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PCOS (Polycystic Ovary Syndrome)...

Although it is not within the scope of this site to provide much information on PCOS, some of the symptoms are so similar to Cushing's Disease that I thought I'd include this information.

If you'd like, feel free to post on the Discussion Boards.

What is polycystic ovary syndrome?

The name sounds worrying, but it doesn't need to be. It is a very common condition affecting as many as 25% of "normal" women in some series. So at one end of the scale there are people with no obvious abnormality, and at the other extreme, people with excessive facial or body hair, infrequent periods and in fertility.

The cause of the condition is not completely understood, but a number of factors seem to be involved. The main problem is a regulatory one - the ovaries are being driven too hard by the pituitary gland, a little gland behind the eyes which regulates the ovaries. As a result, the ovaries make not only female hormone, but also other hormones which encourage hair growth and interfere with periods. The ovaries themselves tend to be slightly enlarged, and contain small fluid-filled cysts. These are a little larger than the follicles or eggs, which are normally found in the ovary, but are usually only a few millimeters in diameter. There is a tendency for people with this condition to be overweight, and this aggravates the regulatory abnormality, and can sometimes lead to a tendency to diabetes and blood fat problems.

How can this condition be detected?

If you have problems with hair growth (hirsutism), menstrual irregularity or infertility, your doctor will suggest some tests. These will probably include blood tests to look for excessive levels of androgens (hair-encouraging hormones) and pituitary gland hormones, and also an ultrasound examination of the ovaries. These tests may not be conclusive, but will exclude other important conditions. If infertility is a problem, then a laparoscopy may be carried out. This involves a short general anesthetic, and a one centimetre cut in the navel which allows a laparoscope to be passed. Through this instrument the ovaries may be directly inspected, also the tubes and any other abnormalities in the pelvis.

What treatment is available?

Treatments for the excessive hair growth and the infertility are available, but at the moment the two types of treatment are incompatible. It is therefore very important that you should decide which treatment should take priority.

Hirsutism

If this is mild, cosmetic methods may be all that are required. These included plucking, bleaching, waxing, depilatory creams which dissolve the hair, or shaving. Many people are worried that shaving will make the hair grow more rapidly, but there is no evidence for this. The disadvantage of these methods is that they are temporary, although they are relatively inexpensive. Electrolysis has a more permanent effect, but takes time (the hair follicles are destroyed one by one), and is therefore more expensive. If the hair growth is more extensive, then medical treatment may be considered. Although different types of treatment are available, the most common used drugs are the antiandrogens (spironolactone or cyproterone acetate). These are not curative, but reduce the rate of hair growth and the coarseness of the hair. They may take three to six months to work, and the effect gradually wears off once the drug is stopped. However many people find that it is very reassuring that the hair growth can be controlled.

Infertility

This is not necessarily a problem, but if present can be treated with drugs that stimulate ovulation (formation of the egg). Clomiphene is used most commonly, and is given in a dose of one tablet on day two after the start of menstruation to day six. If you are not having periods, the tablets can be started at any time, and may result in a period approximately a month later. If necessary the dose can be increased further depending on the response. Ovulation can be checked by a rise in body temperature, or a change in vaginal mucus (it becomes more "tacky") or by a blood or urine test taken between days 22-24 of the cycle. Should treatment with clomiphene fail, then more powerful ovulation stimulation with gonadotrophins is available. This type of treatment requires more careful monitoring, and your doctor will give you further details.

What are the side-effects of these drugs?

From Vanderbilt Medical Center

POLYCYSTIC OVARY SYNDROME (PCOS)

Polycystic ovarian syndrome (PCOS) was originally described in 1905 by Stein and Leventhal as a syndrome consisting of amenorrhea, hirsutism, and obesity in association with enlarged polycystic ovaries. It is now realized that this relatively common syndrome is an extremely heterogenous clinical syndrome that begins soon after menarche and some authors prefer to refer to it as a syndrome of hyperandrogenic chronic anovulation. In fact, earlier studies of PCOS have focused on ovarian morphological findings and were considered to be an important diagnostic criteria. However, it was found that polycystic changes of the ovaries were observed in some normally cycling women. Furthermore, polycystic changes of the ovaries were shown to be associated with other well-defined diseases such as Cushing's syndrome, and an ovarian or adrenal tumor capable of producing androgen.

