are remarkable, but a live birth is never guaranteed. The emotional burden on the couple is considerable, and some planning is helpful.

Planning for Emotional Turmoil.

Decide in advance how many and what kind of procedures will be emotionally and financially acceptable and attempt to determine a final limit. Fertility treatments are expensive. A successful pregnancy often depends on repeated attempts.
Determine alternatives (adoption, donor sperm or egg, or having no children) as early as possible in the fertility process. This can reduce anxiety during treatments and feelings of hopelessness in case conception does not occur.

Managing Emotional Stress During the Process. Managing negative emotions can be viewed as important as medical treatment. The following are some ways women reduce stress while trying to conceive:

Talking to one's spouse, family, and friends is very beneficial. The best support comes from the spouse. Studies suggest that a positive attitude on the husband's part is essential for enabling his wife to deal effectively with either the success or failure of fertility treatments. Men and women may cope differently with the stress, and each should understand the other's special needs. Women tend to want greater personal space and also to want to share the burden with their husbands. Men tend to cope by seeking to improve themselves (for example being strong, or being the "best").
Almost half of women seeking fertility treatments practice good-luck rituals, including praying and wearing charms or special jewelry. No evidence exists that these practices increase fertility, but they may help reduce anxiety and enhance a sense of control.
Cognitive-behavioral therapy, which uses methods that include relaxation training and stress-management, have been associated with higher pregnancy rates. (In one study, 42% became pregnant without medical intervention.)
Attending support groups or counseling services before and after treatment helps many women endure the process and ease the grief should treatment fail. One study indicated that pregnancy rates were twice as high in women who coped with their depression by reaching out to others rather than repressing guilt or rage. (These results held only in cases in which women, not their mates, were infertile.)
Acupuncture may help some women. Some evidence suggests that this alternative treatment has beneficial effects on chemicals in the brain involved with stress and reproduction. Acupuncture is safe, but studies have been mixed on whether it can help improve pregnancy rates. One study indicated that women who received acupuncture achieved significantly higher success rates during fertility treatments (42.5%) than those who did not receive it (26.3%). Several 2006 studies suggested that acupuncture may improve pregnancy success for women who undergo in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) procedures. One of these studies found that acupuncture had a positive effect if it was given during the luteal phase (post-ovulatory period of menstrual cycle.) Another study suggested that acupuncture should be given on the day of embryo transfer.

Managing the Emotional Effects of the Outcome. After enduring the process, the couple must face the outcome, and even a positive outcome has emotional repercussions.

Effects of Failure. The emotional stress of failure can be devastating even on the most loving and affectionate relationships and even in those who have prepared for the possibility of failure. Neither the male nor female partner should hesitate to seek professional help if the emotional burdens are too heavy.
Effects of Genetic Testing. As advanced technologies allow testing and greater genetic information at the earliest stage, potential parents will have to learn to deal with the uncertainties of possible chromosomal abnormalities, which may or may not be significant.
Effects of Successful Treatments. Some studies have indicated that even if successful, some women experience higher stress and fear of failure during pregnancy. According to one study, however, women who achieved pregnancy using fertility treatments felt increasingly better and had higher self esteem and less anxiety as the pregnancy progressed than women whose pregnancies were not due to medical intervention.
Effects of Multiple Births. A successful pregnancy that results in a multiple birth introduces new complexities and emotional problems. One study reported a very high rate of depression in women with triplets, particularly if they had little help from others, and especially if their husbands weren't involved.
Effects on Parenting. Once the fertility treatment-assisted child arrives, parents (both men and women) are more likely to be anxious and to have less confidence than those who conceive naturally.

Medications

Fertility drugs are often used alone as initial treatment to induce ovulation. If they fail as sole therapy, they may be used with assisted reproductive procedures or artificial insemination to produce multiple eggs, a process called superovulation.

Clomiphene citrate (Clomid, Serophene) is usually the first fertility drug of choice for women with infrequent periods and long cycles. Unlike more potent drugs used in superovulation, clomiphene is gentler and works by blocking estrogen, which tricks the pituitary into producing

follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This boosts follicle growth and the release of the egg. Clomiphene can be taken orally, is relatively inexpensive, and the risk for multiple births (about 5%, mostly twins) is lower than with other drugs.

Women with the best chances for success with this drug are those who have the following conditions:

Polycystic ovarian syndrome (PCOS)
Ability to menstruate but irregular menstrual cycle

Women with poorer chances of success with this drug have the following conditions:

Infertility but with normal ovulation
Low estrogen levels
Premature ovarian failure (early menopause)

One or two tablets are taken each day for 5 days, usually starting 2 - 5 days after the period starts. If successful, ovulation occurs about a week after the last pill has been taken. If ovulation does not occur, then a higher dose may be given for the next cycle. If this resgimen is not successful, treatment may be prolonged or additional drugs may be added. Doctors usually do not recommend more than 6 cycles.

Clomiphene often reduces the amount and quality of cervical mucus and may cause thinning of the uterine lining. In such cases, other hormonal drugs may be given to restore thickness. Other side effects of clomiphene include ovarian cysts, hot flashes, nausea, headaches, weight gain, and fatigue. There is a 5% chance of having twins with this drug, and a slightly increased risk for miscarriage.

If clomiphene does not work or is not an appropriate choice, gonadotropin drugs are a second option. Gonadotropins include several different types of drugs that contain either a combination of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), or only FSH. Clomiphene works indirectly by stimulating the pituitary gland to secrete FSH, which prompts follicle production. In contrast, the gonadtropin hormones directly stimulate the ovaries to produce multiple follicles.

Gonadotropins are given in a shot. (Your doctor may show you how to self-administer the injection.) Gonadotropins include:

Human Menopausal Gonadtropins (hMG), also called menotropins
Human Chorionic Gonadotropins (hCG)
Urofollitropin and Follitropin, natural and synthetic forms of FSH
Gonadotropin-releasing hormone (GnRH) analogs, which include GnRH agonists and GnRH antagonists

Gonadotropin drugs are either natural compounds extracted from urine or synthetic compounds that are genetically engineered in a laboratory using recombinant DNA.

Human Menopausal Gonadotropin (hMG). HMG drugs, also called menotropins, contain a mixture of both FSH and LH. These drugs (Pergonal, Repronex, Metrodin, Humegon) are all derived from the urine of postmenopausal women. HMG is administered as a series of injections 2 - 3 days after the period starts. Injections are usually given for 7 - 12 days, but the time may be extended if ovulation does not occur. In such cases, a shot of human chorionic gonadotropin (hCG) may trigger ovulation.

Human Chorionic Gonadotropin (hCG). Human chorionic gonadotropin (hCG) is similar to LH. It mimics the LH surge, which stimulates the follicle to release the egg. Natural hCG drugs, derived from the urine of pregnant women, include Pregnyl, Profasi, Novarel, APL, Chorex, and Follutein. Ovidrel is the only available genetically modified hCG drug. Ovidrel has fewer side effects at the injection site, and its quality can be better controlled than the natural drugs. It is generally used after hMG or FSH to stimulate the final maturation stages of the follicles. Ovulation, if it occurs, does so about 36 - 72 hours after administration.

Urofollitropin and Follitropin. Urofollitropin (Bravelle, Fertinex) is a purified form of FSH, derived from the urine of postmenopausal women. Follitropin drugs (Gonal-F, Follistim) are synthetic versions of FSH. These FSH drugs are sometimes given in combination with an hCG drug.

GnRH Analogs (Agonists or Antagonists). Gonadotropin-releasing hormone (GnRH) is a hormone produced in the hypothalamus part of the brain. GnRH stimulates the pituitary gland to produce LH and FSH. GnRH analogs are synthetic drugs that are classified as either agonists or antagonists. They are similar to natural GnRH but have very different actions. While natural GnRH stimulates LH and FSH, these drugs actually prevent the LH and FSH surge that occurs right before ovulation. This action helps prevent the premature release of the eggs before they can be harvested for assisted reproductive technologies.

GnRH agonists include leuprolide (Lupron), nafarelin (Synarel), and goserelin (Zoladex).
GnRH antagonists include ganirelix (Antagon) and cetrorelix (Cetrotide). GnRH antagonists suppress FSH and LH more than GnRH agonists, and they may require fewer injections.

Women with endometriosis often have an especially hard time getting pregnant. A 2006 review suggested that GnRH agonists may help women with endometriosis quadruple their chances of becoming pregnant when the drug is used 3 - 6 months prior to in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI). [See In-Depth Report #74: Endometriosis.]

Multiple Births. Overproduction of follicles can lead to ovarian enlargement. This event increases the risk for multiple births. There is a 25% chance of multiple births (about 17% for twins and 8% for triplets and or more).

Ovarian Hyperstimulation Syndrome. The most serious complication with superovulation is ovarian hyperstimulation syndrome (OHS), which is associated with the enlarged ovary (although the precise cause is unknown). This can result in dangerous fluid and electrolyte imbalances and endanger the liver and kidney. OHS is also associated with a higher risk for blood clots. In rare cases, it can be fatal. Symptoms include abdominal bloating, nausea, vomiting, and shortness of breath.

Bleeding and Rupture of Ovarian Cysts. Overproduction of follicles, if unchecked, may result in bleeding and rupture of ovarian cysts.

Cancer Concerns. There has been concern that clomiphene and gonadotropins may increase the risks for ovarian and breast cancer. Most evidence to date does not indicate that ovulation-stimulating drugs increase the risks for these types of cancers. However, more research needs to be done. Some studies suggest that clomiphene, which is chemically related to the breast cancer drug tamoxifen, may actually decrease the risk for breast cancer.

Progesterone. Progesterone is a hormone that is produced by the body during the menstrual cycle. Progesterone drugs are sometimes given to women who have experienced frequent miscarriages (a possible sign of progesterone deficiency). A progesterone drug may also be given after egg retrieval during an in vitro fertilization (IVF) cycle to help thicken the uterine lining (endometrium) so it can better hold the egg following implantation.

Aromatase Inhibitors. Aromatase inhibitors block aromatase, an enzyme that is a major source of estrogen in many major body tissues. These drugs include anastrozole (Arimidex) and letrozole (Femara). These drugs are used for treating breast cancer and are being investigated for stimulating ovulation in infertile women. Although letrozole is not approved for treatment of infertility, it has become widely used for this purpose in recent years. Some doctors were concerned that letrozole could increase the risk of birth defects. However, a major 2006 study indicated that letrozole does not increase risk to the fetus. The study compared the rate of birth defects among babies whose mothers conceived with letrozole and those who used clomiphene (the standard first-line fertility drug). Researchers found no differences in birth outcomes between the two groups.

Tamoxifen. Tamoxifen (Nolvadex) is a drug known as a selective estrogen-receptor modulator (SERM). It is used to prevent breast cancer in high-risk women. Studies suggest that it may equal clomiphene in its ability to induce ovulation. It may be especially useful when used along with IVF for preserving fertility in breast cancer patients. This drug is less expensive than clomiphene, but it poses some health hazards, including a risk for blood clots and uterine cancer.

Glucocorticoids. Glucocorticoids are steroid hormones that are sometimes used in combination with IVF and intracytoplasmic sperm injection (ICSI). It is thought that anti-inflammatory effect of these drugs can help make the lining of the uterus more responsive to egg implantation. However, a 2007 review indicated that glucocorticoids do not help improve pregnancy success rates and should not be used routinely with assisted reproductive technologies.

Regimens to induce ovulation vary widely according to individual need. A typical procedure, involving superovulation and in vitro fertilization (IVF) may be as follows:

Doctors make sure that the patient is not pregnant or in the luteal phase of her menstrual cycle (the premenstrual period).
Injections of either human menopausal gonadtropins, which contains luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or pure FSH are administered daily 2 - 4 days after day 1 of the next cycle. Either drug may be used.
After 4 - 8 days of treatment, estrogen levels are monitored. Increasing levels on the fourth day of treatment may be strong indicators of success. If estrogen levels indicate that ovaries are responding, ultrasound is then performed to detect possible overproduction of follicles. Such evaluation should then be conducted every 1 - 2 days and dosages adjusted accordingly.
Gonadotropin-releasing hormone analogs are used to prevent a premature release of LH hormone (and therefore ovulation). GnRH agonists are typically administered either early on or a few days after ovulation in the cycle previous to the one planned for IVF. This approach is referred to as the long protocol, and it serves to suppress the pituitary gland and allows time for the eggs to mature before harvesting. Other protocols using GnRH antagonists are under investigation, but to date the long protocol has the best pregnancy rates.
When at least three follicles have reached a diameter of 18 mm, human chorionic gonadotropins (hCG) is typically administered to release the egg. It is not given if there are signs of overproduction of follicles, which suggests a risk for ovarian hyperstimulation syndrome (OHS), a dangerous complication. (One study reported that giving high doses of progesterone to high-risk women the day of hCG administration may prevent OHS.)
Egg retrieval may be performed about 36 hours following hCG administration, with the transfer of the embryo (the fertilized egg) back into the woman 2 - 3 days after retrieval.
Embryos are transferred to the uterus through a small tube. This process does not require an anesthetic, although the procedure can cause cramping.

Natural (Unstimulated) In Vitro Fertilization Cycles. An alternative to superovulation for some couples is natural in vitro fertilization (IVF) cycles. It allows multiple, consecutive cycles of treatment. Natural IVF is far less expensive than standard hyperstimulation methods and avoids their risks, including multiple births and ovarian hyperstimulation syndrome (OHS).

The process involves ultrasound and hormonal monitoring starting 5 days before the estimated ovulation day.
No superovulation drugs are used, such as follicle-stimulating hormone (FSH) and human menopausal gonadtropins (hMG). The doctor, however, may administer an injection of human chorionic gonadotropins (hCG) to stimulate the luteinizing hormone (LH) surge.
The egg retrieval timing is based on detecting LH surge.
A single egg is retrieved. The procedure that follows is similar to other IVF cycles.

The basic disadvantage to this approach is that the eggs may be released before there is a chance for them to be harvested. Women report far lower stress levels with this approach, however, even though it requires more treatment cycles. In one study, the live-birth rate was 32%. Not all women are appropriate candidates, however. Women should have regular menstrual cycles and infertility of unknown cause or associated with problems in the fallopian tubes. Pregnancy rates are still very low in older women.

Clomiphene. Another gentler alternative to superovulation is the use of clomiphene before IVF, which works slightly better than unstimulated IVF.

Assisted Reproductive Technologies

Assisted reproductive technologies (ART) are medical techniques that help couples conceive. These procedures involve either:

A couple’s own eggs or sperm
Donor eggs, sperm, or embryos

Fertilization may occur either in the laboratory or in the uterus. In the U.S., the number of live birth deliveries from ART increased by 128% between 1996 and 2002. More than 45,000 babies are now born in the U.S. each year using assisted reproductive technologies.

ART includes fertility drug treatments, artificial insemination (AI), in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and other procedures.

Artificial insemination (AI) is the least complex of the assisted reproductive technologies and is often tried first in uncomplicated cases of infertility. AI either involves placing the sperm directly in the cervix (called intracervical insemination) or into the uterus (called intrauterine insemination, or IUI). IUI is the standard AI procedure.

It is useful under the following circumstances:

When the woman's cervical mucus is unreceptive
When donor sperm are required
If the man's sperm count is very low
When unexplained infertility exists in both partners

Those in whom AI fails, couples with specific fertility defects, or older women may be candidates for more advanced reproductive technologies.

Pregnancy Rates. A review of 45 studies reported that in unexplained infertility cases, the per-cycle pregnancy rates were 4% for intrauterine insemination (IUI) alone and 8 - 17% per cycle for IUI combined with superovulation, a procedure that uses fertility drugs to bolster egg recovery.

Researchers in one study suggested IUI as a reasonable first option for many women under age 43. It is less expensive and poses less risk for multiple births than the more advanced assisted reproductive technologies (ART), such as in vitro fertilization. Although IVF procedures are more effective per cycle, couples tend to be able to afford more IUI cycles, so the pregnancy rates over time are very similar.

The Artificial Insemination Procedure. The AI procedure is as follows:

A woman usually (but not always) takes fertility drugs in advance.
The man must produce sperm at the time the woman is ovulating.
The sperm are subjected to certain so-called "washing" procedures. They are then inserted into the uterine cavity through a long, thin catheter.

The administration of fertility drugs and sperm retrieval is timed so that the process can coincide with ovulation.

About 71% of assisted reproductive technologies (ART) procedures now use in vitro fertilization (IVF) with the woman's own eggs. An in vitro procedure is one that is performed in the laboratory. Advances in these procedures have dramatically increased the rate of live births.

The best candidates for IVF are women with damaged fallopian tubes, and some experts believe it is a better option than attempting surgical repair. IVF is also used when infertility is unexplained or when the male partner has the infertility problem. A typical IVF procedure is as follows:

The doctor first induces superovulation using fertility drugs so that several eggs can be harvested from the ovary before they have been released from the follicles. Higher doses of fertility drugs for subsequent cycles do not appear to add any advantage in women who have a poor response the first time.
To harvest eggs, the doctor generally inserts a probe into the vagina and is guided by ultrasound. A needle is then used to drain the liquid from the follicles, and several eggs are retrieved.
The eggs and sperm are combined in a Petri dish. Between 48 - 72 hours later the eggs are usually fertilized.
The resulting embryos (the first stage toward the development of the fetus) are reimplanted into the woman's uterus.
It takes about 2 weeks to determine if the process is successful.

IVF success rates for the first three cycles of treatment are about equal. They then decline modestly for the fourth cycle and drop significantly after the fifth cycle.

Gamete/Zygote Intrafallopian Transfer. Gamete intrafallopian transfer (GIFT) and zygote intrafallopian transfer (ZIFT) are adaptations of IVF. GIFT and ZIFT are used in unexplained female infertility and in mild male infertility. The success rates are similar to those of IVF, but a woman must have at least one functioning fallopian tube.

GIFT: The procedure is as follows:

The eggs are harvested as in IVF.
They are mixed with the sperm but not actively fertilized.
They are immediately injected back into the woman. Laparoscopy, a technique that employs a miniature viewing device, is used with this procedure to guide the placement of the embryos or egg through a long, thin catheter into the fallopian tubes.
The sperm and egg are placed exactly where they would be in natural fertilization.

ZIFT: The procedure is as follows.

The eggs are harvested as in IVF.
They are then mixed with the sperm and, in this case, are fertilized in the laboratory.
They are then implanted in the fallopian tubes as in GIFT. (The advantage of this procedure over GIFT is that the doctor and couple are assured that fertilization has taken place, and the eggs can be examined for defects before implantation.)

In 2002, more than 45,000 American babies were born using in vitro fertilization (IVF). Success rates have increased in all age groups (although they are still considerably lower in older than in younger women). Chances for assisted reproductive technologies (ART) success are also greater among women who do not have uterine abnormalities and have had previous successful pregnancies.

Success rates are also higher or lower depending on whether the woman uses her own eggs or whether they are donated and also whether the eggs are fresh or frozen. The highest live birth rates are with donated fresh eggs (an average of 50% per transfer). The lowest rates are when a woman uses her own frozen eggs (an average of 29% per transfer). However, using frozen eggs is less expensive than fresh eggs, so a couple may be able to afford more cycles with frozen eggs.

Use of Donor Eggs. Older women are more likely to use donor eggs. In a 2002 study, success rates were the same for women who used donors with an age range of 20 - 40. There were also no differences in delivery rates for recipients up to age 45. Women over 45, however, increasingly had problems with implantation, pregnancy, and delivery.

Use of Frozen Eggs. Frozen eggs tend to have lower success rates because of toxins released by cells damaged in the freezing and thawing tissues.

Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology used for couples when male infertility is the main problem. It involves injecting a single sperm into an egg obtained from in vitro fertilization (IVF). The procedure is very simple:

A tiny glass tube (called a holding pipet) stabilizes the egg.
A second glass tube (called the injection pipet) is used to penetrate the egg's membrane and deposit a single sperm into the egg.
The egg is released into a drop of cultured medium.
If fertilized, the egg is allowed to develop for 1 - 2 days, then it is either frozen or implanted.

The greatest concern with this procedure has been whether it increases the risk for birth defects. However, several studies have reported no higher risks of birth defects in children born using ICSI procedures. While some studies have shown a higher number of birth defects in children conceived with ICSI, experts think that this may have more to do with the genetic background of the parents than ICSI itself. Recent research suggests that ICSI children develop normally. A 2006 study of 8-year-old children conceived with ICSI found no important differences between these children and children who were conceived naturally.

A 2007 study in the New England Journal of Medicine indicated that ICSI use has increased 5-fold over the past decade, even though the proportion of men receiving treatment for male infertility has remained the same. In 1995, 11% of IVF cycles used ICSI. By 2004, 57.5% of IVF cycles used ICSI. Doctors caution that while ICSI is an important assisted reproductive technology for male infertility, it may be overused. Some doctors recommend ICSI for women who have failed prior IVF attempts or who have few or poor-quality eggs, even if their male partners have normal semen measurements. There is little evidence that ICSI helps improve pregnancy success for couples who do not have a problem with male factor infertility, according to the Society for Assisted Reproductive Technology.

