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Polycystic Ovary Syndrome

Polycystic Ovary Syndrome

Definition

Polycystic ovary syndrome (PCOS) is a condition characterized by the accumulation of numerous cysts (fluid-filled sacs) on the ovaries associated with high male hormone levels, chronic anovulation (absent ovulation), and other metabolic disturbances. Classic symptoms include excess facial and body hair, acne, obesity, irregular menstrual cycles, and infertility.

Description

PCOS, also called Stein-Leventhal syndrome, is a group of symptoms caused by underlying hormonal and metabolic disturbances that affect about 6% of premenopausal women. PCOS symptoms appear as early as adolescence in the form of amenorrhea (missed periods), obesity, and hirsutism, the abnormal growth of body hair.

A disturbance in normal hormonal signals prevents ovulation in women with PCOS. Throughout the cycle, estrogen levels remain steady, luteinizing hormone (LH) levels are high, and follide stimulating hormone (FSH) and progesterone levels are low. Since eggs are rarely or never released from their follicles, multiple ovarian cysts develop over time.

One of the most important characteristics of PCOS is hyperandrogenism, the excessive production of male hormones (androgens), particularly testosterone, by the ovaries. This accounts for the male hair-growth patterns and acne in women with PCOS. Hyperandrogenism has been linked with insulin resistance (the inability of the body to respond to insulin) and hyperinsulinemia (high blood insulin levels), both of which are common in PCOS.

Causes and symptoms

While the exact cause of PCOS is unknown, it runs in families, so the tendency to develop the syndrome may be inherited. The interaction of hyperinsulinemia and hyperandrogenism is believed to play a role in chronic anovulation in susceptible women.

The numbers and types of PCOS symptoms that appear vary among women. These include:

  • Hirsutism. Related to hyperandrogenism, this occurs in 70% of women.
  • Obesity. Approximately 40-70% of persons with PCOS are overweight.
  • Anovulation and menstrual disturbances. Anovulation appears as amenorrhea in 50% of women, and as heavy uterine bleeding in 30% of women. However, 20% of women with PCOS have normal menstruation.
  • Male-pattern hair loss. Some women with PCOS develop bald spots.
  • Infertility. Achieving pregnancy is difficult for many women with PCOS.
  • Polycystic ovaries. Most, but not all, women with PCOS have multiple cysts on their ovaries.
  • Skin discoloration. Some women with PCOS have dark patches on their skin.
  • Abnormal blood chemistry. Women with PCOS have high levels of low-density lipoprotein (LDL or "bad") cholesterol and triglycerides, and low levels of high-density lipoprotein (HDL or "good") cholesterol.
  • Hyperinsulinemia. Some women with PCOS have high blood insulin levels, particularly if they are overweight.

Diagnosis

PCOS is diagnosed when a woman visits her doctor for treatment of symptoms such as hirsutism, obesity, menstrual irregularities, or infertility. Women with PCOS are treated by a gynecologist, a doctor who treats diseases of the female reproductive organs, or a reproductive endocrinologist, a specialist who treats diseases of the body's endocrine (hormones and glands) system and infertility.

PCOS can be difficult to diagnose because its symptoms are similar to those of many other diseases or conditions, and because all of its symptoms may not occur. A doctor takes a complete medical history, including questions about menstruation and reproduction, and weight gain. Physical examination includes a pelvic examination to determine the size of the ovaries, and visual inspection of the skin for hirsutism, acne, or other changes. Blood tests are performed to measure levels of luteinizing hormone, follicle stimulating hormone, estrogens, androgens, glucose, and insulin. A glucose-tolerance test may be administered. An ultrasound examination of the ovaries is performed to evaluate their size and shape. Most insurance plans cover the costs of diagnosing and treating PCOS and its related problems.

Treatment

PCOS treatment is aimed at correcting anovulation, restoring normal menstrual periods, improving fertility, eliminating hirsutism and acne, and preventing future complications related to high insulin and blood lipid (fat) levels. Treatment consists of weight loss, drugs or surgery, and hair removal, depending upon which symptoms are most bothersome, and whether a woman desires pregnancy.

Weight loss

In overweight women, weight loss (as little as 5%) through diet and exercise may correct hyperandrogenism, and restore normal ovulation and fertility. This is often tried first.

Drugs

HORMONAL DRUGS. Women who do not want to become pregnant and require contraception (spontaneous ovulation occurs occasionally among women with PCOS) are treated with low-dose oral contraceptive pills (OCPs). OCPs bring on regular menstrual periods and correct heavy uterine bleeding, as well as hirsutism, although improvement may not be seen for up to a year.