In addition, recent studies have demonstrated that some women with characteristic clinical features of PCOS have normal-sized ovaries. Indeed, nothing inherently abnormal has thus far been found in the ovaries of PCOS. Therefore, the focus on ovarian morphology was shifted towards the hormonal characteristics of the syndrome.

The incidence of PCOS is about 3% in both adolescents and adults. It is the most common cause of hyperandrogenisim of prepubertal onset. However, it appears that there is some variabilities of PCOS clinical manifestations among races. Obesity and hirsutism are not pronounced in Japanese women with PCOS. In the United States, 70% of patients have hirsutism compared to 10-20% in Japan and the Orient. Obesity, although thought to be common in PCOS is usually noted in 40% of cases. There is no particular pattern with respect to fat distribution. However, obesity is an important feature with
regard to hirsutism because it is associated with decreased sex hormone binding globulin (SHBG), which results in an increased fraction of unbound testosterone.

In addition, obesity contributes to chronic estrogen stimulation because there is increased peripheral conversion of androgen to estrogens in these patients. Among women with resistant acne, not responding to conventional treatments, the polycystic ovary syndrome is very common. The primary affected areas are the facial (angle of the jaw, upper lip, and chin) and suprapubic region of the body. Other common sites include the chest, inner thigh, and perineum. Another clinical sign in hyperandrogenic syndromes is acanthosis nigricans. It is characterized by symmetric, velvet-like, grey-brown hyperpigmentation of the skin. It commonly affects the nape of the neck, axillae and groin.

The most common features of PCOS are chronic anovulation and infertility in addition to the hyperandrogenism. The clinical manifestation of chronic anovulation include irregular menstrual cycles, oligo or amenorrhea interspersed with heavy vaginal bleeding. The menstrual dysfunction usually presents from menarche. In the absence of ovulation, the usual premenstrual molimina does not occur. In addition, because there is unopposed estrogen stimulation of the endometrium, endometrial hyperplasia and in some instances, adenocarcinoma may develop.

Fortunately, adrenocarcinomas associated with PCOS is usually of low histologic grade and presents at an early stage. In PCOS, chronic anovulation reflects abnormal folliculogenesis. As a result, these patients suffer from infertility. Occasionally, spontaneous ovulation and pregnancy may occur in this syndrome. A family history may be present in a subset of patients. However, so far, efforts to elucidate a particular mode of genetic inheritance have been unsuccessful. PCOS is an endocrinologic disorder
of undetermined etiology characterized by inappropriate gonadotropin-releasing hormone (GnRH) pulse amplitude and tonically elevated levels of luteinizing hormone (LH), but not of follicle-stimulating hormone (FSH).

In addition, there are increased circulatory levels of androgens produced by both the ovaries and the adrenal glands. If they are elevated, serum testosterone levels are usually between 70-120ng/dl, and androstenedione levels are usually between 3 and 5ng/ml. Also, about half the women with this syndrome have elevated DHEA-S. The presence or absence of hirsutism depends on whether these androgens are converted peripherally by 5 alpha reductase to the more potent androgen DHT dihydrotestosterone and 3 alpha diol-G as reflected by increased levels of 3 alpha-diol-G. Therefore, it is skin 5-alpha reductase activity that largely determine the presence or absence of hirsutism. The chronically elevated LH are usually above 20 mIU/ml. Because FSH levels in PCOS patients are normal or low, it has been found that an LH/FSH ratio greater than 3, provided the LH level is not lower than 8mIU/ml, may be used to suggest the diagnosis in women with clinical features of PCOS. About 20% of women with PCOS also have mildly elevated levels of prolactin (20-30ng/ml), possibly related to increased pulsatility of GnRH or to a relative dopamine deficiency or to both. In addition, many women with this syndrome have mild degrees of hyperinsulinism and insulin resistance.