In Vitro Maturation. A technique called in vitro maturation allows fertilization without the use of fertility drugs. In this process, follicles are harvested a few days before ovulation. In such cases, up to 50 have already begun to mature. At this time, about 15 of these maturing follicles can be removed, out of which 2 or 3 can produce healthy embryos.

Blastocyst Transfer. Blastocyst transfer is very promising. Instead of implanting the standard 2- or 3-day-old embryos in the uterus, the procedure implants blastocysts, which are more complex, 5-day-old embryos. Fewer blastocysts than embryos need to be implanted, reducing the risk for multiple births. (There is, however, a higher risk for identical twins compared to other procedures.) Offspring may be more likely to be males than females. Pregnancy rates are about 36% with a first attempt but then drop significantly. The procedure is more likely to be successful in younger than older women.

Ooplasmic Transfer. Ooplasmic transfer is a controversial experimental procedure that uses the woman's own egg and a female donor's egg and the male sperm for fertilization. Genetic material from the donor's egg plus the sperm are added to the woman's own egg. This has been successful in a few cases, but studies are very early and long-term effects are unknown. Research on this and similar procedures is currently conducted outside the U.S.

Complications of Assisted Reproductive Technologies

Since assisted reproductive technology (ART) procedures have become more widespread since 1980, multiple births have significantly increased. About 35% of all ART births are multiple ones, with 4.3% being triplets or more. Multiple births increase the risk of complications, for both the mother and the child.

Assisted reproductive technology (ART), and multiple births, increase the risks for pregnancy complications. According to a 2005 study, the type of complications may depend on the infertility treatment:

Fertility drugs. Increase risks of the placenta becoming detached from the uterus (“placental abruption”), third trimester miscarriage, and gestational diabetes.
In vitro fertilization. Increase risks of placental abruption, the placenta developing in the lower section of the uterus (“placenta previa”), dangerously high blood pressure during pregnancy (“pre-eclampsia”), and Caesarean sections.

Multiple births can also increase the risk of pregnancy death. A 2006 study indicated that women who carry multiple fetuses have a 3.6 times greater risk of dying from pregnancy complications than women with singleton pregnancies. The leading causes of death were blood clot (embolism), high blood pressure complications, excessive bleeding (hemorrhage), and infections.

The main risks for children conceived with assisted reproductive technology (ART) are complications associated with pregnancy problems and multiple births. Children conceived with ART are more likely to be born premature and to have extremely low birth weight. These conditions increase the risk for heart and lung problems, as well as learning and developmental disabilities. Premature delivery is also associated with cerebral palsy, a brain injury condition that affects muscle coordination. A 2006 study indicated that children born after in vitro fertilization have an increased risk for cerebral palsy.

However, studies suggest that ART does not increase the risk for chromosomal damage or other major birth defects. Couples undergoing ART may have other factors, such as older age or genetic predispositions, which make complications more likely. Infertility itself, even without ART, can pose a risk factor for birth defects. Children conceived naturally by couples with infertility problems tended to have more disorders of the nervous system, digestive system, and musculoskeletal system than children born to fertile couples, according to a 2006 study in the British Medical Journal. Children born to couples treated for infertility with ART may also have a slightly increased risk for these problems, as well as genital organ malformations, but the overall risk for birth defects appears to be very small.

ART remains a good option for many infertile couples. The likelihood of having a healthy single child of normal birth weight using ART is about 94%. The likelihood of having a child free of major birth defects is about 91%. Frozen eggs do not appear to pose any higher risk for developmental problems.

Preimplantation genetic diagnosis (PGD) is now available in some fertility centers. It can help identify genetic defects in the offspring and may help parents determine future problems. Such testing, however, also raises significant emotional issues that should be addressed beforehand.

Given the hazards of multiple births, parents must make some hard decisions if the treatment produces multiple embryos. The choices are limited:

Carry all of them to term, which increases health risks for both the mother and the developing fetuses
Complete abortion
Embryo reduction, in which the doctor removes one or more embryos (possibly endangering the remaining embryos)

At this time, the best approach is to limit the number of implanted embryos in the first place. Researchers are attempting to develop methods to reduce the risk for multiple births:

Most centers now implant two to three embryos at a time, and the remainder can be frozen for future use. (Frozen eggs do not appear to pose a risk for developmental problems in children conceived using them.) This limits the chance for success, but implanting more than three embryos only increases success rates very slightly, whereas the risk for multiple births increases significantly.
Reducing the dosage of fertility drugs also reduces the risk for multiple births, but not significantly, and it also reduces the chance for successful outcome.
Blastocyst transfer may help reduce the chances for multiple births.

Resources

www.resolve.org -- National Infertility Association
www.asrm.org -- American Society for Reproductive Medicine
www.theafa.org -- American Fertility Association
www.endometriosisassn.org -- The Endometriosis Association
www.acog.org -- American College of Obstetricians and Gynecologists
www.endo-society.org -- The Endocrine Society
www.aace.com -- American Association of Clinical Endocrinologists
www.cdc.gov/reproductivehealth/index.htm -- Centers for Disease Control: Assisted Reproductive Technology Reports

References

Boomsma CM, Keay SD, Macklon NS. Peri-implantation glucocorticoid administration for assisted reproductive technology cycles. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD005996.

Chavarro JE, Rich-Edwards JW, Rosner BA, Willett WC. Iron intake and risk of ovulatory infertility. Obstet Gynecol. 2006 Nov;108(5):1145-52.

Dieterle S, Ying G, Hatzmann W, Neuer A. Effect of acupuncture on the outcome of in vitro fertilization and intracytoplasmic sperm injection: a randomized, prospective, controlled clinical study. Fertil Steril. 2006 May;85(5):1347-51.

Hvidtjorn D, Grove J, Schendel DE, Vaeth M, Ernst E, Nielsen LF, et al. Cerebral palsy among children born after in vitro fertilization: the role of preterm delivery--a population-based, cohort study. Pediatrics. 2006 Aug;118(2):475-82.

Jain T, Gupta RS. Trends in the use of intracytoplasmic sperm injection in the United States. N Engl J Med. 2007 Jul 19;357(3):251-7.

Jensen A, Sharif H, Svare EI, Frederiksen K, Kjaer SK. Risk of breast cancer after exposure to fertility drugs: results from a large Danish cohort study. Cancer Epidemiol Biomarkers Prev. 2007 Jul;16(7):1400-7. Epub 2007 Jun 21.

Lee SJ, Schover LR, Partridge AH, Patrizio P, Wallace WH, Hagerty K, et al. American Society of Clinical Oncology recommendations on fertility preservation in cancer patients. J Clin Oncol. 2006 Jun 20;24(18):2917-31.

Legro RS, Barnhart HX, Schlaff WD, Carr BR, Diamond MP, Carson SA, et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N Engl J Med. 2007 Feb 8;356(6):551-66.

Mackay AP, Berg CJ, King JC, Duran C, Chang J. Pregnancy-Related Mortality Among Women With Multifetal Pregnancies. Obstet Gynecol. 2006 Mar;107(3):563-568.

Ombelet W, Martens G, De Sutter P, Gerris J, Bosmans E, Ruyssinck G, et al. Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study. Hum Reprod. 2006 Apr;21(4):1025-32.

Sallam HN, Garcia-Velasco JA, Dias S, Arici A. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004635.

Shevell T, Malone FD, Vidaver J, Porter TF, Luthy DA, Comstock CH, et al. Assisted reproductive technology and pregnancy outcome. Obstet Gynecol. 2005 Nov;106(5 Pt 1):1039-45.

Smith C, Coyle M, Norman RJ. Influence of acupuncture stimulation on pregnancy rates for women undergoing embryo transfer. Fertil Steril. 2006 May;85(5):1352-8.

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.

Tulandi T, Martin J, Al-Fadhli R, Kabli N, Forman R, Hitkari J, et al. Congenital malformations among 911 newborns conceived after infertility treatment with letrozole or clomiphene citrate. Fertil Steril. 2006 Jun;85(6):1761-5.

Westergaard LG, Mao Q, Krogslund M, Sandrini S, Lenz S, Grinsted J. Acupuncture on the day of embryo transfer significantly improves the reproductive outcome in infertile women: a prospective, randomized trial. Fertil Steril. 2006 May;85(5):1341-6.

Zhu JL, Basso O, Obel C, Bille C, Olsen J. Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. BMJ. 2006 Sep 30;333(7570):679. Epub 2006 Aug 7.

Review Date:
10/29/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Anemia

FitSugar — Wed, 08 Oct 2008 17:34:56 -0700

In This Report

Highlights
Introduction
Causes
Risk Factors
Complications
Symptoms
Diagnosis
Dietary Factors
Treatment
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

FDA Issues Labeling Changes for Drugs That Boost Red Blood Cells

In November 2007, the U.S. Food and Drug Administration (FDA) made several changes to the prescribing labels for erythropoiesis-stimulating drugs. These drugs -- epoietin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp) -- increase the production of red blood cells. They are used to treat anemia associated with chronic kidney failure, cancer chemotherapy, and antiretroviral HIV therapy.

The new labels have stronger warnings and updated dosing-related safety information. The FDA advises:

For cancer, erythropoiesis-stimulating drugs are used only to treat anemia associated with chemotherapy. Dosing should increase hemoglobin levels to no more than 12 g/dL. These drugs can shorten survival time and increase tumor growth when hemoglobin levels are raised beyond this point. Treatment should stop as soon as chemotherapy is completed. Erythropoiesis-stimulating drugs are not safe or appropriate for all patients undergoing chemotherapy. Patients should discuss the risks and benefits with their oncologists.
For chronic kidney failure, erythropoiesis-stimulating drugs should be used to maintain a hemoglobin level between 10 - 12 g/dL. Higher hemoglobin levels increase the risk for stroke, heart attack, heart failure, or death.
Erythropoiesis-stimulating drugs are used to increase red blood cell numbers and reduce the need for blood transfusions. They do not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV.
Patients who take these drugs should contact their doctors if they experience symptoms such as leg pain or swelling, increased shortness of breath, increased blood pressure, dizziness, or extreme fatigue.

Introduction

Anemia is an abnormal reduction in red blood cells.

This photmicrograph shows normal red blood cells (RBCs) as seen in the microscope after staining.

Anemia is a global problem, at its worst in developing countries. But it is by no means absent in industrialized nations. An estimated 3.4 million Americans suffer from anemia. Anemia is not a single disease but a condition, like fever, with many possible causes and many forms. Causes of anemia include nutritional deficiencies, inherited genetic defects, medication-related side effects, and chronic disease. It can also occur because of blood loss from injury or internal bleeding, the destruction of red blood cells, or insufficient red blood cell production. The condition may be temporary or long-term, and can manifest in mild or severe forms.

As it is impossible to discuss all types of anemia, this report focuses on three of the most common forms:

Iron deficiency anemia
Anemia of chronic disease (ACD)
Megaloblastic anemia (caused by deficiencies in the B vitamins folate, vitamin B12, or both)

Some less common causes and types of anemia are included in a table in this report.

Blood has two major components:

Plasma is a clear yellow liquid that contains proteins, nutrients, hormones, electrolytes, and other substances. It constitutes about 55% of blood.
White and red blood cells and platelets make up the balance of blood. The white cells are the infection fighters for the body, and platelets are necessary for blood clotting. The important factors in anemia, however, are red blood cells.

Red blood cells (RBCs), also known as erythrocytes, carry oxygen throughout the body to nourish tissues and sustain life. Red blood cells are the most abundant cells in our bodies. Men have about 5.2 million red blood cells per cubic millimeter of blood, and women have about 4.7 million per cubic millimeter of blood.

Hemoglobin and Iron

Each red blood cell contains 200 - 300 hemoglobin molecules. Hemoglobin is a complex molecule, and it is the most important component of red blood cells. It is composed of protein (globulin) and a molecule (heme), which binds to iron.

In the lungs, the heme component binds to oxygen in exchange for carbon dioxide. The oxygenated red blood cells are then transported to the body's tissues, where the hemoglobin releases the oxygen in exchange for carbon dioxide, and the cycle repeats. The oxygen is used in the mitochondria, the power source within all cells.

Red blood cells typically circulate for about 120 days before they are broken down in the spleen. Most of the iron used in hemoglobin can be recycled from there and reused.

Structure and Shape of Red Blood Cells

Red blood cells -- the erythrocytes -- are extremely small and look something like tiny, flexible inner tubes. This unique shape offers many advantages:

It provides a large surface area to absorb oxygen and carbon dioxide.
Its flexibility allows it to squeeze through capillaries, the tiny blood vessels that join the arteries and veins.

Abnormally shaped or sized erythrocytes are typically destroyed and eliminated.

Blood Cell Production (Erythropoiesis)

The actual process of making red blood cells is called erythropoiesis. (In Greek, erythro means "red," and poiesis means "the making of things.") The process of manufacturing, recycling, and regulating the number of red blood cells is complex and involves many parts of the body:

The body carefully regulates its production of red blood cells so that enough are manufactured to carry oxygen but not so many that the blood becomes thick or sticky (viscous).
Most of the work of erythropoiesis occurs in the bone marrow. In children younger than 5 years old, the marrow in all the bones of the body is enlisted for producing red blood cells. As a person ages, red blood cells are eventually produced only in the marrow of the spine, ribs, and pelvis.
If the body needs more oxygen (at high altitudes, for instance), the kidney triggers the release of the hormone erythropoietin (EPO), a hormone that acts in the bone marrow to increase the production of red blood cells.
The lifespan of a red blood cell is 90 - 120 days. The liver and the spleen remove old red blood cells are removed from the blood by the liver and spleen.
When old red blood cells are broken down for removal, iron is returned to the bone marrow to make new cells.

Click the icon to see an image of the formed elements of blood.

Click the icon to see an image of hemoglobin.

Causes

Iron deficiency anemia occurs when the body lacks mineral iron to produce the hemoglobin it needs to make red blood cells. In general, there are three stages leading from iron deficiency to anemia:

First, there is an insufficient supply of iron, which causes iron stores in the bone marrow to be depleted. This stage generally has no symptoms.
Second, iron deficiencies develop and begin to affect hemoglobin production. (Tests will show low hemoglobin and hematocrit levels.)
Hemoglobin production declines to the point where anemia develops.

Most of the iron used in the body can be recycled from blood and reused. Nevertheless, iron deficiency can occur from a number of conditions.

Inadequate Iron Intake. A healthy diet easily provides enough iron. In general, most people need just 1 mg, and menstruating women need 2 mg of extra iron each day. This means that lack of iron in the diet is not a common cause of iron deficiency anemia, except in infants. In fact, most American adults may be consuming too much iron in their diet. Most of the iron in red blood cells is recycled and reused. Iron-poor diets are a cause of anemia only in people with existing risks for iron deficiency. Children who have not yet eaten iron-fortified formulas or iron-enriched cereal may also become anemic.

Blood Loss. Iron deficiencies most commonly occur from internal blood loss due to other conditions that range in severity. These conditions include:

Peptic ulcers, which may be caused by H. pylori infections, or aspirin and drugs or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen. About 70% of long-term users of these medications have some sign of gastrointestinal bleeding, although it is rarely significant enough to cause anemia.
Duodenal ulcers
Hemorrhoids
Colon polyps
Colon, stomach, and esophageal cancer
Very heavy periods (menorrhagia) are the most common causes of anemia in premenopausal women.
Bleeding from esophageal varices, often present in alcoholics

Impaired Absorption of Iron. Impaired absorption of iron is caused by:

Certain intestinal diseases (inflammatory bowel disease, celiac disease)
Surgical procedures, particularly those involving removal of parts of the stomach and small intestine, can impair the ability of the stomach or intestine to absorb iron. (Such conditions also often impair folic acid absorption as well.)
Pica, the craving for non-food substances such as ice, starch, or clay, is a possible cause of iron deficiency. To complicate matters, pica (particularly ice cravings) may also be a symptom, rather than a cause, of anemia.
Certain intestinal infections, such as hookworm and other parasites.

Click the icon to see an image of inflammatory bowel disease.

Genetic Causes. Some people are born with iron deficiency. Certain cases may be due to a mutation of the Nramp2 gene, which regulates a protein responsible for delivering iron to the cells.

Anemia of chronic disease (ACD), also called anemia of chronic inflammation (ACI), is a common condition associated with a wide variety of persistent inflammatory diseases. It can be very severe and require transfusions.

The Inflammatory Process and ACD. ACD is not completely understood. In ACD, iron is not efficiently recycled from blood cells, and red blood cell survival is reduced. In addition, there is impaired response to erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. (Abnormal function and low levels of erythropoietin, in fact, may be the most important factor in ACD, with iron insufficiencies being a consequence.)

The process leading to ACD may occur in the following way:

The immune system activates white blood cells and releases various compounds during times of infection that are intended to fight invaders and heal wounds. Such an event causes an inflammatory state in the areas of the attack.
White blood cells called macrophages release small but powerful proteins known as cytokines, which are critical in the development of ACD. Cytokines are indispensable for healing. However, cytokines are overproduced often in chronic and inflammatory diseases, causing serious tissue injury and, in some cases, even organ damage. In the case of ACD, they prevent production of erythropoietin, the hormone that acts in the bone marrow to increase the production of red blood cells. Specific cytokines implicated in anemia are interleukin 1 (IL-1), tumor necrosis factor (TNF), and interferons.
As part of this process, mechanisms prevent the release of recycled iron needed in the bone marrow for the manufacturing of red blood cells. Iron absorption in the intestines is also blocked. Theoretically, this is a protective measure, since iron may help infectious organisms proliferate. In such cases, iron stores are high, but the usable iron in circulation is low.
Researchers have identified a peptide called hepcidin, which prevents iron absorption in the intestine and blocks the release of iron by immune factors for red blood cell production. Some experts believe high levels of the peptide may play a central role in preventing the release of iron during infection and inflammatory states, and is critical in ACD.

Diseases Associated with ACD and Inflammation. The chronic diseases that are associated with this process include:

Certain cancers. Examples include lymphomas and Hodgkin's disease.
Autoimmune diseases. Examples include rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, and polymyalgia rheumatica.
Long-term infections. Examples include chronic or recurrent urinary tract infections and osteomyelitis.
Hepatitis C. The liver cirrhosis associated with hepatitis C can reduce the production of red blood cells. Gastrointestinal bleeding may also contribute to blood loss.
Heart failure. Experts estimate that 25 - 60% of patients with heart failure also have anemia. However, it is unclear whether anemia actually causes or worsens heart failure. Recent research suggests it may actually be a sign (marker) of heart failure. Iron deficiency in heart failure can be due to a number of factors. It may be caused by a lack of nutrients in a person’s diet or by the body’s inability to absorb nutrients from food. Heart failure can also cause a back up of fluid (edema). This edema produces a higher volume of blood plasma (the liquid part of blood), which can dilute red blood cells and cause anemia.
Chronic kidney disease. The hormone erythropoietin (EPO) is produced in the kidneys and stimulates the bone marrow production of red blood cells. Diseased kidneys do not release sufficient amounts of EPO; anemia can result and is universal in end-stage renal disease. Chronic kidney disease is a common complication of diabetes.
HIV/AIDS. The inflammatory process associated with AIDS can adversely affect EPO levels and red blood cell production.
Anemia in critically ill patients. Evidence suggests similarities between ACD and severe anemia in patients who are in intensive care. Some experts believe that the cause of anemia in such critically ill patients may also be due to inflammatory responses that promote impaired responsiveness to erythropoietin.

Not all chronic diseases involve the inflammatory process and anemia. For example, high blood pressure is a chronic disease, but it does not affect red blood cells.

Treatment-Related Anemia. Anemia can also result from the therapies used to treat conditions. For example, anemia is a common side effect of cancer treatments. Chemotherapy and radiation can impair the bone marrow's production of red blood cells and contribute to the extreme fatigue that many patients experience during cancer therapy. Patients with hepatitis C frequently receive combination therapy of ribavirin and interferon; ribavirin can induce anemia. Hepatitis C also affects many patients with HIV or AIDS. In addition to ribavirin, patients with HIV or AIDS can develop anemia as a result of highly active anti-retroviral therapy (HAART) and, in particular, from the drug AZT.

Other medications that increase the risk for anemia are certain antibiotics, some antiseizure medications (phenytoin), immunosuppressive drugs (methotrexate, azathioprine), antiarrhythmic drugs (procainamide, quinidine), and anti-clotting drugs (aspirin, warfarin, heparin).

Megaloblastic anemia is the end-product of deficiencies in the B vitamins folate or vitamin B12 (also called cobalamin), or both. Such deficiencies produce abnormally large red blood cells (megaloblastic ) that have a shortened lifespan. Neurologic problems are also associated with these deficiencies. Several conditions can cause these deficiencies.

Click the icon to see an image of red blood cells seen in megaloblastic anemia.