If an infertile woman desires to become pregnant, the first drug usually given to help induce ovulation is clomiphene citrate (Clomid), which results in pregnancy in about 70% of women but can cause multiple births. In the 20-25% of women who do not respond to clomiphene, other drugs that stimulate follicle development and induce ovulation, such as human menstrual gonadotropin (Pergonal) and human chorionic gonadotropin (HCG), are given. However, these drugs have a lower pregnancy rate (less than 30%), a higher rate of multiple pregnancy (from 5-30%, depending on the dose of the drug), and a higher risk of medical problems. Women with PCOS have a high rate of miscarriage (30%), and may be treated with the gonadotropin-releasing hormone agonist leuprolide (Lupron) to reduce this risk.

Since women with PCOS do not have regular endometrial shedding due to high estrogen levels, they are at increased risk for overgrowth of this tissue and endometrial cancer. The drug medroxyprogesterone acetate, when taken for the first 10 days of each month, causes regular shedding of the endometrium, and reduces the risk of cancer. However, in most cases, oral contraceptive pills are used instead to bring about regular menstruation.

OTHER DRUGS. Another drug that helps to trigger ovulation is the steroid hormone dexamethasone. This drug acts by reducing the production of androgens by the adrenal glands.

The antiandrogen spironolactone (Aldactazide), which is usually given with an oral contraceptive, improves hirsutism and male-pattern baldness by reducing androgen production, but has no effect on fertility. The drug causes abnormal uterine bleeding and is linked with birth defects if taken during pregnancy. Another antiandrogen used to treat hirsutism, flutamide (Eulexin), can cause liver abnormalities, fatigue, mood swings, and loss of sexual desire. A drug used to reduce insulin levels, metformin (Glucophage), has shown promising results in women with PCOS hirsutism, but its effects on infertility and other PCOS symptoms are unknown. Drug treatment of hirsutism is long-term, and improvement may not be seen for up to a year or longer.

Acne is treated with antibiotics, antiandrogens, and other drugs such as retinoic acids (vitamin A compounds).

Surgical treatment

Surgical treatment of PCOS may be performed if drug treatment fails, but it is not common. A wedge resection, the surgical removal of part of the ovary and cysts through a laparoscope (an instrument inserted into the pelvis through a small incision), or an abdominal incision, reduces androgen production and restores ovulation. Although laparoscopic surgery is less likely to cause scar tissue formation than abdominal surgery, both are associated with the potential for scarring that may require additional surgery. Laparoscopic ovarian drilling is another type of laparoscopic surgery used to treat PCOS. The ovarian cysts are penetrated with a laser beam and some of the fluid is drained off. Between 50-65% of women may become pregnant after either type of surgery.

Some cases of severe hirsutism are treated by removal of the uterus (hysterectomy ) and the ovaries (oopherectomy), followed by estrogen replacement therapy.

Other treatment

Hirsutism may be treated by hair removal techniques such as shaving, depilatories (chemicals that break down the structure of the hair), tweezing, waxing, electrolysis (destruction of the hair root by an electrical current), or the destruction of hair follicles by laser therapy. However, the treatments may have to be repeated.

Alternative treatment

PCOS can be addressed using many types of alternative treatment. The rebalancing of hormones is a primary focus of all these therapies. Acupuncture works on the body's energy flow according to the meridian system. Chinese herbs, such as gui zhi fu ling wan, can be effective. In naturopathic medicine, treatment focuses on helping the liver function more optimally in the horomonal balancing process. Dietary changes, including reducing animal products and fats, while increasing foods that nourish the liver such as carrots, dark green vegetables, lemons, and beets, can be beneficial. Essential fatty acids, including flax oil, evening primrose oil (Oenothera biennis ), and black currant oil, act as anti-inflammatories and hormonal regulators. Western herbal medicine uses phytoestrogen and phytoprogesteronic herbs, such as blue cohosh (Caulophyllum thalictroides ) and false unicorn root (Chamaelirium luteum ), as well as liver herbs, like dandelion (Taraxacum mongolicum ), to work toward hormonal balance. Supplementation with antioxidants, including zinc, and vitamins A, E, and C, is also recommended. Constitutional homeopathy can bring about a deep level of healing with the correct remedies.