The diagnosis of PCOS is strongly suggested by the clinical history and physical examination. In particular, a pattern of infrequent and irregular menstruation commencing at time of puberty is highly suggestive. Evidence of concomitant excessive hair is almost pathognomonic. The most worrisome consideration in the hirsute woman is the presence of an androgen-producing neoplasm. It is for this reason that a measurement of total testosterone and DHEA-S is recommended. A level greater than 200ng/dl, as determined by radioimmunoassay with chromatographic separation should raise suspicion of an androgen-producing tumor of ovarian or adrenal origin. Serum DHEA-S is the marker of adrenal androgen and a level greater than 700ng/dl implies a possible neoplasm. Mild to moderate hirsutism may reflect the presence of CAH, 21 hydroxylase deficiency, although severe hirsutism is frequently the case.

Other characteristic clinical findings associated with hirsutism in this disorder include regular menstrual cycles, virilization such as clitoromegaly, family history, and short stature. Although 17-OH progesterone is elevated in both PCOS and CAH, 21 hydroxylase deficiency, levels rarely exceed 300ng/dl in PCOS. Therefore, concentration above 300ng/dl suggest CAH, 21 hydroxylase deficiency and ACTH stimulation should be performed. Other enzyme defects of CAH that give rise to hirsutism are deficiencies of 11-beta hydroxylase deficiency and 3-beta hydroxylase deficiency. Diagnosis of the
former is suggested by the presence of coexistent hypertension and salt retention, whereas the latter condition is associated with a marked elevation of serum DHEA-S.

The treatment of PCOS is directed primarily at the problems of hirsutism, menstrual irregularity and infertility. Treatment modalities for hirsutism include ovarian and adrenal suppression, anti-androgen therapy and local depilatory measures. Oral contraceptives are simple and relatively safe method of ovarian suppression, in addition the estrogen component increases the sex hormone binding globulin SHBG with a resultant decrease in free testosterone. A direct target organ effect of the progestins is inhibition of 5 alpha reductase enzyme and competition for androgen receptors. When DHEA-S levels are elevated, the addition of dexamethasone may be helpful. Spironolactone is the preferred anti-androgenic compound. It competitively inhibits intracellular dihydrotestosterone receptors within the hair follicles. Both cimetidine and cyproheptadine (a serotonin and histamine antagonist) have weak anti-androgenic effects.

The drug commonly used to induce ovulation is clomiphene citrate and in patients who do not respond to an optimal dose, the addition of human chorionic gonadotropin may be beneficial. In patients with increased circulating DHEA-S and in patients who fail to ovulate on clomiphene citrate alone, the concomitant use of dexamethasone (0.25-0.5mg/day) has been shown to increase both ovulation and pregnancy rates. Also, human menopausal gonadotrophin (HMG) may be tried in clomiphene citrate resistant patients. Laparoscopy electrocauterization or laser cauterization of all visible subcapsular
follicles of the polycystic ovaries in patients who failed medical therapy remain experimental. Wedge resection is now rarely performed because it can result in pelvic adhesion and many effective hormonal regimens are available.

REFERENCES

Cheung PA et al. Polycystic ovary syndrome. Clin Obst & Gyne 33: 655-667; 1990.

Droegemueller W, Herbert AL, Mishell DR and Stenchaver MA. Hyperandrogenism. In Comprehensive Gynecology. Second ed. 1992.

Lobo RA. Hirsutism in polycystic ovary syndrome: current concepts. Clin Obst & gyne 34: 817-826; 1991.

Rosenfeld RL. Hyperandrogenism in prepubertal girls. Current Issues in Pedia & Adolescent Endocrinology 37: 1333-1358; 1990.