Causes of Vitamin B12 Deficiency. Conditions that cause vitamin B12 deficiencies include:

Vitamin B12 deficiency from diet is very rare, since the liver stores over a 3-year supply. It usually does not occur even in alcoholism, vegetarianism, or in malnourished people with kidney failure or cancer. Since animal products are the chief source, however, true vegan vegetarians may need a supplement, fortified food, or appropriate food selection known to contain adequate amounts of this vitamin
Pernicious anemia. Pernicious anemia is an autoimmune disease in which antibodies are tricked into attacking stomach cells. This results in impaired production of intrinsic factor (IF), a compound that is critical for absorption of vitamin B12. Pernicious anemia is diagnosed in about 1% of people over age 60, with women having a higher risk than men.
Complications of gastrointestinal surgery. Surgeries such as stomach bypass or stapling, which remove part or all of the stomach, pose a 15 - 30% chance of causing vitamin B12 deficiencies.
Overgrowth of intestinal bacteria
Tropical sprue (an acquired malabsorption disease occurring in tropical climates)

Click the icon to see an image of the benefits of vitamin B12.

Causes of Folate Deficiency. The body stores only about 100 times its daily requirements for folate and can exhaust this supply within about 3 months if the diet is deficient in folate.

Poor diet coupled with alcoholism is the most common cause of folate deficiency. Alcohol abuse not only contributes to malnutrition but also causes chemical changes that can result in lower folate levels.
Any condition that disturbs the small intestine and impairs its absorption ability can cause a deficiency. Such disorders include inflammatory bowel disease or celiac sprue (a sensitivity reaction to gluten)

Click the icon to see an image of foods that contain gluten.

Parasitic diseases such as giardiasis
Short bowel syndrome
Deficiencies can also arise due to high demand for folic acid caused by conditions such as cancer, pregnancy, severe psoriasis, severe hyperthyroidism, and hemolytic anemia.
Some drugs, including phenytoin, methotrexate, trimethoprim, and triamterene, may also hinder folate absorption.


Form of Anemia	Description and Diagnosis	Causes and Risk Factors	Treatments
Aplastic Anemia	Bone marrow fails to produce all types of blood cells. Symptoms, in addition to standard anemia, are bleeding in mucous membranes and skin, gingivitis, higher risk for infection, and shortness of breath.	Cause is unknown in half the cases. Known causes include hereditary conditions (Fanconi's anemia), viruses (HIV, hepatitis, Epstein-Barr), autoimmune diseases (lupus, rheumatoid arthritis), medications (valproic acid, tacrolimus, azathioprine) or chemicals (benzene, pesticides).	Transfusions, antibiotics, bone marrow or stem cell transplantation, immunosuppressant drugs. (This anemia used to be nearly always fatal, but survival rates now can reach 92% with successful transplants and up to 87% with immunosuppressants.)
Thalassemia	Genetic blood disease caused by a defect in the rate of production of hemoglobin. The two major forms are thalassemia minor and thalassemia major (Cooley's anemia, beta thalassemia). Thalassemia minor is the more common and milder form, in which lifespan is normal. Thalassemia major can be serious, but it is fortunately very rare.	Affects males and females equally. Most common in people of Mediterranean descent, especially Italians and Greeks. Both types of thalassemia are found in an area that extends from northern Africa and southern Europe to Thailand, including Iran, Iraq, Indonesia, and southern China. Thalassemia major is more common in families who intermarry.	Transfusions to supply enough red blood cells to achieve moderate anemia and avoid iron overload are standard approaches for thalassemia major. Investigations are ongoing to find alternatives to transfusions. Hydroxyurea, 5-azacytidine, erythropoietin, or butyrate analogues may help some patients. Bone marrow transplantation may be needed for some types of thalassemia.
Hemolytic Anemias: Acquired	Anemia caused by hemolysis (premature destruction of red blood cells). Diagnosis considered when there is marked increase in RBC production by bone marrow.	Autoimmune hemolytic anemia is the primary type, in which antibodies produced by the immune system damage RBCs. Cause unknown or associated with disorders such as systemic lupus erythematosus, lymphoma, and paroxysmal nocturnal hemoglobinuria. Other causes are high exposure to certain metals or chemicals (lead, copper, benzene, naphthalene), snake and insect bites, malaria, transfusions, post-surgical complications, and drugs such as methyldopa. In infants, blood group incompatibility between mother and child or infections in the womb.	Corticosteroids for autoimmune hemolytic anemia. Transfusions beneficial in many cases. Various immunosuppressive drugs may be tried, as well as splenectomy. Eculizumab (Soliris) is approved for treatment of paroxysmal nocturnal hemoglobinuria.
Hemolytic Anemias: Inherited	Hemolysis (premature destruction of RBCs) caused by sphere-shaped RBCs, which have difficulties circulating through the spleen.	Inherited defects include membrane defects, hemoglobin abnormalities, and enzyme deficiencies. Fava beans may trigger symptoms. More likely and more serious in males than females.	Blood transfusions may be necessary for some types of hemolytic anemia. Experimental trials use immune globulin. Removal of the spleen (splenectomy) or bone marrow transplantation may help some patients.
Sideroblastic Anemias	Group of anemias caused by impaired ability of bone marrow to produce normal RBCs. Normal-to-high iron levels, but iron cannot be used to make hemoglobin. In addition to the standard symptoms of anemia are jaundice, enlarged liver and spleen, fever, headache, loss of appetite, vomiting, and leg sores. Symptoms can be mild. Usually appears in childhood. Infections, trauma, and pregnancy may trigger symptoms.	Inherited or acquired after excessive alcohol use, certain medications, including chloramphenicol, or other disorders, including some cancers and rheumatoid arthritis. More common in the elderly.	Deferoxamine (Desferal) is used to remove iron. Effectiveness is increased when ascorbate is added to the regimen. Folate and pyridoxine are used, but their effectiveness is under question.
Sickle Cell Anemia	Serious, life-threatening, inherited disease. The sickle-shaped, inflexible RBC has impaired ability to squeeze through vessels. Short lifespan of RBC (10-20 days) causes anemia. In addition to anemia symptoms, joint and bone pain, infections, and heart failure can occur.	Disease occurs in 0.6% and the trait is found in the genetic makeup of 9% of African-Americans. Also occurs in people from India and Spanish-speaking and Mediterranean regions.	Measures to avoid cycling and control pain. Including hydration, hydroxyurea, NSAIDs and narcotic analgesics. Bone marrow transplantation. [For information, see In-Depth Report #58: Sickle-cell disease.]

Click the icon to see an image of red blood cells found in sickle cell anemia.

Risk Factors

Although nutritional iron-deficiency anemia has declined in industrialized nations, it affects an estimated 2 billion people worldwide. Even in the U.S., iron deficiency is the most prevalent nutritional deficiency. It is highly associated with poverty. People in lower socioeconomic groups have double the risk of those who are middle or upper class.

Among Americans with iron deficiency anemia, young children have the highest risk followed by premenopausal women. Adolescent and adult men and postmenopausal women have the lowest risk. Men, in fact, are at risk for iron overload, probably because of their higher meat intake.

General Risk Factors for Anemia in Infants and Children. Up to 20% of American children and 80% of children in developing countries become anemic at some point during their childhood and adolescence. Iron deficiency is the most common cause in children, but other forms of anemia, including hereditary blood disorders, can also cause anemia in this population. Hispanic American children have double the rates of iron deficiency as African-American and Caucasian children.

Iron deficiency affects about 9% of children younger than 2 years. About 3% of children in this age group are anemic as a result. Children in lower-income homes are at higher risk than those in higher income homes. In a study of low-income children, ages 6 months to 5 years, the prevalence of anemia was over 10%, and was nearly 18% in children younger than 2 years. However, children in any income group can develop iron deficiency.

Young children 9 - 18 months have the highest risk for iron deficiency anemia in the U.S. Such children also are at great risk for problems in mental development from anemia. Infant boys may have 10 times more risk than baby girls. In general, full-term, breast-fed infants have enough iron stores for their first 6 months of life. After that, they must rely on other sources for iron.

Iron-deficiency anemia in infants and small children can be due to one or more of the following factors:

Stopping breast-feeding too early or using formula that isn't iron-fortified.
Bottle-feeding too long. Studies indicate that the longer children are bottle-fed, the greater the risk for iron-deficiency and anemia. Toddlers 12 months and older should not drink more than 2 cups of milk a day. Cow’s milk is good for children, but it does not contain enough iron. Too much milk can decrease children’s appetite and prevent them from eating the iron-rich food they need. When babies who are bottle-fed are 7 - 9 months old, they should be weaned from bottles and given sippy cups. By the age of 12 months, all children should be using a cup instead of a bottle.
Toddlers’ preferences for iron-poor food. Parents should make sure that their children eat iron-rich foods, such as beans, meat, fortified cereals, eggs, and green leafy vegetables

Better social services and more accurate ways of diagnosing and monitoring anemia are needed in these high-risk groups. There is still considerable debate on how to define iron deficiency and anemia in infants. New research suggests that a reticulocyte hemoglobin content (CHr) test may be better than a standard hemoglobin test for detecting iron deficiency in babies. Reticulocytes are immature red blood cells. The CHr test measures the amount of hemoglobin in these cells.

Up to 10% or more of adolescent and adult women under 49 years are iron deficient. Hispanic American and African-American women have double the prevalence for anemia compared to Caucasian women. The risk for anemia in adolescent girls is about 3%. Anemia is generally mild in young women, however, and is more likely to occur with one or more of the following conditions:

Heavy menstruation for longer than 5 days
Abnormal uterine bleeding, such as from fibroids
Pregnancy. About 20% of women in industrialized countries have iron deficiency during pregnancy. Multiple pregnancies and births significantly increase the risk.

Although studies have reported various estimates on the prevalence of anemia in older adults, one survey suggested that anemia affects about 10% of adults aged 65 years and older, and more than 20% aged 85 years and older. The causes of anemia in older adults were equally distributed among nutritional deficiencies, chronic inflammatory disease, chronic renal disease, and unexplained anemia. Most cases were mild.

People with alcoholism are at risk for anemia both from internal bleeding as well as folate- and vitamin B deficiency-related anemias.

Although most Americans probably consume too much iron in their diets, some people may be at risk for diet-related iron deficiencies, including:

People whose diets are high in processed foods and lack any meat.
Strict vegetarians. Vegetarians who avoid all animal products may have a slightly higher risk for deficiencies in iron and some B vitamins. Although dried beans and green vegetables often contain iron, it is less easily absorbed from plants than from meat. Fortunately, most commercial cereals are fortified with vitamin B12 and folic acid (the synthetic form of folate).

Anyone with a chronic disease that causes inflammation or bleeding is at risk for anemia. Critical illness in the intensive care unit is also highly associated with anemia.

Working out regularly may cause some iron loss, which is comparable to that from menstruation and rarely worrisome. Dietary choices may account for most cases of sports anemia. Intense, sustained exercise, such as that performed by marathon runners, may cause a condition called sports anemia, which may be due to slight gastrointestinal bleeding, damaged red blood cells, low iron intake, or poor intestinal absorption of iron.

Iron deficiency occurs in 20% of pregnant women in developed countries. Even worse, 50% or more of women in nonindustrialized nations become iron deficient, and 30 - 50% are deficient in folic acid. Severe anemia is associated with a higher mortality rate among pregnant women. Mild-to-moderate anemia, however, does not pose any elevated risk.

Pregnancy increases the risk for anemia in different ways:

It increases the body's demand for folic acid and, therefore, poses a risk for deficiencies and an increased risk for megaloblastic anemia. Low levels of folate during pregnancy increase the risk of neural tube defects in newborns.
It increases the body's demand for iron, thus posing a risk for iron deficiency anemia. Pregnant or nursing women need 30 mg of iron per day. Maternal iron deficiency anemia is associated with increased weight or size of the placenta, a condition that may later pose a risk for high blood pressure in the offspring. Pregnant women with low hemoglobin levels (the iron-bearing component in the blood) have an elevated risk for pre-term or low birth weight infants.
Pregnancy is also associated with fluid retention, which in turn may produce high volumes of plasma (the fluid component of blood). This can dilute red blood cells, which may lead to anemia.
After delivery, heavy bleeding, which occurs in 5 - 10% of women who have given birth, can cause symptoms of anemia.

Diagnosing of Iron Deficiency During Pregnancy. A diagnosis of iron deficiency is problematic in pregnant women. The standard test is a measurement of ferritin levels, which are low in most people with iron deficiency. Pregnant women, however, may have high ferritin blood levels into their third trimester but still be iron deficient. A newer test that measures a factor called serum transferrin receptor may prove to be a useful way of diagnosing iron deficiency in women. Researchers are also investigating Doppler ultrasonography as an imaging technique for detecting anemia in the fetus. Traditionally, fetal anemia is diagnosed through amniocentesis. Doppler ultrasonography is a non-invasive method that does not risk causing a miscarriage or a worsening of fetal anemia.

Preventing Anemia in Pregnant Women.

Iron Supplements. For the past 40 years, iron supplements have been recommended for all pregnant women. This practice has been challenged recently, however. There is no clear-cut evidence that the mild iron deficiency most pregnant women experience is harmful. In addition, iron supplements cause gastrointestinal side effects and may not be completely harmless. Some experts suggest iron supplements for all pregnant women whose hemoglobin levels are less than 11 g/dl, and pregnant women whose serum ferritin levels are low, beginning in their 20th - 24th weeks of pregnancy.
Vitamin Supplements. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid a day. They should be sure this is folic acid and not folate. Folate is the natural form of folic acid, but 400 mcg supplements of folate are half as potent as the same dose of folic acid. Pregnant and nursing women who are vegetarians should be sure to have supplements of folic acid and other B vitamins as well, since many of these nutrients are found primarily in animal products. Vitamin B12 deficiencies during pregnancy can also produce anemia in both mother and child.
Diets Rich in Vitamin C. Eating foods rich in vitamin C can help absorb iron.

Treating Anemia During Pregnancy. Pregnant women who become anemic and need treatment may be given oral iron supplements, or blood transfusions in severe cases. Intravenous or intramuscular administration of iron helps improve blood levels better than oral iron supplements, but may cause more serious side effects.

Complications

Most cases of anemia are mild, including those that occur as a result of chronic disease. Nevertheless, even mild anemia can reduce oxygen transport in the blood, causing fatigue and a diminished physical capacity. Moderate-to-severe iron-deficiency anemia is known to reduce endurance. Some studies indicate that even iron deficiency without anemia can produce a subtle but still lower capacity for exercise.

Because a reduction in red blood cells decreases the ability to absorb oxygen from the lungs, serious problems can occur in prolonged and severe anemia that is not treated. Anemia can lead to secondary organ dysfunction or damage, including heart arrhythmia and heart failure.

Certain inherited forms of anemia, including thalassemia major, pernicious anemia, and sickle-cell anemia, can be life threatening. Thalassemia major and sickle-cell anemia affect children and are particularly devastating.

Pregnant women with significant anemia may have an increased risk for poor pregnancy outcomes, particularly if they are anemic in the first trimester.

In children, severe anemia can impair growth and motor and mental development. Children may exhibit a shortened attention span and decreased alertness. Children with severe iron-deficiency anemia may also have an increased risk for stroke.

Anemia is common in older people and can have significantly more severe complications than anemia in younger adults. Some studies have reported higher mortality rates in anemic individuals 85 and older compared to their non-anemic peers. (The rates were higher in anemic men than in women.) The following are examples of its effects from different studies:

Anemia may have adverse effects on the heart and increase the severity of cardiac conditions, including reducing survival rates from heart failure and heart attacks.
Elderly people with lower levels of hemoglobin are at an increased risk of death.
Anemia may be associated with an increased incidence of falls.
Even mild anemia may possibly lead to cognitive impairment. A 2006 study of elderly women found that mild anemia worsened problem-solving abilities and other cognitive functions. Anemia may worsen an already existing dementia.

In addition to anemia, vitamin B12 deficiency can cause neurologic damage, which can be irreversible if it continues for long periods without treatment.

Anemia is particularly serious in cancer patients. In people with many common cancers, the presence of anemia is associated with a shorter survival time.

Anemia is associated with higher mortality rates and possibly heart disease in patients with kidney disease.

The combination of anemia and heart failure can increase the risk of hospitalization or death by 30 - 60%. Patients with heart failure whose hemoglobin levels decline do worse than patients with stable levels.

Blood transfusions. Patients with certain types of anemia require frequent blood transfusions. These transfusions can cause iron overload. Patients are treated with iron chelation therapy, which uses a drug that binds to iron. Excess iron is then eliminated by the kidneys. The standard drug for iron chelation therapy, deferoxamine (Desferal), is injected intravenously through an infusion pump. The treatment can be difficult for many patients. In 2005, the FDA approved a new drug, deferasirox (Exjade), to treat iron overload due to blood transfusions. Patients dilute the pills in liquid once a day and drink the mixture.

Symptoms

Symptoms of anemia vary depending on the severity of the condition. Anemia may occur without symptoms and be detected only during a medical examination that includes a blood test. When they occur, symptoms may include:

Weakness and fatigue are the most common symptoms of even mild anemia. Even iron deficiency without anemia can reduce working capacity in some people.
Shortness of breath on exertion
Rapid heartbeat
Lightheadedness or dizziness
Headache
Ringing in the ears (tinnitus)
Irritability and other mood disturbances
Pale skin (however, healthy-looking skin color does not rule out anemia if a patient has risk factors and other symptoms of anemia)
Mental confusion
Loss of sexual drive

Pica. One odd symptom, in some cases a cause of iron deficiency, is pica. This is the habit of eating unusual substances, such as ice (called pagophagia), clay, cardboard, foods that crunch, or raw starch. For example, in one study, half of people whose pica took the form of pagophagia (eating at least one tray of ice every day for 2 months) or eating foods that crunch (such as raw potatoes, carrots, or celery) were iron deficient. The pica often stops, particularly in children, when iron supplements are given. Pica is difficult to detect because patients are often ashamed to admit to such cravings.

Frequent Breath Holding. Studies have also indicated that children who hold their breath frequently when angry or upset, even to the point of fainting, may be iron-deficient. In one study, taking iron supplements reduced this phenomenon in 88% of treated children.

Symptoms of Megaloblastic Anemia. The symptoms of megaloblastic anemia from vitamin B12 or folic acid deficiencies include not only standard anemic symptoms but also:

Inflammation of the mouth (stomatitis)
Inflammation of the tongue (glossitis), which involves shrinkage at the surface and edges of the tongue

Over time, psychiatric and neurologic problems develop. Vitamin B12 deficiencies cause neurologic symptoms (numbness and tingling, depression, memory loss, and irritability), and folate deficiency may result in depression and dementia (in severe cases).

Symptoms of Pernicious Anemia. Early neurologic symptoms of pernicious anemia are due to B12 deficiency. They include numbness and tingling, depression, memory loss, and irritability. Advanced nerve damage can cause loss of balance and staggering, confusion, dementia, spasticity, loss of bladder control, and erectile dysfunction. Folic acid deficiency does not cause neurologic damage, although people with this deficiency can be irritable, forgetful, and experience personality changes. Of concern for patients with pernicious anemia and B12 deficiency anemia is that folic acid supplements can mask the presence of this disease in its early stages but not cure it. The only cure is vitamin B12 supplementation.

Diagnosis

The first step in any diagnosis is a physical examination to determine if the patient has symptoms of anemia and any complications. Because anemia may be the first symptom of a serious illness, determining its cause is very important. This may be difficult, particularly in the elderly, malnourished, or people with chronic diseases, whose anemia may be caused by one or more factors. A detailed medical, personal, and dietary history should report:

Any family or personal history of anemia
A history of gallbladder disease, jaundice, or enlarged spleen
Heavy menstrual bleeding in women
Any occurrence of blood in the stool or other signs of internal bleeding. (Even if the patient has not observed any bleeding, nonvisible blood may be present, so a rectal exam and stool test are essential.)
Any dietary history, particularly in people who are elderly, poor, or both

The doctor should examine the patient carefully, especially checking for swollen lymph nodes, an enlarged spleen, and pale skin and nail color.

Specific blood tests are given to determine anemia from any cause.

Blood and Hemoglobin Counts. A complete blood count (CBC) test is performed to determine the presence of anemia. The red blood cells, or erythrocytes, and their iron-bearing component, hemoglobin, are measured.

For example, severe anemia in adults is defined by the World Health Organization as:

Hemoglobin concentrations below 12 g/dL (7.5 mmol/L) in women. (Some evidence suggests that in older women anemia should be diagnosed at 13 g/dL and below.)
Below 13 g/dL (8.1 mmol/L) in men.

A low red blood cell (RBC) count could indicate a number of problems, including bleeding or a failure by bone marrow to manufacture red blood cells.

Hematocrit. Calculating the percentage of red blood cells in blood plasma (a measurement called the hematocrit) is also important. Plasma is the liquid portion of blood. People with a high volume of plasma may be anemic even if their blood count is normal because the blood cells have become diluted.

Normal percentages are highest in the very youngest individuals and decline as people age. They also vary by gender. The following are some examples of normal range:

Newborns: 42 - 60%
Children: 35 - 45%
Adult males: 41 - 53%
Adult women: 36 - 46%

Normal value ranges may vary slightly among different laboratories.

Smokers, people at high altitudes, and those who are dehydrated tend to have higher than normal hematocrit levels. Those at greater risk for low hematocrit levels include pregnant women and patients with cirrhosis, heart failure, and splenomegaly.