Prognosis

With proper diagnosis and treatment, most PCOS symptoms can be adequately controlled or eliminated. Infertility can be corrected and pregnancy achieved in most women although, in some, hormonal disturbances and anovulation may recur. Women should be monitored for endometrial cancer. Because of the high rate of hyperinsulinemia seen in PCOS, women with the disorder should have their glucose levels checked regularly to watch for the development of diabetes. Blood pressure and cholesterol screening are also needed because these women also tend to have high levels of LDL cholesterol and triglycerides, which put them at risk for developing heart disease.

Prevention

There is no known way to prevent PCOS, but if diagnosed and treated early, risks for complications such as and heart disease and diabetes may be minimized. Weight control through diet and exercise stabilizes hormones and lowers insulin levels.

KEY TERMS

Androgens Male sex hormones produced by the adrenal glands and testes, the male sex glands.

Anovulation The absence of ovulation.

Antiandrogens Drugs that inhibit androgen production.

Estrogens Hormones produced by the ovaries, the female sex glands.

Follicle stimulating hormone A hormone that stimulates the growth and maturation of mature eggs in the ovary.

Gynecologist A physician with specialized training in diseases and conditions of the female reproductive system.

Hirsutism An abnormal growth of hair on the face and other parts of the body caused by an excess of androgens.

Hyperandrogenism The excessive secretion of androgens.

Hyperinsulinemia High blood insulin levels.

Insulin resistance An inability to respond to insulin, a hormone produced by the pancreas that helps the body to use glucose.

Laparoscope An instrument inserted into the pelvis through a small incision.

Luteinizing hormone A hormone that stimulates the secretion of sex hormones by the ovary.

Ovarian follicles Structures found within the ovary that produce eggs.

Resources

BOOKS

DeGroot, Leslie J., and J. Larry Jameson. Endocribnology. 4th ed. Philadelphia: W B Saunders, 2001.

Genazzani, A. R., and F. Petraglia. Advances in Gynecological Endocrinology. London: Parthenon Press, 2001.

Nader, Shala. Case Studies in Reproductive Endocrinology. London: Edward Arnold, 2000.

Speroff, Leon. Handbook for Clinical Gynecologic Endocrinology and Infertility Philadelphia: Lippincott Williams & Wilkins, 2001.

Spratt, Daniel, and Nanette Santoro. Endocrinology and Management of Reproduction and Fertility: Practical Diagnosis and Treatment. Totowa, NJ: Humana Press, 2001.

PERIODICALS

Bracero, N., H. A. Zacur. "Polycystic ovary syndrome and hyperprolactinemia." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 77-84.

Calvo, R.M., et al. "Role of the follistatin gene in women with polycystic ovary syndrome." Fertility and Sterility 75, no. 5 (2001): 1020-102.

Dejager, S., et al. "Smaller LDL particle size in women with polycystic ovary syndrome compared to controls." Clinical Endocrinology (Oxford) 54, no. 4 (2001): 455-462.

Heinonen, S., et al. "Apolipoprotein E alleles in women with polycystic ovary syndrome." Fertility and Sterility 75, no. 5 (2001): 878-880.

Hoeger, K. "Obesity and weight loss in polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 85-97.

Iuorno, M. J., and J. E. Nestler. "Insulin-lowering drugs in polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 153-164.

Kalro, B. N., T. L. Loucks, and S. L. Berga. "Neuromodulation in polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 35-62.

Legro, R. S. "Diabetes prevalence and risk factors in polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 99-109.

Lewis, V. "Polycystic ovary syndrome. A diagnostic challenge." Obstetrics and Gynecology Clinics of North America 28, no. 1: 1-20.

Moran, C., and R. Azziz. "The role of the adrenal cortex in polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 63-75.

Padmanabhan, V., et al. "Dynamics of bioactive follicle-stimulating hormone secretion in women with polycystic ovary syndrome: effects of estradiol and progesterone." Fertility and Sterility 75, no. 5 (2001): 881-888.

Phipps, W. R. "Polycystic ovary syndrome and ovulation induction." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 165-182.

Talbott, E. O., et al. "Cardiovascular risk in women with polycystic ovary syndrome." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 111-133.

Zacur, H. A. "Polycystic ovary syndrome, hyperandrogenism, and insulin resistance." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 21-33.

Zborowski, J. V., et al. "Polycystic ovary syndrome, androgen excess, and the impact on bone." Obstetrics and Gynecology Clinics of North America 28, no. 1 (2001): 135-151.

ORGANIZATIONS

American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (913) 906-6000. http://www.aafp.org/. [email protected]

American Medical Association. 515 N. State Street, Chicago, IL 60610. (312) 464-5000. http://www.amaassn.org/.