Taketani Y. Pathophysiology of polycystic ovary syndrome. Horm Res 33: 3-4; 1990.

Fromthe Washington Post

Doctors Find PCOS Has Lifelong Consequences

By Randi Hutter Epstein
Tuesday, January 18, 2000; Page H12

As she looks back, Christine Gray realizes that the signs of her illness had been obvious since puberty. She always had irregular periods, embarrassing hair growth on her arms and legs, and she tended to gain weight more easily than most of her girlfriends.

At the time, it never dawned on Gray that these seemingly unrelated teenage worries were hallmarks of a potentially serious ailment, one that strikes about 5 percent of women. It's called PCOS, or polycystic ovarian syndrome, a poorly understood hormonal imbalance. Not only is the syndrome now seen as a major cause of infertility, but emerging evidence suggests that women with PCOS are at increased risk for such chronic illnesses as heart disease, high blood pressure and diabetes.

"I knew something was truly wrong when I was about 27 and I started to gain weight out of control," says Gray, 34, a Mount Prospect, Ill., product manager.

Gray gained about 70 pounds, weight that would not come off no matter how little she ate, it seemed. She was eating one nonfat granola bar for breakfast and another one for lunch. Dinner was a small serving of pasta without a drop of butter or cream. Little did she know – nor did anyone else seven years ago – her seemingly healthful low-fat diet was not good for her.

Then she noticed even more hair growth, particularly on her upper lip. "And my periods were so irregular, I never had a clue when they were coming. I got married at 26 and started trying to get pregnant without any success. But the doctors told me everything was fine."

Things were far from fine. Finally, after seven years and $30,000 worth of fertility treatments, Gray searched the Internet for information and support.

"I began participating in an infertility support group online," she says. "One day a woman posted something about 'polycystic ovarian syndrome' and described her symptoms. . . . I immediately identified with her."

Gray says her doctor later said he knew she had PCOS but hadn't mentioned it because "it's no big deal."

Sometimes ovarian cysts are no big deal – upwards of a quarter of premenopausal women have them. But sometimes they are a big problem. A necklace of cysts – doctors say they look like a strand of pearls hugging the ovaries – can be a clue that a woman has PCOS.

The classic signs include weight gain, menstrual irregularities, excess body hair (or thinning hair on the top of the head) and adult acne. Some women are also prone to "skin tags," teardrop-shaped pieces of skin, about the size of raisins, that hang in the armpits or other parts of the body.

For years doctors thought women with PCOS were unlucky, but not unhealthy. Now PCOS is regarded as a significant health issue for many women, affecting their lives throughout the childbearing years and well after menopause.

Scandinavian studies suggest that women with PCOS are five times as likely to get diabetes as other women. Even thin women with PCOS sometimes get diabetes, according to a 254-woman study by Richard Legro, associate professor of obstetrics and gynecology at Pennsylvania State University College of Medicine in Hershey, Pa.

PCOS is "clearly the largest cause of ovulatory dysfunction and may be the single largest cause of female infertility," Legro said. Research into PCOS is also pointing toward a fresh approach to treatment – with drugs and possibly a high-protein diet – that not only helps diminish the embarrassing symptoms but may also prevent the chronic health problems.

Many Symptoms, One Source

PCOS is a devious disorder. Few women who have it realize they are at risk. It's easy to dismiss facial hair and weight gain as cosmetic problems, not reasons to get a medical checkup. Plus, many doctors don't think of PCOS when they treat women with irregular periods who also have acne or hirsutism (excess body hair).

While medical tests can produce a definitive diagnosis for many diseases, detecting a syndrome is a different matter. It takes an astute clinician to pull all the clues together, and in the case of PCOS, the clues often seem like a hodgepodge of annoyances.

"PCOS is probably one of the most common, yet least understood, endocrine disorders affecting women in the developed world," says Legro. "Although specialists are very aware of the syndrome and its health consequences, there are many doctors who still do not realize that all the symptoms are related and emanating from a single syndrome."