Reticulocyte Count. Reticulocytes are immature red blood cells, and their count reflects the rate of red blood cell production. The upper normal limit is about 100,000/mL. A low count, when bleeding isn't the cause, suggests problems in production in the bone marrow. An abnormally high count indicates that the red blood cells are being destroyed in high numbers and indicates hemolytic anemia. New research suggests that the reticulocyte hemoglobin content (CHr) test may be more accurate than a standard hemoglobin test for detecting iron deficiency in infants. This test may help identify babies who are at risk for becoming anemic and help them get treated earlier.

Blood Morphology. A blood smear viewed under a microscope allows an expert to classify the blood by its color, size, and shape ( morphology ). Generally red blood cells are categorized as:

Pale-colored (hypochromic) and abnormally small (microcytic)
Normal colored and normal sized (normochromic, normocytic)
Abnormally large (macrocytic)

The shape of the red blood cells, which can be distorted in many blood disorders, is also important in determining a diagnosis.

There are two steps in making a diagnosis in patients with symptoms of iron deficiency anemia:

The first step is to determine if a person is actually deficient in iron.
If iron stores are low, the second step is to diagnose the cause of the iron deficiencies, which will help determine treatment.

Determining if Iron Stores are Low. The following findings are important in determining that a person is iron deficient:

Blood cells viewed under the microscope are pale (hypochromic) and abnormally small (microcytic). They are also mostly uneven in shape. (These findings suggest iron deficiency, but they can also appear in cases of anemia due to chronic disease and thalassemia.)
Hemoglobin and iron levels are low. (These findings further suggest iron deficiency, but they can also occur in cases of anemia due to chronic disease.)
Ferritin levels are low. Ferritin is a protein that binds to iron. Low levels typically mean reduced iron stores. High ferritin levels in the blood do not always mean sufficient iron stores. For example, pregnant women may have high ferritin levels into their third trimester but still be iron deficient. Ferritin levels may also be normal or even elevated in patients with inflammation from anemia due to chronic disease, even if they also have low iron stores.
In children with iron deficiencies, reticulocytehemoglobin levels are low. Reticulocytes are immature red blood cells, and this test may be the most effective approach for diagnosing iron deficiency in children.
A test that measures a factor called serum transferrin receptor (TfR) is proving to be very sensitive in identifying iron deficiency in problematic patients, including the elderly with chronic diseases and possibly pregnant women. (It is often very difficult to identify iron deficiencies in patients who also have anemia due to chronic diseases because their ferritin levels are often normal or even high.) For example, levels of TfR are high in patients with ACD and iron deficiency anemia, but they are normal or only slightly raised in ACD alone. The test is expensive, however, and some experts recommend it should be used only when there is a high suspicion of iron deficiency in the elderly.
Measuring erythrocyte zinc protoporphyrin (ZPP), a product of abnormal heme synthesis, is under investigation and may prove to be a simple and precise measure of iron deficiencies, particularly in children.

If internal bleeding is suspected as the cause, the gastrointestinal tract is usually the first suspect as the source. A diagnosis in these cases can often be made if the patient has noticed blood in the stools, which can be black and tarry or red-streaked. Often, however, bleeding may be present but not visible. If so, stool tests for this hidden (occult ) blood are required. Additional tests may then be needed to diagnose the precipitating condition. Endoscopy, in which a fiber optic tube is used to view into the gastrointestinal tract, is helpful in many patients, particularly when the source of bleeding is unclear. A colonoscopy may also be recommended to rule out colorectal cancer.

If the patient's diet suggests low iron intake and other causes cannot be established using inexpensive or noninvasive techniques, then the patient may simply be given a monthly trial of iron supplements. If the patient fails to respond, further evaluation is needed.

Usually anemia of chronic disease is recognized during the management of the primary disease and, if the anemia is mild, additional diagnostic tests are rarely needed. The following are typical findings in ACD:

The blood cells are normal looking.
Blood tests may typically show low levels of iron in the blood, but ferritin levels are normal or even high. (Low levels of ferritin, a protein that binds to iron, indicate iron deficiency.)

Doctors need a multi-step diagnostic procedure for determining vitamin B deficiencies and the anemias that cause or are caused by them. Doctors may arrive at a diagnosis of vitamin B12 or folic acid deficiencies from different routes:

They may diagnose deficiencies after detecting megaloblastic anemia from abnormal blood tests.
They may suspect vitamin deficiencies first from symptoms and history and then look for anemia.

Diagnosing Megaloblastic Anemia. Very large oval red blood cells indicate megaloblastic anemia. Abnormally shaped neutrophils (certain white blood cells) may also be present. Bone marrow aspiration may need to be performed if the disease is strongly suspected but the diagnosis is not clear.

Determining Vitamin Deficiency. Once megaloblastic anemia has been diagnosed, the doctor will need to determine which vitamin deficiency is causing it. This is extremely important, because if a vitamin B12-deficient patient receives folate replacement only, then irreversible nerve injuries may develop. Even if blood tests for megaloblastic anemia are normal, patients with neurologic and psychiatric abnormalities that have no detectable cause should still be tested for vitamin B12 deficiency.

Often, vitamin B deficiencies cannot be determined by a history or symptoms alone. Blood tests are the primary indicators of both vitamin B12 and folic acid deficiencies, but even blood tests for these vitamins are not always straightforward:

Folic acid and vitamin B12 levels must always be measured at the same time because each vitamin may affect the other.
Folate levels may be temporarily low in some people who are not truly deficient.
Folate levels may temporarily rise in deficient people if they have just eaten foods containing the vitamin.
Antibiotics can interfere with B12 levels.

Measuring methylmalonic acid and homocysteine, substances in the blood that increase when levels of one or both vitamins are low, improves accuracy.

Tests for Pernicious Anemia. Once a vitamin B12 deficiency has been established and the doctor has not found any intestinal abnormalities or other factors to account for the deficiency, the doctor presumes a diagnosis of pernicious anemia. Pernicious anemia may also be diagnosed through various blood (such as complete blood count) or urine tests.

Pernicious anemia is treated with vitamin replacement, but the condition is easily missed, particularly in patients whose diets are rich in folic acid. Folic acid can mask the early symptoms of pernicious anemia but not cure it. Consequently the disease may persist until serious neurologic symptoms occur. With folic acid now a required additive in many commercial foods, some experts are concerned about an increased incidence in pernicious anemia.

Dietary Factors

Iron found in foods is either in the form of heme or non-heme iron:

Heme Iron. Foods containing heme iron are the best sources for increasing or maintaining healthy iron levels. Such foods include (in decreasing order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
Non-Heme Iron. Non-heme iron is less well-absorbed. About 60% of the iron in meat is non-heme (although meat itself helps absorb non-heme iron). Eggs, dairy products, and iron-containing vegetables have only the non-heme form. Such vegetable products 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.

The absorption of non-heme iron often depends on the food balances in meals. The following foods and cooking methods can enhance absorption of iron:

Meat and fish not only contain heme iron -- the best form for maintaining stores -- but they also help absorb non-heme iron.
Increasing intake of vitamin-C rich foods, such as orange juice, may enhance absorption of non-heme iron, although it is not clear if it improves iron stores in iron-deficient people. In any case, vitamin-C rich foods are healthy and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries.
Riboflavin (vitamin B2) may help enhance the response of hemoglobin to iron. Food sources include dairy products, liver, and dried fortified cereals.
Cooking methods can enhance iron stores. Cooking in cast iron pans and skillets is well-known to increase the iron content of food. According to one study, boiling, steaming, or stir-frying in utensils composed of any material significantly increased the release of non-heme iron stored in vegetables.
Vitamins B12 and folate are important for prevention of megaloblastic anemia and for good health in general. 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). As is the case with other B vitamins, however, 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 sources of vitamin B12.

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 now added to commercial grain products. Vitamins are usually made from folic acid, which is about twice as potent as folate. Many experts now recommend that adults have 400 mcg of folic acid daily -- considerably higher than standard recommendations of 400 mcg of folate. Women who are trying to conceive, who are pregnant, and who are breast-feeding should take 400 mcg of folic acid.

Click the icon to see an image of sources of folate.

The Recommended Daily Allowance (RDA) of iron for people who are not iron deficient varies by age group and other risk factors. (Iron supplements are rarely recommended in people without evidence of iron deficiency or anemia.) The RDA recommends these daily amounts of iron:

Children 1 - 3 years old: 10 mg
Teenage boys: 12 mg
Teenage girls and premenopausal women: 15 mg
Pregnant or nursing women: 30 mg
Adult men (up to age 50): 10 mg
Older men and women (over age 50): 10 mg

The main source of iron for an infant from birth to 1 year of age is in milk, from breast milk, iron-fortified infant formula, or cereal. The best methods for preventing iron deficiency during infancy are:

Breast-feeding and Iron-Supplemented Formulas. Mothers should be encouraged to breast-feed their babies for their first year. Up to half of the iron in breast milk is absorbed by the baby and is sufficient to prevent anemia for the first 4 - 6 months, assuming that the mother had adequate iron stores during pregnancy. Breast milk itself is low in iron, but if the mother's diet is healthy, vitamin C and lactose in the breast milk may enhance iron absorption. Breast-fed babies should have iron supplements after 4 - 6 weeks, even if they are still nursing.

Infants who are not breast-fed should start with iron-fortified formulas (7-12 mg/L). Most experts strongly discourage the use of low-iron formulas (less than 4.0 mg/L). Parents should discuss the best formula with their doctor. Children given iron supplements may have a slightly higher risk for diarrhea. Experts advise against cow's milk for the first year of life. When cereals are begun, they should be iron fortified.

Recommendations for Toddlers. Toddlers who did not have iron supplements during infancy should be checked for iron deficiency. After the first year, children should be given a varied diet that is rich in sources of iron, B vitamins, and vitamin C. Milk does not contain enough iron and can decrease children's appetite for iron-rich foods. Toddlers older than 1 year should not drink more than 2 cups of milk a day. A preference for apple juice over vitamin-C rich orange juice does not reduce iron absorption in children with any otherwise healthy diet.

Treatment

Oral iron supplements are the best way to restore iron levels for people who are iron deficient, but they should be used only when dietary measures have failed. However, iron supplements cannot correct anemias that are not due to iron deficiency.

One study reported that doctors prescribed iron pills for 64% of patients with anemia, without performing tests to confirm whether iron deficiency was actually the cause. The study suggested that iron replacement was appropriate in less than half of these patients. Iron replacement therapy can cause gastrointestinal problems, sometimes severe ones. Excess iron may also contribute to heart disease, diabetes, and certain cancers. Experts generally advise against iron supplements in anyone with a healthy diet and no indications of iron deficiency anemia. However, one study suggested that supplements help reduce fatigue in women with low iron stores but no signs of anemia.

Treatment of Anemia of Chronic Disease. In general, the best treatment for anemia of chronic diseases is treating the disease itself. In some cases, iron deficiency accompanies the condition and requires iron replacement. Erythropoietin, most often administered with intravenous iron, is used for some patients.

Treatment of Megaloblastic Anemia. The standard treatments for megaloblastic anemia are vitamin B12 injections and folic acid replacement.

Supplement Forms. To replace iron, the preferred forms of iron tablets are ferrous salts, usually ferrous sulfate (Feosol, Fer-In-Sol, Mol-Iron). Other forms include ferrous fumarate (Femiron, FerroSequels, Feostat, Fumerin, Hemocyte, Ircon), ferrous gluconate (Fergon, Ferralet, Simron), polysaccharide-iron complex (Niferex, Nu-Iron), and carbonyl iron (Elemental Iron, Feosol Caplet, Ferra-Cap). Specific brands and forms may have certain advantages. The following are some examples:

Prolonged-release ferrous sulfate (Slow Fe) may enhance iron absorption with fewer side effects than standard ferrous sulfate pills.
FerroSequels contains a stool softener, which helps prevent constipation.
Polysaccharide-iron complex has fewer side effects and equal absorption rates compared to ferrous salts. It is very expensive, however.
Carbonyl iron is composed of very fine tiny uniform spheres of iron powder and may prove to be less toxic than ferrous iron.
Coated or combination pills do not appear to offer any additional advantages and may hinder absorption of the iron.

Regimen. The general guidelines for iron replacement are as follows:

For adults, doctors usually advise one ferrous sulfate tablet (300 mg) three times a day.
Iron replacement doses for children with deficiencies are significantly lower. In general, they are given as drops or syrup administered three times a day. A single-dose daily regimen is showing promise. IMPORTANT: As few as three adult iron tablets can poison children, even fatally. This includes any form of iron pill.
No one, even adults, should take a double dose of iron if one is missed.

Other tips for taking iron are as follows:

For best absorption, iron should be taken between meals. (Iron may cause stomach and intestinal disturbances, however, and some experts believe that low doses of ferrous sulfate can be taken with food and are still absorbed but with fewer side effects.)
Always drink a full 8 ounces of fluid with an iron pill. Taking orange juice with an iron pill may help increase iron absorption. (Some doctors also recommend taking a vitamin C supplement with the iron pill.)
Tablets should be kept in a cool place. (Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.)

Full recovery takes 6 - 8 weeks. Recovery will take longer in people with internal bleeding that is not under control. Iron replacement therapy must continue for about 6 months, even if anemia has been reversed. Treatment must be continued indefinitely for people with chronic bleeding; in such cases, iron levels should be closely monitored.

Side Effects. Common side effects of iron supplements include the following:

Constipation and diarrhea are very common. They are rarely severe, although iron tablets can aggravate existing gastrointestinal problems such as ulcers and ulcerative colitis.
Nausea and vomiting may occur with high doses, but can be controlled by taking smaller amounts. Switching to ferrous gluconate may help some people with severe gastrointestinal problems.
Black stools are normal when taking iron tablets. In fact, if they do not turn black, the tablets may not be working effectively. This tends to be a more common problem with coated or long-acting iron tablets.
If the stools are tarry looking as well as black, if they have red streaks, or if cramps, sharp pains, or soreness in the stomach occur, gastrointestinal bleeding may be causing the iron deficiency and the patient should call the doctor promptly.
Acute iron poisoning is rare in adults but can be fatal in children who take adult-strength tablets.

Interactions with Other Drugs. Certain medications, including antacids, can reduce iron absorption. Iron tablets may also reduce the effectiveness of other drugs, including the antibiotics tetracycline, penicillamine, and ciprofloxacin and the Parkinson's disease drugs methyldopa, levodopa, and carbidopa. At least 2 hours should elapse between doses of these drugs and iron supplements.

Supplements. The following vitamin and mineral supplements may improve iron absorption:

Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores.
Some studies have found that the addition of zinc to iron supplements increases hemoglobin levels more than iron alone. Some evidence for this suggests that zinc affects a hormone called insulin-like growth factor-I (IGF-I), which plays a role in the regulation of red blood cell production.

In some cases, iron is administered through muscular injections or intravenously. Intravenous iron has the advantage of causing less gastrointestinal discomfort and inconvenience. It may be in the form of iron dextran (Dexferrum, InFed), sodium ferric gluconate complex in sucrose (Ferrlecit), or iron sucrose (Venofer). Ferrlecit or Venofer are proving to be at least equally effective and safer than iron dextran.

Candidates. The injected or intravenous forms should be limited to the following patients with iron deficiency:

People with iron deficiency anemia in whom oral therapy has clearly failed.
Patients with bleeding disorders in which blood loss continues to exceed the rate at which oral iron is absorbed.
In emergencies, when people need red blood cells but transfusion is not appropriate or available.
In people with serious gastrointestinal disorders, such as inflammatory bowel disease, who cannot take iron therapy by mouth.
People undergoing hemodialysis who receive supplemental erythropoietin therapy. Sodium ferric gluconate complex in sucrose (Ferrlecit) or iron sucrose (Venofer) is specifically approved as first-line therapy for these patients.

Certain patients, even if they meet these qualifications, may not be appropriate candidates or should be monitored closely for complications. They include:

Patients with any underlying autoimmune disease.
Malnourished patients who also have an underlying infection.
Patients who are at risk for iron overload.

Side Effects. Some side effects differ depending on how the iron is administered and include the following:

Muscular injections include pain at the site.
Intravenous administration can cause pain in the vein, flushing, and metallic taste, all of which are brief.

For both methods, side effects and serious complications can include:

Blood clots
Fever
Joint aches
Headache
Rashes
A delayed reaction of joint and muscle aches, headache, and malaise occurs 1 - 2 days after the infusion (most commonly with iron dextran) in about 10% of patients. These symptoms respond quickly to NSAIDs, such as ibuprofen or naproxen, in most people.
Iron toxicity. Symptoms include nausea, dizziness, and a sudden drop in blood pressure. Sodium ferric gluconate in sucrose (Ferrlecit) or iron sucrose (Venofer) may pose a lower risk for toxicity than iron dextran.
Allergic reactions. Allergic reactions that occur with intravenous iron can be very serious and, in rare cases, even fatal. Iron dextran appears to pose a much higher risk than sodium ferric gluconate complex in sucrose or iron sucrose, although allergic reactions can also occur with the latter forms.

Oral and injected iron should never be given at the same time. Intravenous iron therapy may be appropriate for some pregnant women who meet these requirements, depending on the pregnancy term and other factors.

Transfusions are used to replace blood loss due to injuries and during certain surgeries. They are also commonly used to treat severely anemic patients who have thalassemia, sickle cell disease, myelodysplastic syndromes, or other types of anemia. Some patients require frequent blood transfusions. Iron overload can be a side effect of these frequent blood transfusions. If left untreated, iron overload can lead to liver and heart damage.

Iron chelation therapy is used to remove the excess iron caused by blood transfusions. Patients take a drug that binds to the iron in the blood. The excess iron is then removed from the body by the kidneys. For many years, deferoxamine (Desferal) was the only drug used in chelation therapy. This drug is usually injected intravenously, using an infusion pump. The infusion can last 8 - 12 hours and may be needed 5 - 7 days a week until iron levels are normal. A new drug, deferasirox (Exjade), was approved in 2005 for children and adults as a once-daily treatment for iron overload due to blood transfusions. It does not require injections. Patients mix the deferasirox tablets in liquid and drink the medicine. Doctors hope that this new drug may make it easier for patients to tolerate chelation therapy. Studies have shown that deferasirox works as well as deferoxamine in ridding the body of excess iron.

Bloodless Medicine. Bloodless medicine and surgery is a new field designed to reduce or minimize blood loss and transfusions. It also attempts to address the problems in treating certain religious groups, such as Jehovah's Witnesses, who refuse transfusions. Some techniques involved in this field include new surgical procedures or drugs that minimize blood loss, the use of erythropoietin, volume expanders (administration of fluids to dilute blood), using tiny blood samples for testing, and methods (Cell Saver) for recovering and recycling blood during surgery.

Erythropoietin is the hormone that acts in the bone marrow to increase the production of red blood cells. It has been genetically engineered as recombinant human erythropoietin (rHuEPO) and is available as epoetin alfa (Epogen, Procrit, and Eprex). Novel erythropoiesis stimulating protein (NESP), also called darbepoetin alfa (Aranesp), lasts longer in the blood than epoetin alfa and requires fewer injections. These medications are also called “erythropoiesis-stimulating drugs.”

Levels of erythropoietin are reduced in anemia of chronic disease. Injections of synthetic erythropoietin can help increase the number of red blood cells in order to avoid receiving blood transfusions. Erythropoietin is used to treat anemia. It does not help improve anemia symptoms, fatigue, or quality of life for patients with cancer or HIV. This drug can cause serious side effects, including blood clots, and is approved only for treating patients with anemia related to the following conditions:

Cancer. For select patients, erythropoietin is used to treat the anemia associated with chemotherapy.
Chronic kidney failure. Erythropoietin is an important anemia treatment for patients with chronic kidney failure, including those on dialysis.
HIV/AIDS. Erythropoietin helps treat the anemia caused by zidovudine (AZT) therapy.

In November 2007, the Food and Drug Administration (FDA) made major changes to the prescribing information for erythropoiesis-stimulating drugs. The new labels describe in detail the risks that Aranesp, Epogen, and Procrit can pose to patients with cancer and chronic kidney disease. The FDA has also established separate dosing recommendations for each of these conditions.

Erythropoiesis-Stimulating Drugs and Cancer. Erythropoietin should be used only to treat anemia caused by chemotherapy -- not anemia due to other causes in patients with cancer. Erythropoietin treatment does not help prolong survival. In fact, these drugs can shorten survival time and cause tumors to grow faster. Discuss with your doctor whether an erythropoiesis-stimulating drug is appropriate for you.

Survival and tumor growth risks are especially pronounced for patients with advanced breast, head and neck, lymphoid, or non-small cell lung cancer when dosing attempts to achieve a hemoglobin level of 12 g/dL or greater. However, there may be similar risks for patients dosed to less than 12 g/dL. (The American Society of Clinical Oncology and the American Society of Hematology recommend starting erythropoietin when a patient’s hemoglobin level falls to less than 10 g/dL.) The doctor should use the lowest effective dose and erythropoietin treatment should be stopped as soon as the chemotherapy course is completed.