Polycystic Ovarian Syndrome Association. PO Box 80517, Portlabd, OR 97280. (877) 775-7267. http://www.pcosupport.org/. [email protected]

OTHER

American Academy of Family Physicians. http://www.aafp.org/afp/20000901/1079.html.

Jewish Hospital of Cincinnati. http://uc.edu/gartsips/polycyst.htm.

Merck Manual. http://www.merck.com/pubs/mmanual/section18/chapter235/235d.htm.

Vanderbilt University School of Medicine. http://www.mc.vanderbilt.edu/peds/pidl/adolesc/polcysov.htm.

Women's Health-UK. http://www.womens-health.co.uk/pcos.htm.

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polycystic ovary syndrome

polycystic ovary syndrome (PCOS, Stein-Leventhal syndrome) n. a disorder characterized by enlarged ovaries with multiple small cysts, infertility due to failure of ovulation, amenorrhoea or oligomenorrhoea, hyperandrogenism, obesity, and insulin resistance.

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Polycystic ovary syndrome

Polycystic ovary syndrome

Definition

Polycystic ovary syndrome (PCOS), formerly Stein-Leventhal syndrome, is a disorder in which women do not experience normal release of eggs from the ovaries, they have an abnormal production of male hormones, and their body is resistant to the effects of the hormone insulin. The disorder results in infertility, abnormal masculinization, and increased risk of developing heart disease and certain cancers.

Description

The normal function of the female reproductive system is complex, requiring the interplay of different organ systems. One set of important organs are the ovaries. The ovaries are two small structures contained in the lower abdomen, on either side of the uterus, that contain small immature eggs, called ova. Ova are stored within the ovaries in individual structures called follicles.

In a monthly cycle, a part of the brain called the pituitary gland secretes two substances into the blood stream—lutenizing hormone (LH) and follicle-stimulating hormone (FSH). As certain levels of LH and FSH build in the blood stream, the follicles of the eggs begin to swell and grow, creating cysts. Eventually, the changing levels of LH and FSH cause one of the ovarian cysts to burst open, releasing a mature egg. This process by which an egg is released from the ovary is called ovulation.

Once a mature egg is released from the ovary, it passes into the fallopian tubes, tube-like structures that are passageways to the uterus. If sperm cells from the male are present within the fallopian tubes, they will join with the egg in a process called fertilization. The fertilized egg can then pass into the uterus and implant into the thickened wall of the uterus where it can develop into a fetus. If no sperm cells are present, the mature egg goes unfertilized and is lost, along with the thickened later of the uterus, in a monthly process called menstruation.

Polycystic ovary syndrome (PCOS), first described by I. F. Stein and M. L. Leventhal in 1935, is a disorder in which normal ovulation does not occur. The term "polycystic" derives from the fact that the egg-containing cysts in the ovaries do not burst open, resulting in enlarged ovaries containing many swelled cysts. The reason for this problem in ovulation is unclear, however several abnormalities have been characterized in women with PCOS. First, there is a disturbance in the production of LH and FSH by the pituitary, leading to altered levels of the substances in the blood stream. There is also evidence that the ovaries do not respond appropriately to the FH and LSH that is present. Second, there is an abnormal over-production of male hormones, called androgens, by the ovaries and the adrenal gland. Finally, women with PCOS are resistant to the effects of the hormone, insulin. Insulin is a hormone made in the pancreas that is responsible for transport of sugar from the blood into the cells. While these abnormalities have been well characterized, it is unclear whether they cause PCOS, or whether they are a result the disease.

Genetic profile

Women diagnosed with PCOS frequently have relatives with symptoms similar to that seen in the disorder. As a result of these observations, many scientists have proposed that genetic factors play a role in the disease. Over the past few decades, researchers have identified families in which PCOS appears to be inherited with an autosomal dominant or an X-linked pattern. However, these cases are rare and do not hold true for the majority of people with PCOS.

Current theories suggest that different genetic changes may result in PCOS or that multiple genetic factors are needed for the full manifestation of the disease. Abnormalities in several genes have been associated with PCOS, including mutations in the genes for follistatin (locus 5p14), 17-beta-hydroxysteroid dehydrogenase (locus 9p22), and a cytochrome P450 enzyme (locus 15q23-q24). Each of these genes plays a different role in the response to LH and FSH, or in the conversion of male hormones to female hormones, although their relationship to PCOS is unclear. Ongoing research is likely to identify further genetic mutations that are associated with PCOS.

