PCOS

Polycystic ovary syndrome (PCOS) is the most common endocrine disturbance in women of reproductive age; it affects an estimated five percent to 10 percent of females. PCOS, which is also is called Stein-Leventhal Syndrome after the doctors who first characterized it in the 1930s, is a cause of infertility. It is also now recognized as being associated with long-term risks of diabetes and cardiovascular disease.

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As the term polycystic ovary syndrome suggests, the syndrome often is accompanied by enlarged ovaries containing multiple small cysts. During the normal ovulatory process, an egg is stimulated in an ovarian follicle, which then ruptures and releases the egg. In women with PCOS, high levels of hormones called androgens halt the normal hormonal process and the egg’s development. These follicles — whose appearance (via an ultrasound) is sometimes likened to a string of pearls — form the cysts observed in PCOS.

Note that the name is a bit misleading — not every woman with PCOS has cysts, and many women who have cysts don’t have PCOS.

While the biochemical imbalances that cause symptoms are becoming better understood, the trigger for PCOS is unknown. Researchers suspect a genetic predisposition plays a role. One recent study at Mt. Sinai Hospital in New York found a possible connection between a gene that helps the body use insulin and PCOS. Other studies have found that excess insulin production stimulates testosterone production and leads to insulin resistance, which is a precursor to Type II diabetes. Insulin also limits production of a hormone that absorbs testosterone and similar compounds.

The most visible symptoms of PCOS stem from excessive levels of androgens, such as testosterone, which in women are produced in the ovaries, adrenal glands and in fat cells. Testosterone can be converted to a more powerful androgen, dihydrotestosterone (DHT) in areas that affect the skin and hair. Androgens often are called “male hormones,” even though they are found in both men and women. They are usually present at much higher levels in men and are an important factor in male traits and reproductive activity. Androgens include testosterone, DHT and androstenedione. Other hormones can be converted into testosterone or DHT, including dehydroepiandrosterone (DHEA), DHEA sulfate and estradiol.

Excessive levels of these hormones (hyperandrogenism) in women can lead to some of the most common symptoms of PCOS, including:

* excess body or facial hair

* oily skin and acne

* oligo ovulation

But such symptoms alone are not enough to support a diagnosis of PCOS. They may only indicate hyperandrogenism, which can be treated with anti-androgen medications.

The diagnosis of PCOS hinges on irregular and/or infrequent ovulation, as indicated by irregular menstrual periods. Birth control pills are usually prescribed to give women regular menses. If periods are absent, it is important to induce them from time to time, whether through daily birth control or less frequent courses of the hormone progesterone, because menstruation prompts the shedding of the uterine lining, preventing a build up of the lining which increases endometrial cancer risk.

PCOS often is a cause of infertility due to failure to ovulate. The usual course of treatment here is a drug called clomiphene citrate. If that doesn’t work, the usual next step is injectable gonadotropins. Many health care professionals are increasingly prescribing insulin-sensitizing drugs designed to treat diabetes to induce ovulation with or without clomiphene citrate. Small studies indicate such drugs may be effective for both infertility and other symptoms of PCOS.

PCOS is strongly linked to obesity and insulin resistance (a precursor to Type II diabetes) and, for women with PCOS who are obese, a treatment plan will usually incorporate a diet and exercise program. About one-third of women with PCOS who are obese have insulin resistance or Type II diabetes.

Obesity in women with PCOS tends to be centered on the abdomen, a fat distribution pattern linked to increased risk of diabetes, heart disease and high blood pressure. Due most likely to underlying endocrinological dysfunction, women with PCOS are more apt to gain weight and have more trouble losing weight.

There is no cure for PCOS. Health care professionals usually address the symptoms that are most bothersome to a particular woman. Because of the complexity of the hormonal interactions, you may need to see an endocrinologist or a reproductive endocrinologist (especially if you are infertile and trying to conceive).

For many, the syndrome begins at puberty, with irregular or absent periods, but for others PCOS symptoms may first become noticeable in their early 20s. Onset of PCOS becomes less likely as a woman ages. The metabolic endocrine abnormalities of PCOS are possible even for women whose ovaries have been removed because androgens can be produced elsewhere in the body.