Erythropoiesis-Stimulating Drugs and Chronic Kidney Failure. For patients with chronic kidney failure, the FDA recommends that erythropoiesis-stimulating drugs be used to maintain hemoglobin levels between 10 - 12 g/dL. (The exact level within this range varies by individual.) There is a greater risk of death and serious cardiovascular events, such as heart attack, stroke, and heart failure when these drugs are used to achieve higher hemoglobin levels (13.5 - 14g/dL) compared to lower hemoglobin levels (10- 11.3 g/dL).

Warning Symptoms. Contact your doctor if you experience any of the following symptoms while being treated with an erythropoiesis-stimulating drug:

Pain or swelling in the legs
Worsening in shortness of breath
Increases in blood pressure (be sure to regularly monitor your blood pressure)
Dizziness or loss of consciousness
Extreme fatigue
Blood clots in hemodialysis vascular access ports

H. pylori, the bacteria that cause peptic ulcers, is associated with anemias from vitamin B12 deficiency and iron deficiency. People whose anemia is associated with H. pylori infection, however, do not respond to iron therapy. Studies indicate that the eradication of H. pylori infection with antibiotics can reverse anemia in such patients and may lead to long-lasting recovery.

Vitamin B12 Therapy. Injections of vitamin B12 (usually formulations called cyanocobalamin or hydroxocobalamin), oral folic acid therapy, or both, rapidly reverse the production of abnormally large red blood cells. (Treatments still may not reverse neurologic symptoms if they are extensive or have continued for too long.)

A typical regimen for vitamin B12 replacement is as follows:

If diagnostic tests indicate pernicious anemia and neurologic symptoms are present, vitamin B12 therapy should begin immediately. (Usually vitamin therapy is not an emergency, however.)
Cyanocobalamin or hydroxocobalamin injections are given every day for up to 2 weeks. Only small doses are needed.
This is followed by injections twice a week for another month. (Hemoglobin levels rise in the first week of therapy and reach normal levels in 8 weeks.)
After that, injections are usually given monthly.
During recovery, there is a risk of potassium deficiency as the new red cells take up the existing supply, so potassium supplements may be needed.

Other forms of vitamin B12 are also available and can be used to treat B12 deficiency. Vitamin B12 nasal spray offers the same advantage of avoiding the need for absorbing the vitamin in the GI tract without the inconvenience of the injections. Some experts feel that even oral B12 in high doses (2,000 mcg/day) can maintain B12 levels once the deficiency is treated.

The injections are safe and have no adverse side effects, but they may mask an underlying medical or psychological condition.

Some doctors give vitamin B12 injections for fatigue and other vague symptoms of general mild discomfort. In one study, 10% of patients in a rural clinic were given regular B12 shots, with 6% of patients having no medical need for them.

Folic Acid Treatment. Folate deficiency is easily remedied in 4 - 5 weeks with daily oral doses of 1 - 2 milligrams of folic acid. Many doctors give vitamin B12 along with folic acid unless B12 deficiency is definitely ruled out.

Resources

www.anemia.org -- National Anemia Action Council
www.nhlbi.nih.gov -- National Heart, Lung and Blood Institute
www.irondisorders.org -- Iron Disorders Institute
www.thalassemia.org -- Cooley's Anemia Foundation
www.aamds.org -- Aplastic Anemia & MDS International Foundation
http://kidney.niddk.nih.gov/kudiseases/pubs/anemia -- National Kidney and Urologic Diseases Clearinghouse (Anemia in kidney disease and dialysis)

References

Brotanek JM, Gosz J, Weitzman M, Flores G. Iron deficiency in early childhood in the United States: risk factors and racial/ethnic disparities. Pediatrics. 2007 Sep;120(3):568-75.

Killip S, Bennett JM, Chambers MD. Iron deficiency anemia. Am Fam Physician. 2007 Mar 1;75(5):671-8.

Komajda M, Anker SD, Charlesworth A, et al. The impact of new onset anaemia on morbidity and mortality in chronic heart failure: results from COMET. Eur Heart J. 2006 Jun;27(12):1440-6. Epub 2006 May 22.

KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007 Sep;50(3):471-530.

Maguire JL, deVeber G, Parkin PC. Association between iron-deficiency anemia and stroke in young children. Pediatrics. 2007 Nov;120(5):1053-7.

Martí-Carvajal AJ, Solà I. Treatment for anemia in people with AIDS. Cochrane Database Syst Rev. 2007 Jan 24;(1):CD004776.

Notebaert E, Chauny JM, Albert M. Short-term benefits and risks of intravenous iron: a systematic review and meta-analysis. Transfusion. 2007 Oct;47(10):1905-18.

Reveiz L, Gyte GM, Cuervo LG. Treatments for iron-deficiency anaemia in pregnancy. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003094.

Rizzo JD, Somerfield MR, Hagerty KL, et al. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update. J Clin Oncol. 2007 Dec 21 [Epub ahead of print]

Review Date:
1/1/2008
Reviewed By:
Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

A.D.A.M. Copyright

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Osteoarthritis

FitSugar — Wed, 08 Oct 2008 17:34:56 -0700

In This Report

Highlights
Introduction
Causes
Symptoms
Conditions with Similar Sym...
Risk Factors
Diagnosis
Prognosis
Lifestyle Changes
Medications
Alternative and Complementa...
Surgery
Resources
References

HEALTH GUIDE REFERENCE FROM A.D.A.M

Highlights

Pain Medications

Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors work equally well for pain management, but both types of drugs increase the risk for heart attacks, according to an important report from the U.S. Agency for Healthcare Quality and Research.
The prescription NSAID diclofenac (Voltaren, Cataflam) may present a higher risk for heart attack than other NSAIDs, suggests a 2006 Journal of the American Medical Association study.
Standard osteoarthritis medications provide moderate pain relief for only 2 - 3 weeks, suggests a 2007 review in the European Journal of Pain.

Acupuncture

Acupuncture may be helpful for people with knee and hip osteoarthritis, according to several 2006 studies:

An Annals of Internal Medicine study of 1,007 people with chronic osteoarthritis knee pain indicated that patients who received acupuncture plus standard care had greater improvement than those who received only physical therapy and anti-inflammatory drugs.
An Arthritis and Rheumatism study of 3,663 patients with chronic osteoarthritis knee or hip pain suggested that acupuncture plus routine care can provide significant improvements in pain relief and quality of life. In both studies, the benefits of acupuncture were sustained for up to 6 months after treatment completion.

Exercise and Knee Osteoarthritis

Weight-bearing exercise (walking, jogging) neither prevents nor increases the risk of knee osteoarthritis in healthy middle-aged and elderly people, suggests a 2007 study in Arthritis and Rheumatism.

Risk of Hip Osteoarthritis

About 1 in 4 Americans can expect to develop osteoarthritis of the hip at some point in life, according to research presented at the 2006 American College of Rheumatology annual meeting. Body weight is a factor. People who are normal weight have a 20% risk, compared to those who are overweight (25%) or obese (39%).

Introduction

Osteoarthritis, also known as degenerative joint disease, is the most common form of arthritis. Scientists now believe osteoarthritis results from a combination of genetic abnormalities and joint injuries. In this disorder, an affected joint experiences a progressive loss of cartilage, the slippery material that cushions the ends of bones.

Osteoarthritis is a chronic disease of the joint cartilage and bone, often thought to result from "wear and tear" on a joint, although there are other causes such as congenital defects, trauma, and metabolic disorders. Joints appear larger, are stiff and painful, and usually feel worse with increased use throughout the day.

As a result, the bone beneath the cartilage undergoes changes that lead to bony overgrowth. The tissue that lines the joint can become inflamed, the ligaments can loosen, and the associated muscles can weaken. The patient experiences pain when using the joint. In addition to humans, nearly all vertebrates suffer from osteoarthritis, including porpoises and whales, as did long-extinct terrestrial travelers such as dinosaurs.

Click the icon to see an animation about osteoarthritis.

Joints are designed to provide flexibility, support, stability, and protection. These functions, essential for normal and painless movement, are primarily supplied by specific parts of the joint: the synovium and cartilage.

Synovium. The synovium is a membrane that surrounds the entire joint. It is filled with synovial fluid, a lubricating liquid that supplies nutrients and oxygen to cartilage.

Cartilage. The cartilage is a slippery tissue that coats the ends of the bones. Cartilage is one of the few tissues in the body that does not have its own blood supply. It has a number of essential components:

Click the icon to see an image of the synovial membrane and cartilage in the knee joint.

Chondrocytes. Chondrocytes, the basic cartilage cells, are critical for balance and function.
Water. Cartilage contains a high percentage of water, although it decreases with age. About 85% of cartilage is water in young people, and about 70% is water in older individuals.
Proteoglycans. These are large molecules that help make up cartilage. Their important value is their capacity to bond to water, which ensures the high-fluid content in cartilage.
Collagen. This is the critical protein in cartilage. It forms a mesh to give support and flexibility to the joint. Collagen is the main protein found in all the connective tissues of the body, including the muscles, ligaments, and tendons.

The combination of the collagen meshwork and the high water content, tightly bound by proteoglycans, creates a resilient and slippery pad in the joint, which resists the compression between bones during muscle movement. The synovial fluid lubricates and provides oxygen and nutrients to the bloodless cartilage.

Deterioration of Cartilage. Osteoarthritis develops when cartilage in a joint deteriorates. The process is usually slow.

In the early stages of the disease the surface of the cartilage, or even the synovium in some people, becomes inflamed and swollen. There is a loss of proteoglycan molecules and other tissue components that cause water loss. Fissures and pits appear in the cartilage.
As the disease progresses and more tissue is lost, the cartilage loses elasticity and fluid. It becomes increasingly prone to damage due to repetitive use and injury.
Eventually large amounts of cartilage are destroyed, leaving the ends of the bone within the joint unprotected.

To compound the process, bone around arthritic joints is not structurally normal. As the body tries to repair damage to the cartilage, problems can develop:

Clusters of damaged cells or fluid-filled cysts may form around the bony areas or near the fissures.
Fluid pockets may also form within the bone marrow itself, causing swelling. The marrow, which runs up through the center of bone, is rich in nerve fibers, and such injuries may be an important source of pain in many patients with osteoarthritis.
Bone cells may respond to damage by multiplying, growing, and forming dense, misshapen plates around exposed areas.
At the margins of the joint, the bone may produce outcroppings, on which new cartilage cells (chondrocytes) proliferate and grow abnormally.

Unlike some other types of arthritis, such as rheumatoid arthritis, osteoarthritis does not spread through the entire body. (In other words, it is not systemic.) Rather, it affects one or several joints. Osteoarthritis affects joints differently depending on their location in the body.

Osteoarthritis is commonly found in joints of the fingers, feet, knees, hips, and spine.
It sometimes occurs in the wrist, elbows, shoulders, and jaw, but is not common in these locations.

Causes

The biologic factors leading to the deterioration of cartilage in osteoarthritis are not entirely understood. Many experts believe that osteoarthritis results from a genetic susceptibility that causes some biologic response to injuries to the joint, which in turn leads to progressive deterioration of cartilage. In addition, the ability to make repairs becomes progressively limited as cartilage cells age.

Although osteoarthritis generally accompanies aging, osteoarthritic cartilage is chemically different from normal aged cartilage. As chondrocytes (the cells that make up cartilage) age, they lose their ability to make repairs and produce more cartilage. This process may play an important role in the development and progression of osteoarthritis.

Researchers report a high correlation of osteoarthritis between parents and children or between siblings. Genetic factors are thought to be involved in about half of osteoarthritis cases in the hands and hips and a somewhat lower percentage of cases in the knee. A number of genes are under investigation that might contribute to an inherited risk.

For example, mutations in the ank gene may be important in some cases. The ank gene regulates pyrophosphate, a chemical that inhibits the formation of mineral deposits, and may protect the cartilage in joints. Mutations in the ank gene then may result in lower pyrophosphate levels in the joint, leading to accumulation of mineral deposits and arthritis. (About 60% of people with osteoarthritis have mineral deposits in their cartilage.)

Another gene, called the osteoprotegerin gene, is important in regulating bone and cartilage formation. Mutations in this gene may play a role in osteoarthritis.

The inflammatory response is an overreaction of the immune system to an injury or other assault in the body, such as an infection. This response causes specific immune factors, called cytokines, to gather in injured areas and cause inflammation and damage to body tissue and cells. The inflammatory response plays an important role in rheumatoid arthritis and other muscle and joint problems associated with autoimmune diseases. It has generally been believed that inflammation plays at most a minor role in osteoarthritis and is more likely to be a result -- not a cause -- of the disease.

However, recent studies suggest that inflammation may play an important role in the progression of osteoarthritis and its chronic nature. For example, a 2003 study found evidence of severe inflammation in the lining of the joints in 30% of patients with osteoarthritis. Still, the effects of the inflammatory response in osteoarthritis are likely to be different from those in rheumatoid arthritis and less severe.

Some theories on how this response may contribute to osteoarthritis involve overproduction of enzymes called matrix metalloproteinases or MMPs (also called collagenases). In large amounts they break down collagen, the building blocks of cartilage. Some studies suggest that immune factors called vascular endothelial growth factor (VEGF) are overproduced during the inflammatory response and in turn increase production of MMPs.

Another theory suggests that the inflammatory response is triggered by the changes and injuries in the bone that occur during osteoarthritis. According to this theory, immune factors released in this process diffuse into the cartilage, where they suppress cartilage cell growth and activate MMPs.

Joint injuries are the starting point in the disease process. Osteoarthritis sometimes develops years after a single traumatic injury to or near a joint. One large study found that by age 65, osteoarthritis developed in almost 14% of those who had joint injuries as young adults, compared to just 6% in those without earlier injuries. Patients with knee injuries were five times more likely to have osteoarthritis in the injured knee than those without injuries, and patients with hip injuries were more than three times more likely to develop arthritis in the injured hip. Proper treatment of injuries, such as surgical repair of ligament tears in the knee with a strong rehabilitation approach, may help to prevent the development of osteoarthritis.

Other causes of osteoarthritis include:

Bleeding disorders such as hemophilia that cause bleeding to occur in the joint
Disorders such as avascular necrosis that block the blood supply near the joint
Complications of persistent, inflammatory arthritic conditions, particularly chronic gout, pseudogout, or rheumatoid arthritis
Conditions that cause iron build-up in the joints such as hemochromatosis

Symptoms

The pain of osteoarthritis typically begins gradually and progresses slowly over many years. People under age 40 may have the condition with no symptoms at all. Osteoarthritis is commonly identified by the following symptoms:

The most common symptom of osteoarthritis in any joint is pain that worsens during activity and gets better during rest. As the disease advances, the pain may occur even when the joint is at rest.
Pain is generally described as aching, stiffness, and loss of mobility.
The pain may behave like a roller coaster, with bad spells followed by periods of relative relief.
Pain seems to increase in humid weather.
Some people experience muscle spasm and contractions in the tendons.
Osteoarthritis in the knee may cause a crackling-like noise (called crepitus) when moved.

Hand. Osteoarthritis of the hand occurs most often in older women and may be inherited within families. The following joints are most frequently affected:

Distal interphalangeal (DIP) joint. The first joint below the fingertips is the most common location of osteoarthritis of the hand. These joints can develop bony growths known as Heberden's nodes.
Carpometacarpal (CMC) joint. The joint at the base of the thumb, where the thumb joint connects with the wrist, is the second most common location.
Proximal interphalangeal (PIP) joint. The middle joints of the fingers can also develop osteoarthritis. These joints may develop small, solid lumps (nodules) known as Bouchard's nodes.

Click the icon to see an image of osteoarthritis.

Recent studies suggest that osteoarthritis of the hand may predict the later development of osteoarthritis in the hip or knee. A 2005 study found that patients with hand osteoarthritis were three times more likely to develop hip arthritis. Osteoarthritis of the hand also slightly increased the risk for knee osteoarthritis.

Knee. Osteoarthritis is particularly debilitating in the weight-bearing joints of the knees. The joint is usually stable until the disease reaches an advanced stage when the knee becomes enlarged and swollen. Although painful, the arthritic knee usually retains reasonable flexibility.

Osteoarthritis can cause loss of cartilage in the knee. The meniscus, the cartilage pad between the joint formed by the thighbone and the shinbone, plays an important role in protecting the joint. It acts as a shock absorber. In knee surgery called meniscectomy, the doctor removes the damaged cartilage. However, a 2006 study suggested that preserving the meniscus, even if it is damaged, is better than removing it. Researchers showed that even a small amount of meniscus helps protect the joint and prevent osteoarthritis from worsening. Experts recommend that patients try lifestyle changes (exercise and weight loss), braces, and medication before undergoing knee surgery.

Click the icon to see an image of the knee joint.

Hips. About 1 in 4 people will develop hip arthritis over the course of their lifetime. Being obese increases the risk. Osteoarthritis frequently strikes the weight-bearing joints in one or both hips. Pain develops slowly, usually in the groin and on the outside of the hips, or sometimes in the buttocks. The pain also may radiate to the knee, confusing the diagnosis. Those with osteoarthritis of the hip often have a restricted range of motion (particularly when trying to rotate the hip) and walk with a limp, because they slightly turn the affected leg to avoid pain.

Click the icon to see an image of the hip joint.

Spine. Osteoarthritis may affect the cartilage in the disks that form cushions between the bones of the spine, the moving joints of the spine itself, or both. Osteoarthritis in any of these locations can cause pain, muscle spasms, and diminished mobility. In some cases, the nerves may become pinched, which also produces pain. Advanced disease may result in numbness and muscle weakness. Osteoarthritis of the spine is most troublesome when it occurs in the lower back or in the neck, where it can cause difficulty in swallowing.

Click the icon to see an image of the spine.

Shoulder. Osteoarthritis is less common in the shoulder area than in other joints, but it may develop in the shoulder joint (the glenohumeral joint). In such cases, it is most often associated with a previous injury, and patients gradually develop pain and stiffness in the back of the shoulder. Osteoarthritis also can develop in the acromioclavicular (AC) joint, which is between the shoulder blade and the collarbone. However, it rarely causes symptoms in this location.

Conditions with Similar Symptoms

Numerous conditions have symptoms of joint aches and pains. Something as benign as sleeping on a bad mattress to the serious afflictions associated with cancer can mirror symptoms of osteoarthritis. Other problems that can cause aches and pains in the joints include physical injuries, infections, tendinitis, and poor circulation. A number of rare genetic diseases attack the joints.

Osteoarthritis can generally be distinguished from other joint diseases by considering several factors together:

Osteoarthritis usually occurs in older people and is located in only one or a few joints
The joints are less inflamed than in other arthritic conditions
Progression of pain is usually gradual.

A few of the most common disorders that can be confused with, or may even accompany, osteoarthritis are discussed below.

Osteoarthritis may be confused with rheumatoid arthritis, particularly when osteoarthritis affects multiple joints in the body. Rheumatoid arthritis begins in the synovial membrane rather than the cartilage. It normally occurs earlier in life than osteoarthritis, often striking people in their 30s and 40s. Rheumatoid arthritis affects many joints, and often occurs symmetrically on both sides of the body. People generally have morning stiffness that lasts for at least an hour. (Stiffness from osteoarthritis usually clears up within half an hour.)

X-rays show changes in the bones that differ from those occurring in osteoarthritis. In rheumatoid arthritis, blood tests often show a specific antibody, known as rheumatoid factor, which is not present with osteoarthritis. In another blood test, levels of a factor called erythrocyte sedimentation rate (ESR) are often elevated in rheumatoid arthritis, but they are generally normal in osteoarthritis. Rheumatoid arthritis also does not usually show up in the fingertips where osteoarthritis is common.

Rheumatoid arthritis is a body-wide (systemic) autoimmune disease that initially attacks the synovium, a connective tissue membrane that lines the cavity between joints and secretes a lubricating fluid.

Click the icon to see an image of osteoarthritis vs. rheumatoid arthritis.

Chondrocalcinosis is a disease in which certain calcium crystals known as CPPD (calcium pyrophosphate dihydrate) are deposited in the joints. It affects about 25% of the population and can accompany and even worsen osteoarthritis. The problem has been called pseudogout or pseudo-osteoarthritis, in the latter case particularly when it affects the knees. A doctor can usually differentiate between the two disorders, however, because chondrocalcinosis usually damages other joints (such as wrists, elbows, and shoulders) that are not usually affected by osteoarthritis. The condition may explain why some patients with osteoarthritis receive benefit from colchicine, a drug used for gout and other crystal-induced joint diseases.

Charcot's joint occurs when an underlying disease, usually diabetes, causes nerve damage in the joint, which leads to swelling, bleeding, increased temperature, and changes in bone. There may be a loss of sensation that leads to an increased risk for injury from overuse.

Risk Factors

Osteoarthritis is the most common type of arthritis. In the U.S., about 12.1% of Americans (21 million people) age 25 and older have osteoarthritis. The prevalence in osteoarthritis increases as people age. Experts estimate that by 2030, 20% of Americans (72 million people) age 65 years and older will be at risk for developing osteoarthritis.

Before age 45, osteoarthritis occurs more frequently in males (although it is not common in younger adults). After age 55, it develops more often in females. In a 2000 study, 33% of women had osteoarthritis compared to 25% of men. Some research suggests that women may also experience greater muscle and joint pain, in general, than men. And, women also tend to be undertreated for pain compared to men. The causes of such differences in pain sensitivity and treatment are largely unknown and most likely are due to a complicated mix of biologic, psychologic, and social factors.