Demographics

Estimates of the prevalence of PCOS in the general population have ranged from 2-20% with recent studies suggesting that 3-6% of women of reproductive age are affected by the disorder. This makes PCOS one of the most common hormone disorders in women of reproductive age.

It is unclear whether this disease is distributed uniformly among different geographical areas and ethnic groups, however, studies performed in 1999 show the prevalence of this disorder in the United States is just over 3% in African-American females and almost 5% in Caucasian females. The prevalence of PCOS in Greek women was shown to be higher, nearly 7%.

Signs and symptoms

The first signs of PCOS tend to manifest at puberty. As a result of the failure to ovulate normally, young women with PCOS may fail to menstruate or menstruate only erratically. A small percentage of women may have normal menstrual cycles. Women affected with PCOS often experience infertility, an inability to become pregnant. Additionally, women with PCOS tend to gain weight, and 70% eventually become obese.

The overproduction of androgens leads to changes in the body that are more typical of male development. For example, approximately 70% of women with PCOS will show hair growth on the face, chest, stomach, and thighs (hirsuitism). Simultaneously, they show thinning of the hair more typical of male-pattern baldness. Other male characteristics, such as deep voice, acne, and increased sex drive may also be present, and affected women often have decreased breast size.

Women with PCOS do not respond appropriately to the hormone, insulin. As a result, 15% of women with PCOS may develop high levels of sugar in the blood later in life, a condition known as diabetes. Resistance to insulin is also associated with dark, warty skin growths in the groin and armpits, known as acanthosis nigricans.

Untreated PCOS is a risk factor for the development of several dangerous conditions. The hormone abnormalities in PCOS place women at considerable risk for endometrial cancer and possibly breast cancer . The risk of endometrial cancer is three times higher in women with PCOS than in normal women, and small studies suggest that the risk of breast cancer may by three to four times higher. PCOS also results in increased risk of high blood pressure, diabetes, and high cholesterol, all of which contribute to heart disease and stroke.

Diagnosis

A diagnostic search for PCOS is usually initiated when women experience an absence of menstrual periods for at least six months, an inability to become pregnant, and/or abnormal hair growth or acne. A comprehensive physical exam performed at that time may reveal excessive body hair, low voice, acanthosis nigricans, or obesity. Enlarged ovaries are also identifiable on pelvic examination in about 50% of patients.

Blood tests can be performed that may yield results consistent with PCOS, including abnormal levels of LH and FSH (typically in a ratio of 3:1), abnormally high levels of androgens (testosterone, DHEA, DHEAS), abnormally high levels of insulin, and abnormally low levels of a substance called sex hormone-binding globulin. In addition, a physician may perform a diagnostic test called a "progesterone challenge". In this test, a physician administers a hormone called progesterone to the patient to determine if it will provoke menstruation. If menstruation does occur in response to the progesterone, it is likely that a patient has PCOS.

Finally, an ultrasound examination of the ovaries may be performed to determine if large cystic follicles can be documented. With this approach, the diagnosis of PCOS is based on the finding of more than eight enlarged follicles in the ovary.

Treatment and management

There is no cure for PCOS, thus treatment focuses on several goals, including the restoration of the menstrual cycle, blocking the effect of androgens, reducing insulin resistance, lowering the risk of cancer and heart disease, and possibly restoring ovulation and fertility.

In patients who do not desire pregnancy, hormones can be administered in the form of birth control pills, which may result in normal menstrual cycles, decreased hair growth and acne, and a lower risk of developing endometrial cancer. Although women will note a decrease in hair growth after approximately six months of treatment with birth control pills, additional cosmetic hair removal therapy is often necessary. In women who do not respond appropriately to birth control pills, another medication known as luprolide (Lupron) can be used, but with more long term side effects (e.g., hot flushes, bone demineralization, atrophic vaginitis).

Other types of medication can be used to block the effects of androgens. When these medications are taken with birth control pills, 75% of women report decreased body hair growth. The most commonly used medications to block androgen effects are spironolactone (Aldactone), flutamide (Eulexin), and cyproterone (Cyprostat).

Treatment with medications that restore the body's normal response to insulin has been shown to decrease LH and androgen levels. Recent studies have demonstrated that such agents restore the menstrual cycle in 68-95% of patients treated for as short a time as four to six months. One of the most commonly used medications to improve the effects of insulin is metformin (Glucophage).