Armand Newman, a dermatologist in Beverly Hills, Calif., who specializes in PCOS, said women who don't suspect PCOS often see a dermatologist, primarily to treat hirsutism or acne. Few dermatologists ask women with these symptoms about their menstrual cycles or fertility, he said.

Even the name of the illness is misleading. It harks back to the 1930s when doctors thought PCOS patients had a lot of untreatable cosmetic ailments stemming from cysts on the ovaries. Now doctors say cysts from PCOS are just one manifestation of hormones gone awry. Some doctors suspect there are even a few women who suffer from the syndrome but do not have any cysts.

As doctors unravel more clues about PCOS, they are detecting it in more women. They say women can have the syndrome and the long-term consequences without all the symptoms. Not all PCOS women, for example, are obese. Not all have facial hair. Yet they may all have the same underlying hormonal imbalance and many may face the later health risks.

"I thought I had four or five different things going on," said Patricia Barfield Hicks, 33, of Lexington, Ky. "The weight gain, the infertility. It was such a relief to finally find out it's all tied together. Ideally it can be taken care of with the right combination of medicine."

Hicks, like many women, was told by her physician that nothing was wrong except that she was too fat. It was not until last year, after she saw a television show about PCOS, that she found help. She switched doctors and insisted on trying one of the new treatments. Since then, many of her symptoms have faded.

Some scientists speculate that women with PCOS are born with a faulty gene or set of genes that trigger abnormally high levels of male hormones. That explains the "male" features, such as body hair and thinning hair on the scalp, and perhaps even the infertility. While all women have a bit of testosterone, too much of the hormone botches the messages between the ovary and brain.

Many PCOS women also tend to be resistant to their own insulin, hormone that clears sugar from the blood, and this may explain the tendency for weight gain and the link to diabetes. Whether these two imbalances – testosterone and insulin – stem from one flawed gene or whether one causes the other is hotly debated among doctors studying PCOS. Tantalizing evidence suggests a link, because treatments targeted at insulin cause testosterone levels to plummet.

A study published last year in the Proceedings of the National Academy of Sciences suggests that the follistatin gene may be linked to PCOS. Interestingly, follistatin has at least two functions: It is necessary for the ovaries and for the insulin-making system.

"Follistatin is particularly intriguing because it could play a role in both the reproductive and the metabolic features of the syndrome," said Andrea Dunaif, the senior author of the paper and the chief of the Division of Women's Health at Brigham and Women's Hospital in Boston. "Follistatin could explain some cases of PCOS; however, it is likely that at least several other genes are involved."

Getting a Diagnosis

Traditionally women treated symptoms of PCOS individually. They used electrolysis or tweezing to remove facial hair. With fertility drugs they increased their chances of becoming pregnant. And they confronted their weight problem with diets galore. But it's now clear that none of these measures tackled the root of the problem or addressed the serious later effects of PCOS.

"When I was a teenager I was having wacky periods – every 10 days – and I had some of the hair problem," said 30-year-old Suzanne Cerquone, of Philadelphia. "My doctor said I probably had cysts on my ovaries and here's a package of birth control pills to regulate your periods. He said I had the facial hair because my testosterone was too high.

"It wasn't until last year when I got on the Internet that I found out all the new treatments and diets. Because the majority of the symptoms are cosmetic, no one considers it a serious thing, but the underlying thing is it's not just cosmetic."

The challenge lies in distinguishing healthy women who just have a few extra pounds to lose and an occasional irregular period from those whose hirsutism and menstrual irregularities signal a disorder that may require treatment.

In a study published in 1998 in the journal Fertility and Sterility, Ricardo Azziz, a professor of obstetrics and gynecology at the University of Alabama at Birmingham, looked at 132 women with too much body hair who thought they were having regular periods. By measuring their progesterone levels, he found that 40 percent of them actually ovulating irregularly. That suggests PCOS.

A Harvard study found that 80 percent of women with fewer than six periods a year had abnormally high levels of male hormones. They, too, may be PCOS women.