The incidence is highest in lower educational levels. In a 2000 study, 41% of adults with less than a high school education had arthritis compared to 21% of college graduates.

Although the average rate of osteoarthritis among older adults in the U.S. is 60%, it can vary widely in certain geographical regions. In the U.S., the rates in older adults are lowest (34%) in Hawaii and highest (70%) in Alabama. In general, the highest prevalence of arthritis in America occurs in the central and northwestern states.

The rate of osteoarthritis varies by ethnic group. In the U.S., Caucasians and African-Americans have higher rates of arthritis than Hispanics or other ethnic groups. Osteoarthritis also tends to favor specific joints over others in certain ethnic groups. The following are some examples:

Older African-American men are about 33% more likely than Caucasian men to have hip osteoarthritis. In one study, although men in both groups had equal risks for arthritic knees, African-American men were more likely to have arthritis in both knees and to have more severe cases. Although comparable disparities in knee arthritis were observed between African-American and Caucasian women, they might be explained by greater average weight among African-American women. The study could not account for the differences among men, however.
Asians appear to have a higher incidence of osteoarthritis in the knee, an equal risk for osteoarthritis in the spine, and a lower risk for osteoarthritis in the hips than Caucasians.

Genes that determine the angles, amount of force, and other structural factors in the hip joints, or genes that regulate the chemistry in the joints, may account for ethnic differences.

Some researchers suggest that a number of people have anatomical abnormalities, such as mismatched surfaces on the joints, which could be damaged over time by abnormal stress. Legs of unequal length or skewed feet can cause jerky movement and may cause osteoarthritis. One study reported that those whose knees bent inward ("knock-kneed") or outward ("bow-legged"), for example, were more likely to have progressive osteoarthritis of the knee.

Obesity, defined as being 20% over one's healthy weight, places people (particularly women) at increased risk for osteoarthritis. It also worsens osteoarthritis once deterioration begins. This higher risk is due to increased weight on the joints. However, being obese also increases the risk for osteoarthritis in the fingers as well as the knees and hips, suggesting that being overweight may contribute to osteoarthritis in other ways. Some research indicates that obesity may produce an inflammatory response, which is now a major suspect in age-related diseases -- not only osteoarthritis but also heart disease. [See In-Depth Report #53: Weight control and diet.]

Because injuries can trigger the disease process, people whose work or leisure activities place them at risk for muscle and joint injuries may face a higher risk for osteoarthritis later on.

Workers at Higher Risk. Certain occupations that require repeated stressful motions (such as squatting or kneeling with heavy lifting) can contribute to deterioration of cartilage. One study suggested that workers whose jobs require kneeling or squatting for more than an hour a day are at high risk for knee osteoarthritis. (In the study, jobs that involved heaving lifting, climbing stairs, or walking also posed some, but not as high, a risk. Being heavier compounded the chances for osteoarthritis.)

Exercise. There has been some question about the role of strenuous exercise in osteoarthritis. Sports that definitely pose a higher risk for osteoarthritis are those that require repetitive or direct joint impact (such as football), twisting, or both (baseball pitching, soccer).

Marathon runners, however, have a relatively low rate of osteoarthritis. Some scientists speculate that running enhances cartilage health because the rhythmical compression of cartilage expels wastes and promotes absorption of nutrients.

In any case, regular and moderate exercise is important for everyone and does not increase the risk for osteoarthritis. In fact, a 2006 study of middle-aged and elderly people found that recreational weight-bearing exercise (walking, jogging) neither protects against nor increases the risk for osteoarthritis. Furthermore, many factors associated with a sedentary life (muscle weakness, obesity) are associated with a higher risk for osteoarthritis.

Diagnosis

Osteoarthritis is often visible in x-rays. Cartilage loss is indicated by certain images:

If the normal space between the bones in a joint is narrowed.
If there is an abnormal increase in bone density.
If bony projections, cysts, or erosions are evident.
X-rays can also reveal any cysts that might develop in osteoarthritic joints. If other conditions are suspected or if the diagnosis is uncertain, additional tests are necessary.
An MRI may show evidence of osteoarthritis that x-rays miss.

X-rays are a form of electromagnetic radiation (like light); they are of higher energy, however, and can penetrate the body to form an image on film. Structures that are dense (such as bone) will appear white, air will be black, and other structures will be shades of gray depending on density. X-rays can provide information about obstructions, tumors, and other diseases, especially when coupled with the use of barium and air contrast within the bowel.

Blood test results may help diagnose or rule out osteoarthritis. Some examples include:

Elevated levels of rheumatoid factor (specific antibodies in the synovium) and so-called erythrocyte sedimentation rates (ESR or sed rate) indicate rheumatoid arthritis.
Hyaluronic acid (HA), a joint lubricant, is being tested as a potential biomarker for osteoarthritis. High levels of HA may indicate increased risk for osteoarthritis.
Elevated levels of a factor called C-reactive protein, which is produced by the liver in response to inflammation, are proving to be good predictors of osteoarthritic progression in the knee.

If the diagnosis is uncertain or infection is suspected, a doctor may attempt to withdraw synovial fluid from the joint using a needle. There will not be enough fluid to withdraw if the joint is normal. If the doctor can withdraw fluid, problems are likely, and the fluid will be tested for factors that might confirm or rule out osteoarthritis:

Cartilage cells in the fluid are signs of osteoarthritis.
A high white blood cell count is a sign of infection.
High uric acid in the fluid is an indication of gout.

Click the icon to see an animation on gout.

Other factors may be present that suggest different arthritic conditions, including Lyme disease and rheumatoid arthritis.
In people with known osteoarthritis, researchers may look for certain factors in synovial fluid (sulfated glycosaminoglycan, keratin sulfate, and link protein) that can suggest a more or less severe condition.

Prognosis

Osteoarthritis itself is not life-threatening, but a person's quality of life can significantly deteriorate from pain and loss of mobility. The negative effects on activities and physical and mental health are significant regardless of age, educational level, or gender. Only heart disease has a greater impact on work. Five percent of those who leave the work force do so because of osteoarthritis. Unless alleviated by medication or corrected by surgery, advanced osteoarthritis can force the patient to forgo even relatively low-impact activities, such as walking. No treatment can cure osteoarthritis, and none can alter its progression with certainty, but many available therapies can relieve symptoms and significantly improve the quality of life.

Lifestyle Changes

Many doctors suggest first trying lifestyle changes to reduce stress on affected joints. Physical therapy and supportive devices can be helpful. Intensive education on how to protect and care for an osteoarthritic joint may help patients avoid multiple visits to their doctor.

Once osteoarthritis has been diagnosed, patients should reduce shock to the affected joint. Hammering away at deteriorating cartilage is likely to speed up the degeneration. People in occupations requiring repetitive and stressful movement should explore ways to reduce trauma. Adjusting the work area or substituting tasks that produce less stress on joints helps reduce shock.

Joints require motion to stay healthy. Long periods of inactivity cause the arthritic joint to stiffen and the adjoining tissue to atrophy. A moderate exercise program that includes low-impact aerobics and power and strength training has benefits for osteoarthritic patients, even if exercise does not slow down the disease progression. Exercise helps:

Reduce stiffness and increase flexibility. It may also help improve the strength and elasticity of knee cartilage.
Promote weight loss.
Improve strength, which in turn improves balance and endurance.
Reduce stress and improve feelings of well being, which helps patients cope with the emotional burden of pain.

Exercise especially helps patients with mild-to-moderate osteoarthritis in the hip or in the knee. Many patients who begin an aerobic or resistance exercise program report less disability and pain. They are better able to perform daily chores and remain more independent than their inactive peers. Older patients and those with medical problems should always check with their doctor before embarking on an exercise program.

Three types of exercise are best for people with osteoarthritis:

Strengthening exercise
Range-of-motion exercise
Aerobic, or endurance, exercise

Strengthening Exercise. Strengthening exercises include isometric exercises (pushing or pulling against static resistance). Isometric training builds muscle strength while burning fat, helps maintain bone density, and improves digestion.

Some experts encourage patients to emphasize strengthening leg muscles as a first treatment step, before using pain relievers. Patients who rely on painkilling drugs may overuse knees, which do not have muscle tissue sufficiently strong enough to protect the joints from further damage. However, some studies suggest that building up thigh muscles may worsen osteoarthritis in people whose knees are misaligned (for instance those who are "bow-legged" or "knock-kneed"). Such individuals should check with a physical therapist for the best options. Strengthening the thigh muscles is certainly protective for people who have not yet developed osteoarthritis.

Exercise, such as weightlifting, helps build muscle that is usually lost with age and puts stress on bones, helping keep them strong and healthy.

Range-of-Motion Exercise. These exercises increase the amount of movement in a joint and muscle. In general, they are stretching exercises. The best examples are yoga and tai chi, which focus on flexibility, balance, and proper breathing. In one study, older adults who practiced the gentle movement, breathing, and meditation exercises of tai chi for 10 weeks reported less pain than their peers who did not learn the technique.

Click the icon to see an image of cholesterol.

Aerobic (Endurance) Exercise. These exercises help control weight and may reduce inflammation in some joints. Low-impact workouts also help stabilize and support the joint. Cycling and walking are beneficial, and swimming or exercising in water is highly recommended for people with arthritis. (Patients with osteoarthritis should avoid high-impact sports, such as jogging, tennis, and racquetball.)

Click the icon to see an image of exercise.

In addition to exercise, manipulation of muscles and joints by a trained therapist may be helpful. In one study, patients who had a combination of physical therapy and an exercise program reported 30 - 40% improvement after only two to four visits.

Overweight patients with osteoarthritis can lessen the shock on their joints by losing weight. Knees, for example, sustain an impact three to five times the body weight when descending stairs. Losing 5 pounds of weight can eliminate 20 pounds of stress on the knee. The greater the weight loss, the greater the benefit. [See In-Depth Report #53:Weight loss and diet.]

Plant Chemicals. A large study reported significant improvement in symptoms when patients took extracts from avocados and soybeans called saponins. Another study noted that although these substances did not relieve hip pain, they did slow progression of joint deterioration. Soy has chemicals called isoflavones that may have additional benefits, such as preventing bone loss.

Fish Oil and Omega-3 Fatty Acids. Omega-3 fatty acids, which are found in fish oil, canola oil, black currant or primrose seed oils, and flax seeds, have anti-inflammatory properties and may help protect against cartilage deterioration. Supplements of omega-3 fatty acids, such as docosahexaenoic (DHA) and eicosapentaneoic (EPA) acids that are found in fish oil, are available.

Vitamin B3 (Niacin). Some research suggests that vitamin B3 may have some benefits for people with osteoarthritis.

Click the icon to see an image of the benefits of vitamin B3.

Click the icon to see an image of the sources of vitamin B3.

Calcium and Vitamin D. Calcium and vitamin D are important for strong bones. Although osteoarthritis is primarily a disease of joints, bone strength is also important, particularly in older people.

Click the icon to see an image of osteoporosis.

Many experts now recommend 1,000 mg of calcium a day for most adults and 1,200 - 1,500 mg for adolescents. Pregnant women, postmenopausal women not on estrogen therapy, and those on corticosteroids should get 1,500 mg per day; breast feeding women should get 2,000 mg/day. Because calcium supplements increase the risk for kidney stones, an upper limit of 2,500 mg is recommended.

Current guidelines recommend 400 IU of vitamin D per day and 600 IU per day after age 60. Lack of sunlight and unhealthy diets contribute to deficiencies in vitamin D. Good dietary sources include fortified milk, sardines, herring, salmon, tuna, liver, dairy products, and egg yolks. Although supplements are often necessary, vitamin D can be toxic in high doses, and no one should take more than 1,200 IU per day.

Selenium. Selenium is a trace mineral found in grains, nuts, vegetables, and some meats and seafood. Preliminary research suggests that people who do not get enough selenium in their diet may be more likely to develop knee osteoarthritis. Researchers are investigating whether selenium supplements may help protect against osteoarthritis and prevent it from worsening.

Ice. When a joint is inflamed (particularly in the knee) applying ice for 20 - 30 minutes can be effective. If an ice pack is not available, a package of frozen vegetables works just as well.

Heat Treatments. Patients afflicted with osteoarthritis of the hands can relieve pain with hot soaks and warm paraffin application. Osteoarthritis of the hip can be treated with heating pads.

Interestingly, moving to a warm climate does not seem to make much difference. According to one study, people who live in warmer places are actually more sensitive to small shifts in temperature than people who live in cold damp climates, and they experience pain as readily as their northern peers do in response to larger temperature shifts.

A wide variety of devices are available to help support and protect joints:

Splints or braces, worn while the joint is at rest or in use, help align joints and properly distribute weight. They are used most frequently to treat arthritic hands, wrists, knees, ankles, and feet. Many of these devices allow some movement within the affected joint and do not restrict nearby joints. They are usually made from lightweight metal, leather, elastic, foam, and moldable plastic with easy-to-use Velcro straps. Any brace, splint, or other device for joint protection should be custom-fitted by a physical or occupational therapist, or an orthotist. Poorly fitting or improperly used orthoses can cause more harm than good.
Using elastic supports on affected joints may benefit some people. For example, in one study, wearing insoles plus elastic straps supporting the ankle joint helped overweight women with osteoarthritis in the knee. It is important to consult with a doctor about how to use elastic supports.
Wrapping the knee with special therapeutic tape that provides support to specific parts of the joint may be effective. In one trial, patients experienced a 40% reduction in pain within a few days. They wore the tape for 3 weeks, and pain relief continued for 3 more weeks following treatment. The tape should be applied by physical therapists or other trained health professionals. Longer-term studies are needed to determine any continuous benefits.
Wearing shock-absorbing soles in shoes or orthopedic shoes can help in daily activities and during gentle exercise. Heel wedges in the shoes can sometimes help patients avoid knee replacement surgery.
A neck brace or corset may relieve back pain.
A firm mattress also often proves beneficial.
In extreme cases of back pain, lying in traction might be necessary.
Canes, crutches, or walkers offer benefits to patients with advanced arthritis.
Specially designed hip protectors, worn under the clothes, can also protect against hip fractures in elderly patients with impaired mobility who are apt to fall.

Medications

Many medications are available for relieving the symptoms of osteoarthritis. A major analysis indicated that drug therapy is generally more effective than non-drug treatments (surgery, acupuncture). However, a 2006 review of knee osteoarthritis studies found that pain-relief medications generally help only for the first 2 - 3 weeks of treatment. The following are some of the medications used in mild-to-severe cases:

Acetaminophen
Nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors
Capsaicin
Tramadol
Narcotic pain relievers (oxycodone, oxymorphone, or morphine)
Glucosamine and chondroitin (see Alternative and Complementary Medicine section)

Acetaminophen (Tylenol, Anacin-3, Panadal, Phenaphen, Valadol, and others) is currently the first choice for treating osteoarthritis. However, several major analyses report that acetaminophen is less effective than NSAIDs in reducing moderate-to-severe pain. Because acetaminophen has fewer side effects, most experts suggest trying this drug first, then switching to an NSAID if acetaminophen does not provide sufficient pain relief.

Side Effects. Acetaminophen is inexpensive and generally safe. It poses far less of a risk for gastrointestinal problems than NSAIDs and does not appear to increase the risk for miscarriage (as NSAIDs do), even when used regularly.

It does have some adverse effects, however, and the daily dose should not exceed 4 grams (4,000 mg). Patients who take high doses of this drug for long periods are at risk for liver damage, particularly if they drink alcohol and do not eat regularly.

The kidneys are responsible for removing wastes from the body, regulating electrolyte balance and blood pressure, and the stimulation of red blood cell production.

Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandins, the substances that dilate blood vessels and cause inflammation and pain. There are dozens of NSAIDs:

Over-the-counter NSAIDs include aspirin, ibuprofen (Advil, Nuprin, Motrin IB, Rufen), naproxen (Aleve, Naprosyn), ketoprofen (Actron, Orudis KT).
Prescription NSAIDs include ibuprofen (Motrin), naproxen (Naprosyn, Anaprox), flurbiprofen (Ansaid), diclofenac (Voltaren, Cataflam), tolmetin (Tolectin), ketoprofen (Orudis, Oruvail), nabumetone (Relafen), dexibuprofen (Seractil), indomethacin (Indocin), meloxicam (Mobic, generic).
Topical NSAIDs delivered in gels, creams, or patches do not appear to provide any long-term benefits in reducing arthritic pain. A review of clinical trial data, published in 2004, suggested that guidelines that recommend topical NSAIDs for treatment of osteoarthritis should be revised.

Many experts now recommend that patients use oral NSAIDs for only a short period of time. A 2004 review, published in the British Medical Journal, suggested that long-term use of NSAIDs does not actually reduce osteoarthritis pain and may increase patients’ risk of experiencing side effects. High dosages of NSAIDs can cause heart problems (such as increased blood pressure), kidney problems, and stomach bleeding.

In April 2005, the Food and Drug Administration (FDA) asked drug manufacturers of prescription NSAIDs to include with their products the same boxed warning used for the COX-2 inhibitor celecoxib (Celebrex). This boxed warning emphasizes an increased risk for cardiovascular events and gastrointestinal bleeding in people taking these drugs. The FDA also requested manufacturers of over-the-counter NSAIDs to revise their labels to include more specific language concerning potential cardiovascular and gastrointestinal risks. Due to its proven heart benefits, aspirin was excluded from these labeling revisions.

A 2006 comprehensive report from the U.S. Agency for Healthcare Quality and Research indicated that both NSAIDs and COX-2 inhibitors are equally effective for pain relief and pose similar risks for heart attacks. The report found that one particular NSAID, naproxen (Aleve, Naprosyn), presents less risk of heart attack for some patients. A 2006 Journal of the American Medical Association study suggested that diclofenac (Voltaren, Cataflam) may pose a higher risk for heart attack than other NSAIDs. All patients should talk to their doctors before switching any medications.

Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is the second most common cause of ulcers, and the rate of NSAID-caused ulcers is increasing. Such ulcers are also more likely to bleed than those caused by the bacteria H. pylori. NSAID-related bleeding and stomach problems may be responsible for 107,000 hospital admissions and 16,500 deaths each year. Because there are usually no gastrointestinal symptoms from NSAIDs until bleeding begins, doctors cannot predict which patients taking these drugs will develop bleeding.

Among the groups at high risk for bleeding are elderly people, anyone with a history of ulcers of GI bleeding, patients with serious heart conditions, alcohol abusers, and those on certain medications, such anticoagulants ("blood thinners"), corticosteroids, or bisphosphonates (drugs used for osteoporosis). Proton-pump inhibitors may help to prevent and heal ulcers caused by NSAIDs. Proton-pump inhibitors include omeprazole (Prilosec), esomeprazole (Nexium), and lansoprazole (Prevacid)

Click the icon to see an image of a gastric ulcer.

Drugs for Prevention NSAID-Induced Ulcers. If you have NSAID-induced ulcers, follow these steps:

Switch to alternative pain relievers. This is the first step in preventing or healing ulcers caused by NSAIDs. If people cannot change drugs, they should use the lowest NSAID dose possible.
Try proton-pump inhibitors (PPIs). These drugs help reduce NSAID-ulcer rates by as much as 80% compared with no treatment. Brands include omeprazole (Prilosec), esomeprazole (Nexium), lansoprazole (Prevacid), rabeprazole (Aciphex), and pantoprazole (Protonix).
Try misoprostol or Arthrotec. If other drugs are inappropriate, misoprostol protects against the major intestinal toxicity of NSAIDs. It was the first drug approved for preventing NSAID-induced ulcers. It is equally, or even more, effective than some of the PPIs, but it does not heal existing ulcers and has more side effects than PPIs. Patients tend to stop using it. Arthrotec is a combination of an ulcer protective drug called misoprostol and the NSAID diclofenac. One study found that patients taking Arthrotec had 65 - 80% fewer ulcers than those who took NSAIDs alone.

Healing Existing Ulcers. A number of drugs are available to heal NSAID-induced ulcers. Treatment takes about 2 - 6 weeks. Proton-pump inhibitors are the most effective drugs. Others that may be beneficial include sucralfate or H2 blockers, such as famotidine (Pepcid AC), cimetidine (Tagamet), ranitidine (Zantac).

Coxibs inhibit an inflammation-promoting enzyme called COX-2. This drug class was initially thought to provide benefits equal to NSAIDs but cause less gastrointestinal distress. However, following numerous reports of cardiovascular events, as well as skin rashes and other adverse effects, the FDA has been re-evaluating the relative risks and benefits of this drug class. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the United States market. Celecoxib (Celebrex) is still available, but patients should discuss with their doctors whether this drug is appropriate and safe for them.

A newer COX-2 inhibitor, etoricoxib (Arcoxia) is approved in 60 countries but not the United States. A 2006 Lancet study indicated that etoricoxib is similar to the NSAID diclofenac in risks for heart attack and stroke. (However, diclofenac has already been shown to have a higher risk of heart attack than any other NSAID, so some experts do not find this study result reassuring.) Etoricoxib caused more high blood pressure and fluid retention (edema) than diclofenac. Etoricoxib appeared to pose a lower risk than diclofenac for uncomplicated upper gastrointestinal problems, (obstruction, perforation, bleeding, ulcers), but there was little difference between the two drugs for more serious gastrointestinal complications. In 2007, the FDA rejected an application to market etoricoxib in the U.S.