There is no simple test for PCOS. Your health care professional will do a thorough history and physical examination, perhaps with lab tests, to determine whether your symptoms stem from PCOS or another disorder. Diagnosis begins with an inventory of symptoms, the most common of which are:

* hirsutism (excess body and/or facial hair, particularly on the chin, upper lip, breasts, inner thighs and abdomen)

* irregular or infrequent periods

* obesity

* acne and/or oily skin (particularly severe acne in teenagers or acne that persists into adulthood)

* infertility

* ovarian cysts

* hair loss or balding

* acanthosis nigricans (darkening of the skin, usually on the neck; AN is a sign of insulin problems as well)

* skin tags, small pieces of excess skin in the armpit or neck area

Women with PCOS may have varying combinations of symptoms, but two essential features of the disorder are:

* Hyperandrogenism, excess blood levels of androgens or symptoms indicating hyperandrogenism. Androgens are hormones such as testosterone that, in excess quantities, cause such symptoms as hirsutism and acne. In more severe cases, “virilization” may take place, including such symptoms as clitoromegaly (an enlarged clitoris), balding at the temples, voice deepening, and muscle growth.

* Lack of ovulation, or irregular ovulation along with irregular or absent menstruation. Women with PCOS may have oligomenorrhea (eight or fewer periods per year) or amenorrhea (absence of periods for extended periods). Some women with PCOS have polymenorrhea, or periods that are too frequent.

Hormonal disorders are complex and symptoms often suggest more than one potential cause. The diagnostic process likely will include a thorough physical and history to check for hypothyroid, Cushing’s syndrome and tumors. While there is no test for PCOS, a health care professional may want to measure your blood levels of the following:

* thyroid hormone (low thyroid symptoms often are similar to those of PCOS)

* prolactin (high levels of this hormone, which stimulates milk production, often are similar to those of PCOS)

* androgens, including dehydroepiandrosterone sulfate and testosterone (high levels of these hormones, often referred to as “male hormones,” are frequently associated with PCOS and cause “male-like” symptoms such as excess body or facial hair)

* level of follicle-stimulating hormone and luteinizing hormone (a high ratio of LH to FSH — typically three-to-one — is characteristic of PCOS; follicle stimulating hormone promotes the development of egg-containing follicles in the ovaries, while luteinizing hormone stimulates ovulation and encourages the empty follicle to revert to glandular tissue.)

These tests should be interpreted by a health care professional familiar with them, such as an endocrinologist. The best time to be tested is in the morning shortly after the beginning of a menstrual period (you may need medication to induce menstruation). You should know that birth control pills, because they change hormonal balance, might make the tests difficult to interpret.

Your health care professional may also order ultrasound imaging of the ovaries to look for the characteristic picture of multiple cysts. The test involves insertion of a probe into the vagina. Such a test, however, is not definitive, since it is very common for women without PCOS to have cysts; it is also common for women with PCOS to not have cysts. The ultrasound, however, can help confirm a diagnosis and examine the endometrial lining for abnormalities. Health care professionals rarely remove benign cysts, opting more often to prescribe lifestyle modifications and medication to treat symptoms.

If you have PCOS, you should be tested and treated for other conditions that are associated with the syndrome (or thought to be), such as insulin resistance and Type II diabetes, obesity, high blood pressure and elevated blood lipids (cholesterol and triglycerides). The connection between PCOS and insulin and lipid problems is a strong one, though the reasons are not thoroughly understood.

About one in 10 cases of diabetes in premenopausal women can be linked to PCOS. The syndrome may also boost risk for heart disease, although long-term, definitive studies have yet to be completed.

Some drugs are associated with “masculinization” symptoms, most notably steroids. Alternative medications may take care of the problem.

Occasionally, such symptoms are the result of an androgen-producing tumor. If your testosterone level is above 200 mg/dl, your health care professional may want to investigate further.

Treatment of polycystic ovary syndrome (PCOS) centers on lifestyle modifications and medication. Surgical procedures — cauterization of ovarian cysts or wedge resection to reduce the size of cysts – are less likely to be performed today, due to recent successes with ovulation-inducing medications. Usually, a health care professional will recommend surgical removal only if a cyst is thought to be potentially cancerous.