"These were women not going to the doctor to complain," said Dunaif. "The most frequent thing the doctor would say was, 'You are too fat, lose weight,' or 'Take a birth control pill.' The disturbing thing is that not only do the irregular periods need to be taken care of because of the increased risk of endometrial cancer, but women need to be treated because of all of the other health consequences associated with PCOS."

There is often no simple proof that a woman has polycystic ovarian syndrome (PCOS); diagnosis is based primarily on a woman's medical history and tests for insulin resistance. But the presence of several of the symptoms – infertility, hirsutism, menstrual irregularities and insulin resistance – is strong evidence.

Doctors advise any woman with menstrual irregularities – which are signs of a metabolic problem – to consult an endocrinologist or gynecologist and insist on a thorough examination, including blood tests to measure hormone levels. Those who think they may have PCOS should also be checked for diabetes.

Kristin Chapman, 32, of Atlanta, found out about PCOS when her ovaries nearly burst after a fertility treatment. "The doctors told me they blew up to the size of cantaloupes," she says. Chapman, like many other women with PCOS, had ignored her other symptoms until she wanted to have a baby.

Chapman was hospitalized and the fluid was drained. Two subsequent attempts to get pregnant were unsuccessful – the culmination of six years of failed attempts with fertility drugs. She and her husband had had enough. Then Chapman attended a seminar by Mark Perloe, director of reproductive endocrinology and infertility at the Atlanta Medical Center. He talked about metformin, a diabetes drug, which apparently corrects the insulin defect in some women with PCOS and helps to restore ovulation.

As a last-ditch effort, Chapman went through a series of tests and learned that she was "borderline" insulin-resistant. She opted to try the drug, which is marketed as Glucophage. "It was refreshing to hear this approach," says Chapman. "It wasn't treating the symptoms but treating the PCOS."

Chapman started metformin in January 1998, got pregnant the first time she ovulated in April and gave birth to a daughter this past January.

Treatment With Drugs and Diet

No one knows why metformin or another insulin-sensitizing drug, troglitazone (Rezulin), seem to promote ovulation. But since word of these treatments hit cyberspace, women with PCOS-like symptoms are demanding prescriptions. Experts warn that many women on the drugs do not get pregnant, but they have been hyped nonetheless as a diabetes-fertility cure that also helps you lose weight. What could be better?

The drugs "offer exciting possibilities," said Brigham and Women's Dunaif. "However, I don't think we yet have enough information to recommend them for all women with the syndrome. That caution is especially appropriate for women with PCOS who want to get pregnant, because there is very little data on the safety of these drugs on the developing fetus."

In addition to the few experimental drugs under study, low-carbohydrate diets – the kind touted in the popular protein-power books – are gaining a reputation for relieving many PCOS symptoms. No formal studies support this impression, but many women who changed their eating habits say they lost weight and got pregnant. (See "Low Carbohydrate PCOS Diets: Hype, Hoax or Cure?")

While much research remains to be done on the causes and treatment of the syndrome, one encouraging sign for women who have it is the growing awareness that PCOS is common and can be dangerous.

Gray, the Illinois woman who went through years of unsuccessful fertility treatments, founded the Polycystic Ovarian Syndrome Association three years ago out of desperation. "There were no associations, no books, no one to talk to," she recalls. "I got the names of 30 women from the infertility support group who seemed to fit the PCOS pattern and I e-mailed them. As we started to talk, we decided to form a group."

A combination of a low-carbohydrate diet and anti-diabetes pills have helped minimize Gray's symptoms and, she hopes, are preventing the later consequences. Better yet, Gray has shed 70 pounds and is back to her slender, pre-marriage physique.

Perhaps best of all, Gray feels like her body is starting to act the way a woman's body should. She has a regular period, though she is not ovulating every month.

"I get terrible PMS," she says. "I'm nasty, bloated, and my breasts get tender.

"Thank God."

© 2000 The Washington Post Company

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