Capsaicin is a component of hot red peppers and may bring pain relief when used as a skin cream (Zostrix). This is the only skin preparation that does more than just mask pain or reduce it temporarily. Capsaicin seems to reduce a substance in the body, known as substance P, which contributes both to inflammation and the delivery of pain impulses from the central nervous system. A small amount of capsaicin must be applied to the area of inflammation about four times a day. During the first few days of use, the patient will experience a warm, stinging sensation when the cream is applied. This sensation goes away, and pain relief usually begins within 1 - 2 weeks.

Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. It has opioid-like properties but is not as addictive. (Dependence and abuse have been reported, however.) It can cause nausea but does not cause severe gastrointestinal problems, as NSAIDs can. Some patients experience severe itching. A combination of tramadol and acetaminophen (Ultracet) is now available and provides more rapid pain relief than tramadol alone with more long-lasting benefits than acetaminophen. Side effects are the same as for each of these drugs.

Narcotics, pain-relieving and sleep-inducing drugs that act on the central nervous system, are the most powerful medications available for the management of moderate to severe pain. There are two types of narcotics:

Opiates, which are derived from natural opium (morphine and codeine).
Opioids, which are synthetic drugs. They include oxycodone (Percodan, Percocet, Roxicodone, Oxycontin), hydrocodone (Vicodin), oxymorphone (Numorphan), and fentanyl (Duragesic).

Although the use of narcotics for arthritic pain is controversial, many studies have suggested that they are rarely addictive for pain sufferers except among patients with a history of substance abuse. Some experts believe that opioids have a place in osteoarthritis treatment when milder drugs are not effective or appropriate. For example, a 2006 study suggested that a fentanyl skin patch may offer pain relief and improved function to some patients with severe knee or hip osteoarthritis who have not been helped by, or who cannot tolerate, NSAIDs or weaker opioids.

The use of such drugs may be beneficial when included as part of a comprehensive pain management program. Such a program involves screening prospective patients for possible drug abuse and then regularly monitoring those who are taking it, adjusting the dose as necessary to achieve an acceptable balance between pain relief and side effects. Common side effects include anxiety, constipation, nausea and vomiting, dizziness, drowsiness, paranoia, urinary retention, restlessness, and labored or slow breathing. Unfortunately, opioid abuse among young people is a major concern.

When pain becomes a major problem and less potent pain relievers are ineffective, doctors may resort to corticosteroid (steroid) injections, usually by administering a shot into the affected joint every 3 months. Corticosteroid shots are useful only if inflammation is present in the joint. Relief from pain and inflammation is of short duration, and this treatment is rarely used for chronic osteoarthritis. These drugs may not be as effective for women as for men.

Corticosteroids mask pain, and the patient must be very careful to avoid over-use of the affected joints. Patients are usually advised not to have more than two or three injections a year, since there is some concern that repeated injections over the long term may be harmful. A reassuring study found no greater disease progression in people who had injections every 3 months for 2 years compared to those who were given sham injections on the same schedule. Because long-term use of corticosteroids has many potentially serious side effects, steroid medications are never given orally or systemically for the treatment of osteoarthritis.

Injections of hyaluronic acid (Hyalgan, Synvisc, Artzal, Nuflexxa) into the joint -- a procedure called viscosupplementation -- is now recommended as one of the treatments for osteoarthritis. Hyaluronic acid is a naturally occurring substance in joints that acts as a lubricant for slow movements and a shock absorber for fast motions. In high amounts, it also may have anti-inflammatory effects.

Patients receive a series of three to five injections once a week.
The drug is injected into the joint.
A health care worker will apply local anesthetic because these viscous (sticky) injections require a large needle.
Patients need to avoid weight-bearing activities for about 48 hours after each shot.

Hyaluronic injections appear to be about as effective as NSAIDs and corticosteroid injections for relieving pain, at least in men, and they have no adverse effects in the stomach or intestines. One study reported that between 39 - 56% of patients were at least nearly free of weight-bearing pain up to 24 weeks after the final injection. In another study, response was judged better or much better for 87% of knees after a second course, which was administered about 8 months later. Nevertheless, a number of studies on viscosupplementation have shown little or no benefits, particularly in women, and more research is needed to determine if they are useful. Injections are also expensive. Accurate placement of the needle directly into the knee joint space is important and may be difficult, even for experienced doctors, if there is no fluid build-up in the joint. Best success rates are with a specific approach into the kneecap called the lateral midpatellar.

Side Effects. Serious adverse reactions are rare. The most common side effects, pain at the injection site and knee pain and swelling, are usually mild and temporary. More research is needed to confirm benefits and long-term risks.

Researchers are studying various drugs that may provide pain relief or stop the disease process itself:

Bisphosphonates such as alendronate (Fosamax) and risedronate (Actonel) help prevent bone loss in people with osteoporosis. They are currently being investigated for osteoarthritis as well. A 2005 study reported that risedronate may delay joint destruction in patients with knee osteoarthritis.
Lidocaine, a local anesthetic, is available in patch form (Lidoderm) and has been used specifically for herpes zoster pain. Early studies indicate that it may provide significant pain relief for osteoarthritis.
Tetracycline antibiotics, such as doxycycline, may have a role to play in treating osteoarthritis. At low concentrations, the drug reduces the production of collagenases, which are enzymes critical to disease development and progression. Initial results from clinical trials suggest that doxycycline may help delay joint space narrowing.
Licofelone is a drug that inhibits both the COX enzyme plus an inflammatory substance called lipoxygenase 5. Early trials indicate it may be effective and safer than either NSAIDs or COX-2 inhibitors.
Diacerein inhibits an inflammatory substance in arthritic joints called interleukin-1b. It has shown promise in clinical trials. A 2006 review indicated that diacerein may be slightly better than NSAIDs for pain relief.
Botulinum toxin type A (Botox) injections may provide sustained pain relief for patients with knee osteoarthritis according to research presented at the 2006 American College of Rheumatology annual meeting.
Nitric oxide increases blood flow in the mucous lining and secretions of mucus and bicarbonate. Combining nitric oxide with NSAIDs may reduce the adverse effects on the gastrointestinal tract.
Trials of gene therapies that either fight joint degradation or strengthen cartilage are in very early stages.

Alternative and Complementary Medicine

Glucosamine hydrochloride and chondroitin sulfate are natural substances that are part of the building blocks found in and around cartilage. Extracts have been used in Europe for more than a decade to reduce pain and improve mobility in patients with osteoarthritis. For many years, researchers in the U.S. have been studying whether these dietary supplements really work for relieving osteoarthritis pain.

In 2006, the New England Journal of Medicine published the results from a major trial sponsored by the U.S. National Institutes of Health. Researchers compared the effects of glucosamine and chondroitin, alone and in combination, with the COX-2 inhibitor celecoxib (Celebrex) in nearly 1,600 patients with knee osteoarthritis. The dietary supplements were also compared with placebo (an inactive substance). Patients took the assigned substance once a day for 6 months.

The results indicated that, for most patients, neither glucosamine nor chondroitin were better than placebo in relieving knee pain. However, for patients with moderate-to-severe pain, a combination of glucosamine and chondroitin was significantly more effective than the other remedies. Celebrex worked best for patients with mild pain.

The next stage of the study will evaluate whether glucosamine and chondroitin, alone and in combination, can halt the progression of knee osteoarthritis.

Research presented at the 2006 American College of Rheumatology annual meeting suggested that chondroitin may prevent joint narrowing in patients with knee osteoarthritis.

Dosage. There are no current standard recommended dosages. Patients in the GAIT trial took 1,500 mg of glucosamine and 1,200 mg of chondroitin.

Side Effects. The safety records of both substances appear excellent. Long-term effects are still unknown, but studies of up to 3 years have reported no significant side effects. However, there are some concerns that glucosamine may affect insulin and blood sugar (glucose) metabolism. Patients with diabetes should not take glucosamine without first talking to their doctors.

Oral Enzymes. People in Europe have used natural enzymes -- including bromelain, trypsin, papain, and rutin -- to treat arthritic pain. Such enzymes have been marketed alone and in combinations (Wobenzym, Phlogenzym). They are not painkillers, and any benefits derived from them may take several weeks.

Ginger (Zingiberaceae). A 2001 study of patients with knee arthritis found that an extract of ginger reduced pain while standing and after walking. By using ginger, patients were able to reduce their pain medications after 6 weeks. Side effects included mild digestive upset.

S-adenosylmethionine (SAMe). S-adenosylmethionine (SAMe, pronounced "Sammy") is a synthetic form of a natural byproduct of the amino acid methionine. It has been marketed as a remedy for both depression and arthritis. Some research suggests that it may work as well as NSAIDs for short-term treatment of osteoarthritis. Other studies suggest that it may help rebuild damaged cartilage.

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 several 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.

Acupuncture is being increasingly used to reduce osteoarthritis pain. The technique is painless and involves the insertion of small fine needles at select points in the body. Several study reviews have found that acupuncture provides at least short-term pain relief for osteoarthritis of the knee. Other studies have suggested that acupuncture’s benefits are mainly due to a strong placebo effect, or to the psychologically beneficial effects of close contact with health care providers.

In 2004, researchers published results from an important clinical trial that studied the effects of acupuncture on nearly 600 people with osteoarthritis of the knee. The results indicated that acupuncture can relieve pain and improve function. Several 2006 studies of thousands of patients with chronic osteoarthritis pain compared acupuncture to conventional treatment (physical therapy, anti-inflammatory drugs). These studies showed positive results and suggested that acupuncture’s benefits may be sustained for up to 6 months after treatment. In any case, acupuncture appears to be a safe and beneficial addition to standard therapy for certain patients, such as pregnant women, who cannot take most pain medications.

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.

Transcutaneous electric nerve stimulation (TENS) uses low-level electrical pulses to suppress pain. Patients are barely aware of the sensation. According to one study, the optimal treatment length is 40 minutes. A variant (sometimes called percutaneous electrical nerve stimulation, or PENS) applies these pulses through a small needle to acupuncture points. A review of trials reported that both methods were better than placebo (sham treatments) in treating osteoarthritis of the knee, although additional well-designed studies are needed.

Low-level laser therapy (LLLT) generates extremely pure light in a single wavelength. It does not produce heat and is painless. Some researchers are combining LLLT with transcutaneous electric nerve stimulation (TENS). Studies report widely varying results, with some showing significant reductions in pain and others reporting no effect. The differences may be due to different approaches, and standardized methods are needed to determine any benefits.

Hydrotherapy, also called spa therapy or balneotherapy, is an ancient therapy that uses bathing in mineral baths for soothing pain. Although many studies report positive results, including improved quality of life, very few have been rigorously conducted. A major analysis reported weak evidence on any real effect on pain or quality of life, but some patients may find comfort from this pleasant therapy.

Surgery

Different surgical procedures are available as a final measure to relieve pain and increase function in patients with osteoarthritis. Certain surgical procedures can help relieve pain if medications fail. Even with these procedures, however, joint replacement may still be needed later on.

Arthroscopy is performed to clean out bone and cartilage fragments that, in theory at least, may cause pain and inflammation. More than 650,000 of these procedures are done on arthritic knees each year in the U.S., and about half of patients report less pain after the procedure.

A rigorous 2002 trial, however, found that arthroscopic knee surgery was no more effective than sham surgery, (in which surgeons only pretended to operate on the knee), for relief of osteoarthritic pain or stiffness. The study, which followed patients at a Veterans Affairs hospital for 2 years, has called into serious question whether the popular procedure has any real benefits for osteoarthritis beyond what might be achieved by a placebo response. Research and debate continues on whether arthroscopy provides true benefits for those with osteoarthritis and, if so, which patients it may most help.

Click the icon to see an illustrated series detailing knee arthroscopy surgery.

When osteoarthritis becomes so severe that pain and immobility make normal functioning impossible, many people become candidates for artificial (prosthetic) joint implants using a procedure called arthroplasty. Hip replacement is the most established and successful replacement procedure, followed by knee replacement. Knee replacement, in fact, has a slightly better long-term success rate than hip replacement. Other joint surgeries (shoulders, elbows, wrists, fingers) are less common, and some arthritic joints (in the spine, for instance) cannot yet be treated in this manner. When two joints, such as both knees, need to be replaced, having the operations done sequentially rather than at the same time may result in fewer complications.

Click the icon to see an illustrated series detailing knee joint replacement surgery.

Candidates. The primary indications for surgery are pain and significant limitations of movement, including walking, that cannot be treated by less invasive therapies. Some experts suggest, however, that joint replacement should be considered earlier rather than as a last resort. They argue that patients who wait until they are severely disabled do not recover as completely as those who have the procedure earlier.

Patients who may not be good candidates are those with the following conditions:

Severe neurologic, emotional, or mental disorders
Severe osteoporosis
Other chronic medical conditions
Obesity

Surgeons often prefer to delay prosthetic implantation in younger patients, because implants wear out and they will require at least one revision procedure later on. Newer, more long-lasting materials, however, may help reduce the rate of re-operations.

Procedure Description. Although the following is mostly a description of hip replacement surgery, the principles are similar for other arthroplasties.

The surgeon removes the ball and socket joint that joins the pelvis and thigh bone (femur) and replaces it with an artificial joint (a prosthesis). It is composed of two pieces:

A cup-like device fits in the hip socket (called the acetabula), which has been hollowed out. This ball-and-socket cup is positioned to form the new joint.
A metal shaft, or stem, with a polished metal ball at the top, is inserted into the narrow center of the femur.

The prosthesis is usually made of a metal alloy and plastic. A ceramic implant may prove to last longer than other materials and be a safe option for younger patients.

There are different options available for attaching it to the adjoining bones:

A cement made of polymethylmethacrylate (usually preferred for older patients who generally have thinner bones).
So-called cementless implants, in which the prosthesis is coated with a porous material that allows bone to grow into and eventually adhere to the device. These implants are usually used for patients younger than age 65, who are likely to need repeat surgery in their lifetime.

Click the icon to see an illustrated series detailing hip joint replacement surgery.

Complications. Complications can occur, and, although uncommon, some can be life-threatening. There is a 1% chance of death within 3 months of an initial procedure and a 2.6% risk after a repeat procedure. The risks are highest in the first 3 months. Those at highest risks for complications are elderly adults, men (compared to women), African-Americans, and those with serious medical conditions.

Specific complications include the following:

Deep blood clots (known as deep vein thrombosis) and pulmonary embolism. Deep blood clots can develop in the legs after this surgery. This poses a very small risk (0.9%) for pulmonary embolism -- a dangerous condition in which the clot travels to the lungs. Anticoagulants (blood thinners) are important for preventing blood clots. These drugs include warfarin and low-molecular weight heparin. Anticoagulant therapy is given during the hospital stay and continued for several weeks at home. The patient also wears specially fitted elastic stockings to help prevent clots. Patients who are overweight are at higher than average risk for post-operative blood clots
Infection. Wound infection occurs in about 0.2% of joint replacements and requires prompt removal of the implant to treat the infection. A new prosthesis must be re-implanted at a later time. Any pre-existing infection must be treated and cured before surgery is performed. (Older women should be aware of urinary tract infections, which may require postponing surgery.) After surgery, patients should take certain precautions. For example, they should take antibiotics before invasive dental procedures or other surgery because bacteria can be introduced into the bloodstream and infect the areas around the artificial joints.
Hip dislocation. Occurs in about 3.1% of first hip procedures. The rate is much higher (14.4%) in revision operations.

Click the icon to see an image of a dislocated hip.

Pain. Thigh pain can occur after hip replacement. Porous hip prostheses are more likely to produce thigh pain than cement implants, although advanced techniques using a tapered shaft are reducing this complication.
Failure. The primary reason for implant failure is osteolysis (bone destruction) caused by long-term wear. The main source of wear is from tiny particles released from the prosthesis.
Other complications. These include uneven leg lengths, nerve damage that can cause numbness or weakness, urinary tract infections, delayed healing, and allergic reactions to the metal. Long-term, there have been rare reports of a possible autoimmune response, in which loose particles released from the prosthetic device trick certain immune system factors into attacking healthy cells. Any incidence of unexplained weight loss and fatigue may be symptoms of this uncommon event.

Rehabilitation. Aside from the surgeon's skill and the patient's underlying condition, the success rate depends on the kind and degree of activity the joint receives following replacement surgery.

The patient is urged and aided into getting out of bed and walking the day after surgery. Most hip replacement patients leave the hospital within a week and can walk with crutches within 2 - 4 weeks, recovering fully in about 3 months.

Physical therapy takes about 6 weeks to rebuild adjoining muscle and strengthen surrounding ligaments. Studies suggest that an exercise program started before surgery and resumed afterward can improve recovery. Continuous passive motion (CPM) is an effective regimen for knee replacement patients. It uses a mechanical device that slowly moves the joint through an arc of motion for an extended period of time. It is used to prevent scar tissue from developing. In one review, a combination of physical therapy and CPM were more beneficial than physical therapy alone.

Limitations After Surgery. While many patients find that joint replacement provides remarkable pain relief and restores some mobility, they need time to adjust to the artificial joint.

Limitations after hip surgery include:

Usually patients with new hips are able to walk several miles a day and climb stairs, but they cannot run.
Prosthetic hips should not be flexed beyond 90 degrees, so patients must learn new ways to perform activities requiring bending down (like tying a shoe).

Limitations after knee surgery include:

Walking distance improves in 80% of patients after knee replacement surgery, but patients still cannot run.
Only slightly more than half of patients report improvement in stair climbing. (Artificial knee joints generally have a range of motion of just 110 degrees.)

Failure Rates. Infection is a major cause of early failure and always requires revision. Improper balancing of the ligaments and other tissues surrounding the joint and resulting poor joint stability is also a common reason for failure of arthroplasties. Surgical expertise is important for avoiding this complication.

Older cement prostheses have a particularly high rate of bone loss and loosening due to cement deterioration. In general, studies report reoperation rates of over 30% after 10 years. Fortunately, advances in cement and prosthetic implants are improving the implant survival rates and reducing the need for revision procedures.

Uncemented arthroplasty using porous material has shown good results for the hip, although it may be less successful for knee replacement. In spite of short-term success, longer experience with this method suggests it may not be superior to cement prostheses. Failure of bone to grow into the porous material is a relatively common event, a problem that does not occur with cement prostheses. Some experts recommend cement implants over cementless ones for total knee arthroplasty.

A repair procedure called arthroplasty revision may be used in cases where the original transplant fails. The specific procedure depends on whether the bone defects that occurred are contained or uncontained.

Contained defects can be repaired with small bone grafts, the use of cement, or oversized cementless implants as required.
Uncontained defects are more severe and may require a large bone graft or specially constructed implants to restore bone.

If a second arthroplasty is required, the potential for complications is magnified: more bone is cut, more blood is lost, and the operation takes longer. Patients are also generally older and more vulnerable to complications.

Resection Arthroplasty. In resection arthroplasty, a false joint of scar tissue is created. This procedure is used most often in treating arthritis of the foot.

Osteotomy. If only a certain section (the medial compartment) of the knee is damaged and deformed by osteoarthritis, the surgeon may choose to perform osteotomy:

A surgeon opens the knee.
The surgeon performs a debridement (removal of damaged tissue) in the joint to eliminate the loose or torn fragments that are causing pain and inflammation.
The bone is then reshaped to remove the deformity.
The procedure may ease symptoms and slow disease progression. It is best used in heavier adults who are under 60 years old.

Hemicallotasis. Hemicallotasis is a procedure for the knee that may be a less invasive alternative to osteotomy. The surgeon attaches the knee with pins to an external frame-like device that lengthens the deformed part of the knee over several weeks. The patient is mobile during this period. Infections at the pin site are the most common complications.

Arthrodesis. If the affected joint cannot be replaced, surgeons can perform a procedure called arthrodesis that eliminates pain by fusing the bones together. The patient must understand, however, that fusing the bones makes movement of the joint impossible. Bone fusion is most often done in the spine and in the small joints of the hands and feet.

Unicompartmental Knee Arthroplasty. Unicompartmental knee arthroplasty (also called unicondylar knee arthroplasty) may be a useful procedure in cases of limited knee damage. It is recommended for relatively sedentary patients who are 60 years or older and not obese. It may relieve pain and delay the need for a total knee replacement. The procedure involves a small incision and insertion of small implants. It retains important knee ligaments, which preserve more movement than a total knee replacement.

Cartilage Transplants. Autologous chondrocyte implantation, also called chondroplasty or the Carticel approach, is used for knees damaged by injuries. In this procedure, arthroscopy is used to first remove cartilage in eroded areas. The results have been good to excellent, although long-term benefits are questionable. Whether it has any benefit for older patients with osteoarthritis is not yet known. Other cartilage transplant procedures are also under study.

Hip Resurfacing. Hip resurfacing is a surgical alternative to total hip replacement. It involves scraping the surfaces of the hip joint and femur and placing a metal cap over the bone. The procedure preserves much of the bone, so that a standard hip replacement can be done years later if needed. It may provide more stability, a faster recovery, and greater range of motion, making it a potentially good option for young, physically active patients.