Because the primary cause of PCOS is unknown, treatment is presently directed at the symptoms of the disorder. For some women, the most bothersome symptom is hirsutism (excess facial and/or body hair, often dark and coarse). This symptom, as well as acne and oily skin, stems from overproduction of androgens. For women with such symptoms, spironolactone (Aldactone or Spironol) may be prescribed. The drug, a diuretic, has few side effects, and at high doses can clear oily skin and make unwanted hair finer (electrolysis or laser processes can remove hair permanently). It works by blocking the action of testosterone at the hair cell. Flutamide (Eulexin) is similar to spironolactone, but has potentially severe side effects. If you are trying to conceive, however, an anti-androgen medication cannot be used because it can cross the placenta and cause defects in a male fetus.

Bear in mind that it can take up to nine months to see effects on hair growth, and a year to achieve peak effect. The hair will still be there, but will generally grow more slowly and will be lighter and finer. Electrolysis or repeated laser treatments are the only ways to get rid of the hair for extended periods or permanently.

Recently, the U.S. Food and Drug Administration (FDA) approved Vaniqa (eflornithine hydrochloride), a prescription medication cream that reduces unwanted facial hair. The medication is applied to the face twice per day in the same manner as moisturizer and works by blocking a key enzyme that makes hair grow. It must be used regularly or else hair growth will resume.

For acne, spironolactone, and birth control pills (which decrease ovarian androgen production) are often particularly effective in combination, although other medications may also be prescribed for acne, such as oral or topical antibiotics, Accutane (which can cause birth defects), or peeling medications such as Retin-A.

A steroid such as dexamethasone may be prescribed if the primary source of excess androgens appears to be the adrenal glands (as evidenced by high levels of DHEA-S). Because they are used at very low doses, they do not cause the usual side effects associated with steroids.

There has been some speculation that a drug used to treat enlarged prostate and baldness in men — called finasteride (Propecia) — may be useful in women with hyperandrogenism symptoms, including hirsutism. The drug stops an enzyme called 5-alpha reductase, which converts testosterone to the more powerful dihydrotestosterone. Finasteride, however, can cause birth defects (indeed, pregnant women should not even handle crushed tablets).

If irregular and/or infrequent menstruation is a problem, birth control pills (typically incorporating estrogen and progestin) can probably get you on schedule again. During menstruation, the lining of the uterus is shed, providing protection against uterine cancer, so restoring regular periods is essential. Some women may not want to take a daily medication, so a course of progestogen may be prescribed several times a year for women who are amenorrheic (absence of menstruation) to induce periods. Side effects of oral contraceptives include migraines, blood clots (especially among smokers), gallbladder disease and high blood pressure. Note that it is critical to have at least four periods a year to promote shedding of the endometrial lining; build up can lead to cancer.

Infertility often is a consequence of PCOS. The first line of treatment if you have the syndrome and cannot conceive is usually an ovulation-stimulating drug called clomiphene citrate, which is sold under the brand name Clomid.

Until recently, a combination of injectable chorionic gonadotropin and gonadotropin was the next step for women who did not get pregnant using clomiphene. But this gonadotropin, in addition to being inconvenient and expensive, can lead to ovarian hyperstimulation syndrome, which is more common in women with PCOS and can lead to enlarged ovaries, escape of fluid into the abdomen, low blood volume and stroke.

Insulin-sensitizing drugs offer a new alternative for treating PCOS symptoms, particularly infertility, and are increasingly being prescribed if an initial course of clomiphene doesn’t result in pregnancy. These products were designed to treat Type II diabetes and are approved by the FDA for that. The class includes metformin (sold under the name Glucophage), pioglitazone (Actos) and rosiglitazone (Avandia). Clinical trials are under way that may ultimately lead to the FDA’s sanctioning them specifically for PCOS.

Some physicians prescribe metformin for women with PCOS, not just those with fertility problems. Some women resume regular menstrual cycles on metformin, but so far only one long-term study has been done, and it showed that the male-hormone symptoms didn’t get better (someone with severe male hormone problems would need an anti-androgen as well). Health care professionals are sharply divided on the issue of using insulin-sensitizers in PCOS patients.

If prescribed an insulin sensitizer, be sure to inform your health care professional of all other medications you take, including over-the-counter medicines, to prevent drug interactions.

If you are among the seven to eight percent of women with PCOS who already have Type II diabetes, metformin is a good therapeutic option.