In patients who are trying to become pregnant, a physician can administer medications that will cause ovulation. The main medication used to induce ovulation is clomiphene citrate (Clomid). Ovulation is successful in approximately 75% of women treated with clomiphene, but only 30-40% of women will successfully become pregnant. Another medication, follitropin alpha (Gonal-F), has achieved pregnancy rates of 58-82%, but may cause more side effects and frequently results in more than one baby per pregnancy.

Some women who do not respond to medications may undergo surgery to remove portions of the ovary. For reasons that are not completely understood, removal of a portion of the ovary may result in some degree of normal menstrual cycles.

While medications and surgery may provide a degree of symptomatic relief for some women, other simultaneous strategies can increase their benefits. Behavior modifications, including weight reduction, diet, and exercise, are recommended for all women with PCOS. As little as a 7% reduction in body weight can lead to a significant decrease in androgen levels and to the resumption of ovulation in obese women with PCOS. Cosmetic techniques, including electrolysis (destruction of the hair follicle using electricity) and laser therapy, may be used to decrease hair growth. Finally, women should be seen regularly for full physical examinations including pelvic exams to aid in the early detection of ovarian, breast, and uterine cancer and should be managed by an interdisciplinary health care team including a primary care physician, obstetrician/gynecologist and reproductive endocrinologist.

Prognosis

While PCOS is one of the most common hormone disorders in young women, proper diagnosis and treatment has greatly increased the quality of life in these individuals. Roughly half of women with PCOS will be able to achieve pregnancy, and about three-fourths will see reduction in masculine traits such as hair growth with proper medical treatment. Initiation of vigorous exercise and a restricted diet may result in even better outcomes. It should be noted that patients with PCOS are at higher risk of developing diabetes, heart disease, and certain cancers and should be seen regularly by a physician. Barring these developments, lifespan in patients with PCOS is approximately the same as the general population.

Resources

BOOKS

"Disorders of Ovarian Function" In Williams Textbook of Endocrinology, edited by J. D. Wilson. Philadelphia: W.B. Saunders, 1998, pp 781-801.

"Hypofunction of the Ovaries." In Nelson Textbook of Pediatrics, edited by R.E. Behrman. Philadelphia: W.B. Saunders, 2000, pp 1752-1758.

Kistner's Gynecology and Women's Health, edited by K. J. Ryan. St. Louis: Mosby, 1999.

PERIODICALS

Hunter, M.H. "Polycystic Ovary Syndrome: It's Not Just Infertility." American Family Physician 62(September 2000): 1079-1088.

ORGANIZATIONS

Polycystic Ovarian Syndrome Association. PO Box 80517, Portland, OR 97280. (877) 775-PCOS. <http://www.pcosupport.org>.

WEBSITES

"Polycystic Ovary Syndrome 1." OMIM—Online Mendelian Inheritance in Man.<http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=184700>.

Oren Traub, MD, PhD

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Polycystic Ovary Syndrome

Polycystic ovary syndrome

Definition

Polycystic ovary syndrome (PCOS), formerly Stein-Leventhal syndrome, is a disorder in which women do not experience normal release of eggs from the ovaries, they have an abnormal production of male hormones, and their body is resistant to the effects of the hormone insulin. The disorder results in infertility, abnormal masculinization, and increased risk of developing heart disease and certain cancers.

Description

The normal function of the female reproductive system is complex, requiring the interplay of different organ systems. One set of important organs are the ovaries. The ovaries are two small structures contained in the lower abdomen, on either side of the uterus, that contain small immature eggs, called ova. Ova are stored within the ovaries in individual structures called follicles.

In a monthly cycle, a part of the brain called the pituitary gland secretes two substances into the blood stream—lutenizing hormone (LH) and follicle-stimulating hormone (FSH). As certain levels of LH and FSH build in the blood stream, the follicles of the eggs begin to swell and grow, creating cysts. Eventually, the changing levels of LH and FSH cause one of the ovarian cysts to burst open, releasing a mature egg. This process by which an egg is released from the ovary is called ovulation.

Once a mature egg is released from the ovary, it passes into the fallopian tubes, tube-like structures that are passageways to the uterus. If sperm cells from the male are present within the fallopian tubes, they will join with the egg in a process called fertilization. The fertilized egg can then pass into the uterus and implant into the thickened wall of the uterus where it can develop into a fetus. If no sperm cells are present, the mature egg goes unfertilized and is lost, along with the thickened later of the uterus, in a monthly process called menstruation.