Resources

www.rheumatology.org -- American College of Rheumatology
www.arthritis.org -- Arthritis Foundation
www.niams.nih.gov -- National Institute of Arthritis and Musculoskeletal and Skin Diseases
www.aaos.org -- American Academy of Orthopaedic Surgeons
www.fda.gov/cder/drug/infopage/cox2 -- FDA NSAID and COX-2 Inhibitor Information

References

Bjordal JM, Klovning A, Ljunggren AE, Slordal L. Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials. Eur J Pain. 2007 Feb;11(2):125-38.

Cannon CP, Curtis SP, FitzGerald GA, Krum H, Kaur A, Bolognese JA, et al. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2006 Nov 18;368(9549):1771-81.

Chou R, Helfland M, Peterson K, Dana T, Roberts C. Comparative Effectiveness and Safety of Analgesics for Osteoarthritis. Comparative Effectiveness Review No. 4. (Prepared by the Oregon Evidence-based Practice Center under Contract No. 290-02-0024.) Rockville, MD: Agency for Healthcare Quality and Research. September 2006.

Felson DT, Niu J, Clancy M, Sack B, Aliabadi P, Zhang Y. Effect of recreational physical activities on the development of knee osteoarthritis in older adults of different weights: the Framingham Study. Arthritis Rheum. 2007 Feb 15;57(1):6-12.

Laine L, Curtis SP, Cryer B, Kaur A, Cannon CP; MEDAL Steering Committee. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomized comparison. Lancet. 2007 Feb 10;369(9560):465-73.

Langford R, McKenna F, Ratcliffe S, Vojtassak J, Richarz U. Transdermal fentanyl for improvement of pain and functioning in osteoarthritis: a randomized, placebo-controlled trial. Arthritis Rheum. 2006 Jun;54(6):1829-37.

McGettigan P, Henry D. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase2. JAMA. 2006 Oct 4;296(13):1633-44.

Rintelen B, Neumann K, Leeb BF. A meta-analysis of controlled clinical studies with diacerein in the treatment of osteoarthritis. Arch Intern Med. 2006 Sep 25;166(17):1899-906.

Scharf HP, Mansmann U, Streitberger K, Witte S, Kramer J, Maier C, et al. Acupuncture and knee osteoarthritis: a three-armed randomized trial. Ann Intern Med. 2006 Jul 4;145(1):12-20.

Witt CM, Jena S, Brinkhaus B, Liecker B, Wegscheider K, Willich SN. Acupuncture in patients with osteoarthritis of the knee or hip: a randomized, controlled trial with an additional nonrandomized arm. Arthritis Rheum. 2006 Nov;54(11):3485-93.

Review Date:
3/19/2007
Reviewed By:
Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

A.D.A.M. Copyright

adam.com

Part 2 - You Asked: Losing Too Much Weight Running?

FitSugar — Wed, 20 Aug 2008 05:30:00 -0700

Yesterday DrSugar answered the health related portion of this question.

Dear DrSugar,
I have a problem that might seem a little odd, but I am not dieting and I am losing too much weight. I am training for a marathon, and exercise daily about 2 hours Monday through Friday (running outside mixed with swimming, spin class, body pump, and running on Treadmill). My Saturday workout is always a long run, and my Sunday workout is a short run. I know I am not pregnant, but my last period was 5 months ago. Is this due to too much exercise? Other than the missing period, I feel strong and fine. And I eat healthy meals every 2 to 3 hours. Is this something that I need to worry about?
Running Rita

The sweet doctor and I decided to tackle this question in two parts, since there are so many aspects to this important question. To see what DrSugar had to say about the missing periods read his answer here. For my input on nutrition and rest days read more.

First let me say that I think it is great that you're cross training with swimming, spinning and strength training, but you need at least one rest day a week, if not two. Rest days are vital for your body to recuperate and repair itself. Here are two plans one from Runner's World and one from Marathon Training and each plan has two rest days. Without rest days, you run the risk (pun intended) of creating over use injuries, which can certainly derail you marathon plans.

Maintaining your weight is also important and you need to make sure you're replacing all the calories you're expending while training. It sounds like you're coming up short on calories, aka fuel. Coach Jenny, over at Runner's World offers some incredibly sane advice about maintaining weight while training. It might be a good idea to have your metabolic rate checked to ensure you have a solid baseline understanding of your caloric needs. Wearing a heart rate monitor that calculates calories burned will help you know how much you need to eat to replenish all the calories you burned while working out. Make sure you're eating a healthy and balanced diet that is a little heavy in whole grain carbs. Don't forget the healthy fats either. Avocado and salmon are two runner friendly fatty foods.

I think running a marathon is a wonderful goal, but do not put your health at risk to do so. You might also want to evaluate why you are driving yourself to train so intensely. Compulsive exercise falls under eating disorders as an alternative way to "purge." There are many online resources, like SomethingFishy.org should you feel you need some help.

Good luck on the marathon. Take some rest days and add some healthy calories to your day. Hopefully this equation will help you return to your previous weight and then help you maintain it.

Source

Common cold

FitSugar — Wed, 08 Oct 2008 17:35:26 -0700

Overview

Signs and Symptoms
Causes
Risk Factors
Diagnosis
Preventive Care
Treatment Approach
Other Considerations
Supporting Research

HEALTH GUIDE REFERENCE FROM A.D.A.M

A cold is an upper respiratory infection caused by a virus. They tend to occur most often in winter, although scientists aren't sure why. In the United States, adults usually have between two and four colds per year, and children have as many 10.

There is no foolproof way to prevent a cold – and no way to cure it – but you can treat the symptoms. Colds tend to last about a week, and can be accompanied by sore throat and cough. Unlike the flu, colds don't usually cause you to run a high fever (above 102 degrees Fahrenheit).

Signs and Symptoms

Sneezing and runny nose from nasal congestion
Sore throat
Cough
Hoarseness
Low-grade fever (less than 102 degrees)
Headache
Fatigue

Causes

Colds are caused by more than 100 different viruses, although most colds are caused by rhinoviruses. You can get a cold by touching a person with a cold (for example, by shaking hands) and then touching your nose or eyes, or by touching a surface that a person with a cold has touched (such as telephone or keyboard). Colds are also transmitted through the air, when someone with a cold coughs or sneezes. Although you're more likely to get a cold in winter, exposure to cold outdoor air and fatigue do not increase your risk of getting sick (but stress may do so).

Risk Factors

People more likely to get colds include:

Children, especially those who attend day care or whose parents smoke
Smokers and those exposed to second hand smoke
Those exposed to industrial smoke, toxic fumes, or other air pollutants
People with immune system disorders, such as HIV, AIDS, or cancer, or who take medications that suppress the immune system, such as corticosteroids
People under a fair amount of stress

Diagnosis

Most people treat colds without seeing a doctor. If you do see your doctor, the diagnosis will be made based on your symptoms and exam. He or she may take a throat culture to rule out strep throat. If you have an underlying lung condition, such as asthma or emphysema, you should let your doctor know right away when you get a cold.

Preventive Care

Although anyone and everyone can get a cold, there are a few things that you can do that may help improve your immune system and make you less susceptible to getting colds:

Wash your hands frequently
Exercise regularly
Eat a diet rich in fruits and vegetables and low in fat
Get sufficient rest
Minimize your stress and your reaction to stress. Yoga, tai chi, or other forms of relaxation may help.

Treatment Approach

With a cold, the goal of treatment is to improve your symptoms as quickly as possible. But even if you do nothing, they should go away within a week to 10 days. Antibiotics cannot help your cold. However, there are medications, herbs, supplements, and homeopathic remedies that may make you feel better while you have a cold.

Lifestyle

Drink a lot of water to help loosen mucus.
Rest to restore your energy and avoid complications such as bronchitis or pneumonia.
Eat a diet rich in fresh fruits and vegetables. These foods provide lots of antioxidants (substances that may help boost your immune system), especially vitamins A and C.

Medications

A number of over-the-counter medications are available to help treat cold symptoms. Children under the age of six should not be given any over-the-counter cold or cough medicine.

Decongestants - help open your nasal passages so you can breathe easier. If decongestant nasal sprays or drops are used for more than three days, however, they can cause rebound congestion. Decongestants are often combined in cold medicines with antihistamines, cough suppressants, and pain relievers. People with heart disease, high blood pressure, diabetes, or glaucoma should not take decongestants. Popular brands of decongestants include Sudafed, Afrin, and Neo-Synephrine.

Antihistamines - can temporarily relieve a runny nose by drying up nasal secretions. Non-drowsy antihistamines available over the counter include loratadine (Claritin); others, such as fexofenadine (Allegra) and cetirizine (Zyrtec), are available by prescription.

Cough medicines - cough suppressants (for a dry cough) or expectorants (for a wet, productive cough that brings up mucous) are available over the counter and by prescription.

Pain relievers - such as aspirin, acetaminophen (Tylenol), and ibuprofen (Advil, Motrin) can be used for fever, body aches, and headaches. Children under the age of 16 should not take aspirin due to the risk of a rare but serious illness called Reye's syndrome.

Nutrition and Dietary Supplements

Because supplements may have side effects or interact with medications, they should be taken only under the supervision of a knowledgeable healthcare provider. Be sure to talk to your physician about any supplements you are taking or considering taking.

Chicken soup - It’s about as traditional a remedy for a cold as you can find (at least in modern history). In fact, chicken soup and warm liquids (broth, tea) can help soothe a sore throat and loosen mucus, which in turn helps ease congestion from a cold.
Probiotics (Lactobacillus) - So-called “good” bacteria or probiotics help prevent infections in the intestines, and there is preliminary evidence that they might help prevent colds, too. One study found that children in daycare centers who drank milk fortified with Lactobacillus had fewer and less severe colds. Several studies that examined probiotics combined with vitamins and minerals also found a reduction in the number of colds caught by adults, although it’s not possible to say whether the vitamins, minerals, or probiotics were most responsible for the benefit.
Vitamin C - Despite the popular belief that vitamin C can cure the common cold, the scientific evidence hasn't found that to be true. Only a small reduction in the duration of a cold (about 1 day) has been found when some people take vitamin C supplements regularly (not just at the beginning of a cold). The only other piece of evidence supporting vitamin C for preventing colds comes from studies examining people exercising in extreme environments (athletes such as skiers and marathon runners, and soldiers in the Arctic). In these studies, vitamin C did seem to reduce the risk of getting a cold. Talk to your doctor about any pros and cons with regards to using vitamin C during cold and flu season. Some people believe that you have to take very high doses of vitamin C to get any benefit, and they suggest taking enough to cause diarrhea and then reducing the dose. You should only use such high doses of vitamin C under your doctor’s supervision.
Zinc - Your body needs zinc for its immune system to function properly, so it has long been thought that zinc could help protect against catching a cold. But the evidence has been decidedly mixed, with some studies finding a benefit from zinc lozenges but others showing no effect. Recently, a review of studies that compared zinc to placebo found that most of them had flaws that made any positive results unreliable. Only four studies were deemed reliable, and three found no benefit from zinc lozenges. The remaining positive study suggested that zinc nasal sprays might help reduce nasal stuffiness. If you do decide to try zinc lozenges for a cold, remember that getting too much zinc (more than 50 mg per day over a long period of time) can be dangerous.

Herbs

The use of herbs is a time-honored approach to strengthening the body and treating disease. Herbs, however, can trigger side effects and can interact with other herbs, supplements, or medications. For these reasons, herbs should be taken with care, under the supervision of a healthcare practitioner. Before giving any herbs to a child to treat a cold, talk to your pediatrician.

Echinacea (Echinacea purpurea, 300 mg three times per day) – Although evidence on whether echinacea works to prevent or treat colds has gone back and forth, recent evidence is encouraging. An analysis of 14 scientific studies found that people who took echinacea reduced their risk of getting a cold by 58 percent and reduced the duration of a cold by an average of a day and a half. However, many of the studies used echinacea in combination with another herb or vitamin, so it’s impossible to say which one was responsible for the benefit. Echinacea should not be used by women who are pregnant or breastfeeding, or by anyone taking drugs that suppress the immune system (such as corticosteroids or methotrexate).

Preventing colds

In addition to echinacea, several other herbs that are used to strengthen the immune system may also be beneficial in preventing you from catching a cold. As is true with echinacea, these herbs should be avoided by anyone taking drugs to suppress their immune system.

Andrographis (Andrographic paniculata) - One study found that andrographis, an herb used in Ayurvedic medicine, combined with eleuthero or Siberian ginseng (Eleutherococcus senticosus) in a formula called Kan Jang, helped reduce cold symptoms.
Garlic (Allium sativum) - In one study, people who took garlic for 12 weeks between November and February had 63 percent fewer colds than people who took placebo. Those who did get a cold recovered about one day faster. Because garlic can increase the risk of bleeding, people who take anticoagulants (blood-thinners, such as aspirin or warfarin) should not take garlic. Women who are pregnant or breastfeeding should talk to their doctor before taking garlic supplements.
Ginseng (Panax quinquefolius, 400 mg per day) - At least two studies suggest that taking American ginseng may help prevent colds, as well as reduce the number of colds experienced and the severity of symptoms.

Treating colds

Elder or elderberry (Sambucus nigra) - By lessening congestion and possibly helping you sweat, elder may help reduce the symptoms of colds and flu. One study suggested that using a standardized elderberry extract, Sambucol™, could shorten the duration of flu by about three days. Sambucol™ also contains other herbs plus vitamin C, so it isn’t known whether elder by itself would have the same effect. Pregnant and breast-feeding women should not take elder.
Eucalyptus (Eucalyptus globulus) - Eucalyptus is used in many remedies to treat cold symptoms, particularly cough. It can be found in many lozenges, cough syrups, and vapor baths throughout the United States and Europe. Fresh leaves can be used in teas and gargles to soothe sore throats. Ointments containing eucalyptus leaves are also applied to the nose and chest to relieve congestion and loosen phlegm.
Goldenseal (Hydrastis canadensis) - Goldenseal is often combined with echinacea in herbal cold remedies, although scientific evidence that it works is lacking. Women who are pregnant or breast-feeding should talk to their doctor before taking goldenseal.
Licorice (Glycyrrhiza glabra) - Licorice root is a traditional treatment for sore throat, although scientific evidence is lacking. Licorice interacts with a number of medications, so ask your doctor before taking it. People with high blood pressure or heart disease, women who are pregnant or breast-feeding, and those who take anticoagulants (blood thinners) should not take licorice.
Marshmallow (Althea officinalis) - Although there isn’t any scientific evidence that it works, marshmallow has been used traditionally to treat sore throat and cough.
Peppermint (Mentha x piperita) - Like eucalyptus, peppermint is widely used to treat cold symptoms. Its main active agent, menthol, is a good decongestants. Menthol also thins mucus and works as an expectorant, meaning that it helps loosen and break up phlegm. It is soothing and calming for sore throats and dry coughs as well.
Slippery elm (Ulmus fulva) - Slippery elm may help ease sore a sore throat and has been used traditionally for this purpose, although scientific evidence is lacking.

Homeopathy

Although very few studies have examined the effectiveness of specific homeopathic therapies, professional homeopaths may consider the following remedies for the treatment of the common cold based on their knowledge and experience. It is important to note, however, that cold symptoms are viewed in homeopathic medicine as the body's natural way of eliminating a virus. For this reason, homeopathic doctors may recommend no treatment at all. If a remedy is selected, usually it is intended to boost the body's natural immune response. Before prescribing a remedy, homeopaths take into account a person's constitutional type. A constitutional type is defined as a person's physical, emotional, and psychological makeup. An experienced homeopath assesses all of these factors when determining the most appropriate treatment for each individual.

Aconitum - for symptoms including fever, anxiety, and thirst, that start abruptly, often following exposure to a cold climate or draft; most effective during the first 24 hours of the illness
Allium cepa - for colds with clear watery discharge that burns and/or irritates the nostrils; red, burning eyes; and symptoms that worsen in warm rooms and in the evening
Arsenicum album - for colds with watery, burning discharge from the eyes and nose, throbbing headache, nasal congestion that is not relieved by sneezing, dry mouth, sensitivity to cold, and a thirst for small sips of fluid
Belladonna - for colds with sudden onset of high fever, flushed face, watery nasal discharge, sore throat, throbbing headache, earache, and cough that tends to worsen at night; this remedy is most appropriate for individuals who are often agitated and sometimes delirious; these symptoms may cause children to cry
Bryonia - for chest colds with spastic cough that produces only a small amount of mucus and sharp chest pain that worsens with inhalation and while coughing; a dull headache, little to no nasal discharge, and sneezing may also be present
Euphrasia - for colds with excessive, non-irritating watery discharge that tends to worsen in the morning and when the person is lying down
Ferrum phosphoricum - for the early stages of a cold with slight fever, flushed face (redness may be patchy), and fatigue; may also be used in children with nosebleeds or bloody nasal discharge
Gelsemium - for colds that have gradual onset with watery nasal discharge that causes irritation, a feeling of fullness or tickling in the nose and/or the back of the throat, muscle aches, fatigue, lack of energy, lightheadedness or spaciness, and a headache with pain in the back of the head
Hepar sulphuricum - for late stages of a cold when nasal discharge turns from watery to thick, yellow, and foul smelling; symptoms tend to worsen in the evening and with cold and wind
Mercurius - for fluctuating body temperature and thick, yellow nasal discharge with a foul odor; symptoms may also include bad breath and a swollen tongue
Pulsatilla - for coughs and nasal congestion with thick, yellow-green mucus that does not burn the skin; symptoms tend to worsen in warm, stuffy rooms and when the person is lying on his or her back; this remedy is most appropriate for children (even newborns) and adults who are weepy, have mood swings, and are easily influenced by others

Mind-Body Medicine

A study of a small number of university students suggests that practicing relaxation techniques on a regular basis may help reduce the duration of a cold or the flu. A similar study of children reached the same conclusion. Some good stress reduction techniques include meditation, deep relaxation, yoga, tai chi, and breathing exercises.

Other Considerations

Pregnancy

Tell your healthcare provider if you are pregnant or think you are pregnant. Some medications, herbs, and supplements may be harmful to your baby and should not be taken if you are pregnant or trying to become pregnant.

Special Populations

If you have asthma, emphysema, or any other respiratory disease, you should talk to your doctor as soon as you develop cold symptoms.

Warnings and Precautions

If your symptoms aren’t better in 7 to 10 days, you should call your doctor. Other reasons to see your doctor include high fever (above 102° Fahrenheit), thick, green nasal discharge, or development of a productive cough (cough with phlegm), especially if it is thick and green as well.

Prognosis and Complications

Colds usually get better within 7 to 10 days. Some potential complications include:

Worsening of a pre-existing respiratory condition, such as asthma or emphysema
Bronchitis
Pneumonia
Ear infection
Sinusitis

Supporting Research

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Review Date:
12/19/2007
Reviewed By:
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

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Fly Pig Marathon: 5.6.07

FitSugar — Tue, 09 Jan 2007 09:15:00 -0800

Looking for a marathon in the Midwest to satisfy your desire to be a marathon runner?

This year's annual Cincinnati Flying Pig Marathon (Half Marathon, Flying Pig 10K and Flying Pig 5K) will be on May 6th, 2007. The Flying Pig Marathon has made its mark as being the third-largest first-timer's marathon in the country. Welcoming athletes of all running abilities, this is a race where you can find out if this 'marathon thing' is really for you. What's more? With over 25 support stations and entertainment all along the course, you might even have a good time running.

Registration is going on now and if you register before January 19th, 2007 the fee is only $60 (the later you wait, the higher the fee is and you risk the races filling up). For more info and to register, visit the Flying Pig Marathon site.

Part 1 - DrSugar Answers: Losing Too Much Weight Running?

DrSugar — Tue, 19 Aug 2008 05:30:00 -0700

DrSugar is in the house and answering your questions.

This is an interesting multi-faceted question. DrSugar and I decided we should both tackle this one. To read what DrSugar has to say about this, just read more.

First, your workout regimen is very impressive and I commend your marathon aspirations. However, there is such a thing as too much of a good thing. In women, missed periods are a sign of excessive exercise. There are many different causes of missed periods, but given your exercise routine, over exercise is the most likely cause. The missed periods themselves are not dangerous, but they are a sign that you may be over stressing your body and putting yourself at risk for injury. The loss of periods is a reflection of decreased levels of estrogen, which can lead to osteoporosis. To help prevent this unintended consequence of strenuous exercise it is important to consume adequate amounts of calcium and vitamin D. Other potential detrimental effects of excessive exercise include stress fractures, decreased immune system function, joint problems, headaches, insomnia, and emotional problems. It is important to maintain an adequate caloric intake and to take days off to let your body rest and heal. Good luck with the marathon and remember that there is such a thing as too much training.

Don't forget to read part two of this answer: Part 2 - You Asked: Losing Too Much Weight Running?

If you have a question for DrSugar, send me a private message here and I will forward it to the good doctor.

DrSugar's posts are for informational purposes only and should not be considered medical advice, diagnosis, or treatment recommendations. Click here for more details.