Another available option for women who fail to ovulate with clomiphene or metformin therapy, or are unwilling/unable to use gonadotropins, is a new surgical procedure known as laparoscopic ovarian drilling. The technique employs a laser fibre or electrosurgical needle to puncture each ovary four to 20 times. This treatment results in a dramatic lowering of male hormones within days. Over a dozen studies have shown that up to 80 percent of women with PCOS will benefit from such treatment. Many who failed to ovulate with clomiphene or metformin therapy will respond when re-challenged with these medications after ovarian drilling. The success rates for laparoscopic ovarian drilling appear to be better for patients at or near their ideal body weight, as opposed to those with obesity. Interestingly, women in these studies who are smokers, rarely responded to the drilling procedure. Side effects are rare, but may result in adhesion formation or ovarian failure if an inexperienced surgeon performs the procedure.

PCOS is associated with insulin resistance and diabetes, but not all women who have PCOS are insulin-resistant or diabetic. If you have PCOS, you should also be evaluated for diabetes with both a fasting glucose test and a glucose challenge test with insulin levels. The fasting glucose test is the standard, but that test alone misses about half the women with concomitant insulin levels with PCOS who have diabetes or insulin resistance.

Long-term non-medical treatment is geared toward modifying your risk factors for health problems that often are associated with PCOS, including diabetes, uncontrollable weight and heart disease. A healthy low-sugar diet and an exercise program can reduce the risk.

You can take care of some problems associated with PCOS without medications. Excess hair can be removed by shaving, tweezing, waxing or using depilatory creams, or by electrolysis or laser techniques administered by a trained professional. Since lasers work by attacking a skin pigment, they should be used with caution by darker skinned women. If you are overweight and have PCOS, weight loss is recommended. Losing weight can lower levels of androgens and insulin, thereby reducing your risk of developing insulin resistance and diabetes. One study found that when obese women lose even seven percent of body weight, they cut androgen levels significantly and improve menstrual regularity.

There is no known way to prevent polycystic ovary syndrome (PCOS). Researchers are still working to understand the underlying causes. However, there are steps you can take to prevent some of the worst consequences of the disorder — diabetes, uterine cancer, high blood pressure and high levels of blood lipids (a risk factor for heart disease).

If you do not menstruate, inducing menstruation should be a top priority. During menstruation, the endometrial lining is shed in response to the progestogen hormone. Without this shedding, your risk of uterine cancer rises significantly. Birth control pills, which combine estrogen and progestin, can restore regular periods. If you don’t want to take a daily medication, a course of a progestogen may be prescribed about four times a year.

If you are overweight, losing weight is a big step toward lowering your risk for diabetes and heart disease. Losing weight can help restore regular periods and improve other hormonal imbalances, but weight loss is often an incomplete solution to PCOS.

Research and New Treatments on the Horizon

At the 57th Annual Meeting of the American Society for Reproductive Medicine (Oct. 20-25, 2001, Orlando, Florida) researchers at the University of Toronto, Canada presented results of a study investigating letrazole as a single-dose treatment of infertility in PCOS patients and patients with unexplained infertility. Unlike clomiphene, it has no adverse, antiestrogenic effects on the endometrium. Currently, it is available in the U.S. as an adjuvant treatment for breast cancer. Further large, prospective studies will have to evaluate letrazole as an ovulation-inducing agent, but the data presented so far are promising. Letrazole could become another treatment option for unexplained infertility and PCOS.

Studies are being conducted to see if the insulin sensitizer D-chiro-inositol, a natural substance found in buckwheat, increases the action of insulin, leading to improved ovulatory function and reducing androgen production, blood pressure, and triglycerides. Clinical trials are currently underway to identify the gene or genes that predispose individuals to PCOS. The discovery of a PCOS gene(s) will increase knowledge about this condition and potentially lead to better diagnostic testing and treatment.

Studies are being conducted to examine the effect of a new surgical procedure called “laparoscopic ovarian diathermy” on the body’s level of insulin and to see what relationship there is between the insulin levels and male hormones. The surgical procedure lowers levels of male hormone produced by the ovary. The study will also examine the effect that lowering male hormone levels will have on one of the brain messengers to the ovary, luteinizing hormone.

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