Polycystic ovary syndrome (PCOS), first described by I. F. Stein and M. L. Leventhal in 1935, is a disorder in which normal ovulation does not occur. The term "polycystic" derives from the fact that the egg-containing cysts in the ovaries do not burst open, resulting in enlarged ovaries containing many swelled cysts. The reason for this problem in ovulation is unclear, however several abnormalities have been characterized in women with PCOS. First, there is a disturbance in the production of LH and FSH by the pituitary, leading to altered levels of the substances in the blood stream. There is also evidence that the ovaries do not respond appropriately to the FH and LSH that is present. Second, there is an

abnormal over-production of male hormones, called androgens, by the ovaries and the adrenal gland. Finally, women with PCOS are resistant to the effects of the hormone, insulin. Insulin is a hormone made in the pancreas that is responsible for transport of sugar from the blood into the cells. While these abnormalities have been well characterized, it is unclear whether they cause PCOS, or whether they are a result the disease.

Genetic profile

Women diagnosed with PCOS frequently have relatives with symptoms similar to that seen in the disorder. As a result of these observations, many scientists have proposed that genetic factors play a role in the disease. Over the past few decades, researchers have identified families in which PCOS appears to be inherited with an autosomal dominant or an X-linked pattern. However, these cases are rare and do not hold true for the majority of people with PCOS.

Current theories suggest that different genetic changes may result in PCOS or that multiple genetic factors are needed for the full manifestation of the disease. Abnormalities in several genes have been associated with PCOS, including mutations in the genes for follistatin (locus 5p14), 17-beta-hydroxysteroid dehydrogenase (locus 9p22), and a cytochrome P450 enzyme (locus 15q23-q24). Each of these genes plays a different role in the response to LH and FSH, or in the conversion of male hormones to female hormones, although their relationship to PCOS is unclear. Ongoing research is likely to identify further genetic mutations that are associated with PCOS.

Demographics

Estimates of the prevalence of PCOS in the general population have ranged from 2-20% with recent studies suggesting that 3-6% of women of reproductive age are affected by the disorder. This makes PCOS one of the most common hormone disorders in women of reproductive age.

It is unclear whether this disease is distributed uniformly among different geographical areas and ethnic groups, however, studies performed in 1999 show the prevalence of this disorder in the United States is just over 3% in African-American females and almost 5% in Caucasian females. The prevalence of PCOS in Greek women was shown to be higher, nearly 7%.

Signs and symptoms

The first signs of PCOS tend to manifest at puberty. As a result of the failure to ovulate normally, young women with PCOS may fail to menstruate or menstruate only erratically. A small percentage of women may have normal menstrual cycles. Women affected with PCOS often experience infertility, an inability to become pregnant. Additionally, women with PCOS tend to gain weight, and 70% eventually become obese.

The overproduction of androgens leads to changes in the body that are more typical of male development. For example, approximately 70% of women with PCOS will show hair growth on the face, chest, stomach, and thighs (hirsuitism). Simultaneously, they show thinning of the hair more typical of male-pattern baldness. Other male characteristics, such as deep voice, acne, and increased sex drive may also be present, and affected women often have decreased breast size.

Women with PCOS do not respond appropriately to the hormone, insulin. As a result, 15% of women with PCOS may develop high levels of sugar in the blood later in life, a condition known as diabetes . Resistance to insulin is also associated with dark, warty skin growths in the groin and armpits, known as acanthosis nigricans.

Untreated PCOS is a risk factor for the development of several dangerous conditions. The hormone abnormalities in PCOS place women at considerable risk for endometrial cancer and possibly breast cancer . The risk of endometrial cancer is three times higher in women with PCOS than in normal women, and small studies suggest that the risk of breast cancer may by three to four times higher. PCOS also results in increased risk of high blood pressure, diabetes, and high cholesterol, all of which contribute to heart disease and stroke.

Diagnosis

A diagnostic search for PCOS is usually initiated when women experience an absence of menstrual periods for at least six months, an inability to become pregnant, and/or abnormal hair growth or acne. A comprehensive physical exam performed at that time may reveal excessive body hair, low voice, acanthosis nigricans, or obesity. Enlarged ovaries are also identifiable on pelvic examination in about 50% of patients.

Blood tests can be performed that may yield results consistent with PCOS, including abnormal levels of LH and FSH (typically in a ratio of 3:1), abnormally high levels of androgens (testosterone, DHEA, DHEAS), abnormally high levels of insulin, and abnormally low levels of a substance called sex hormone-binding globulin. In addition, a physician may perform a diagnostic test called a "progesterone challenge". In this test, a physician administers a hormone called progesterone to the patient to determine if it will provoke menstruation. If menstruation does occur in response to the progesterone, it is likely that a patient has PCOS.

Finally, an ultrasound examination of the ovaries may be performed to determine if large cystic follicles can be documented. With this approach, the diagnosis of PCOS is based on the finding of more than eight enlarged follicles in the ovary.

Treatment and management

There is no cure for PCOS, thus treatment focuses on several goals, including the restoration of the menstrual cycle, blocking the effect of androgens, reducing insulin resistance, lowering the risk of cancer and heart disease, and possibly restoring ovulation and fertility.

In patients who do not desire pregnancy, hormones can be administered in the form of birth control pills, which may result in normal menstrual cycles, decreased hair growth and acne, and a lower risk of developing endometrial cancer. Although women will note a decrease in hair growth after approximately six months of treatment with birth control pills, additional cosmetic hair removal therapy is often necessary. In women who do not respond appropriately to birth control pills, another medication known as luprolide (Lupron) can be used, but with more long term side effects (e.g., hot flushes, bone demineralization, atrophic vaginitis).

Other types of medication can be used to block the effects of androgens. When these medications are taken with birth control pills, 75% of women report decreased body hair growth. The most commonly used medications to block androgen effects are spironolactone (Aldactone), flutamide (Eulexin), and cyproterone (Cyprostat).

Treatment with medications that restore the body's normal response to insulin has been shown to decrease LH and androgen levels. Recent studies have demonstrated that such agents restore the menstrual cycle in 68-95% of patients treated for as short a time as four to six months. One of the most commonly used medications to improve the effects of insulin is metformin (Glucophage).

In patients who are trying to become pregnant, a physician can administer medications that will cause ovulation. The main medication used to induce ovulation is clomiphene citrate (Clomid). Ovulation is successful in approximately 75% of women treated with clomiphene, but only 30-40% of women will successfully become pregnant. Another medication, follitropin alpha (Gonal-F), has achieved pregnancy rates of 58-82%, but may cause more side effects and frequently results in more than one baby per pregnancy.

Some women who do not respond to medications may undergo surgery to remove portions of the ovary. For reasons that are not completely understood, removal of a portion of the ovary may result in some degree of normal menstrual cycles.

While medications and surgery may provide a degree of symptomatic relief for some women, other simultaneous strategies can increase their benefits. Behavior modifications, including weight reduction, diet and exercise, are recommended for all women with PCOS. As little as a 7% reduction in body weight can lead to a significant decrease in androgen levels and to the resumption of ovulation in obese women with PCOS. Cosmetic techniques, including electrolysis (destruction of the hair follicle using electricity) and laser therapy, may be used to decrease hair growth. Finally, women should be seen regularly for full physical examinations including pelvic exams to aid in the early detection of ovarian, breast, and uterine cancer and should be managed by an interdisciplinary health care team including a primary care physician, obstetrician/gynecologist and reproductive endocrinologist.

Prognosis

While PCOS is one of the most common hormone disorders in young women, proper diagnosis and treatment has greatly increased the quality of life in these individuals. Roughly half of women with PCOS will be able to achieve pregnancy, and about three-fourths will see reduction in masculine traits such as hair growth with proper medical treatment. Initiation of vigorous exercise and a restricted diet may result in even better outcomes. It should be noted that patients with PCOS are at higher risk of developing diabetes, heart disease, and certain cancers and should be seen regularly by a physician. Barring these developments, life span in patients with PCOS is approximately the same as the general population.

Resources

BOOKS

"Disorders of Ovarian Function" In Williams Textbook of Endocrinology, edited by J. D. Wilson. Philadelphia: W.B. Saunders, 1998, pp 781-801.

"Hypofunction of the Ovaries." In Nelson Textbook of Pediatrics, edited by R.E. Behrman. Philadelphia: W.B. Saunders, 2000, pp 1752-1758.

Kistner's Gynecology and Women's Health, edited by K. J. Ryan. St. Louis: Mosby, 1999.

PERIODICALS

Hunter, M.H. "Polycystic Ovary Syndrome: It's Not Just Infertility." American Family Physician 62(September 2000): 1079-1088.

ORGANIZATIONS

Polycystic Ovarian Syndrome Association. PO Box 80517, Portland, OR 97280. (877) 775-PCOS. <http://www.pcosupport.org>.

WEBSITES

"Polycystic Ovary Syndrome 1." OMIM—Online Mendelian Inheritance in Man. <http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=184700>.

Oren Traub, MD, PhD

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