Virtually all patients with PCOS will have at least subtle laboratory abnormalities. The reported results may be only on the upper limits of the 'normal range,' showing only a tendency, not a discrete abnormality. Often a pattern will emerge after considering a group of tests together. These subtleties may reveal dysfunction in the control mechanisms of the hypothalamus, pituitary, ovary and adrenal (HPOA axis) working collectively. In distinction, serious pathology may be more evident by a marked elevation, or suppression of a single test. Though the value of repeated blood testing for the same hormones could be questioned, it is recommended that each PCOS patient have an initial, relatively comprehensive evaluation and interpretation by an individual familiar with this testing. Any level that is twice the upper or lower limit of normal, is particularly important and may indicate a serious problem. The marginally elevated test is almost always dysfunctional, rather than pathologic. As a rule, endocrine testing, other than a pregnancy test, is probably best performed in the morning, soon after a spontaneous, or induced menses. The days around ovulation or mid-cycle should be avoided. Hormonal evaluation in patients on oral contraceptive will often give misleading results with suppression of gonadotropin, ovarian steroid and SHBG levels. It is of limited value to determine these hormone levels in patients on the pill. Glucose and lipid evaluation should be in the morning after fasting (no food or drink after midnight the night before). Fasting insulin levels and a glucose tolerance test can be very important in the diagnosis of insulin resistance.

Ultrasound
Sonography of the pelvis is warranted in virtually every potential PCOS patient. Evaluation should be performed by individuals experienced in judging ovarian and endometrial function. The finding of greater than ten cystic structures less than 10 mm in either ovary, meets the generally established ultrasound criteria of PCOS. Often cysts of PCOS are located in a peripheral subcortical ring leading to the reference of a "string of pearls." The PCOS ovaries are typically 1.5 to three times normal size. In some cases the ovary is virtually filled with small cysts. In other cases, it is heterogeneously dense with hardly detectable microcystic changes. It must be remembered that any hyperandrogenic state may be manifested by the PCO-appearing ovary. Diffusely enlarged ovaries without discrete mass on ultrasound, in the absence of adrenal findings, are consistent with the diagnosis of hyperthecosis which is probably a less common variant in the PCOS spectrum.

Etiology
The cause of PCOS is unknown. However, the story is starting to unravel and several important lines of evidence have emerged that offer clues about a central mechanism. Is there only one, or are there many causes of PCOS? PCOS is a "final common pathway" of a variety of disorders and the diagnosis PCOS itself remains one of exclusion. It is a near universal finding that PCOS is genetic, but the heritage is complex. This genetic predisposition is not as simple as brown eyes or blue, but has a complex heritage. The tendency to develop PCOS may be inherited from either the mother's side, (maternal origin), from the father's side (paternal origin), or from both sides. A paternal origin is equally likely, but often is overlooked. Also, various characteristic traits of PCOS may be passed down with varying degrees of severity. Insulin resistance may be a key player. Women with PCOS produce too much insulin, which in turn signals their bodies to release the male hormone testosterone. Too much testosterone creates facial hair, acne, weight gain and multiple cysts on the ovaries. Doctors believe the same insulin and testosterone overload that may cause PCOS in women may also be responsible for premature male-pattern balding in men. Several medications are on the market and clinical trials are now underway testing new medications that control the release of insulin.

Therapy for PCOS

Weight Loss
With weight loss there is often an improvement in endocrine parameters and sometimes return of menses. Clearly important, but always much easier said than done.

Progestins
A progestin is a medication that mimics the action of progesterone. While progestins may be used to regulate the menstrual cycle and blood levels of LH may be reduced by progestins, they appear to be of little use in reduction of hair growth, or possibly metabolic derangements. Examples are Provera, Aygestin, Cycrin.

Oral Contraceptives
Oral contraceptives (OC's) are a mainstay of treatment of PCOS in women who do not want to become pregnant. They increase the SHBG which "traps" circulating androgens. The pill also reduces LH. Menses are often regulated and overall there are numerous positive health benefits.

Corticosteroids
Steroids have the ability to suppress adrenal androgen production and may be useful in treatment of PCOS with an adrenal component. Overall, their use is better in theory than practice and they are often discontinued by patients because of unwanted side effects.

Anti-androgens
This group of medications can be used only when not attempting a pregnancy or without some form of adequate birth control. There is, at least a theoretical, risk of feminizing the genitals of a male fetus. The value of the agents for PCOS patients is to improve the skin problems that occur with PCOS. None of these medications are approved for treatment of hirsutism or PCOS. Some may have potentially serious side effects. Examples are spironolactone (Aldactone), Flutamide, cyproterone acetate, and Finasteride.

GnRH Analogs
Gonadotropin releasing hormone (GnRH) is a hormone that is released from the hypothalamus and promotes production and release of the gonadotropins (LH and FSH) from the pituitary gland. While quite a good therapy for suppression of the ovary and its abnormal hormonal production of PCOS, the high cost and undesirable side-effects limits GnRH use.

Fertility Therapy
In PCOS, the normal mechanisms of hypothalamic-pituitary-ovarian (HPO) axis and therefore, follicle growth and ovulation are disturbed. "Fertility drugs" are commonly used in an attempt to temporarily override the problem and facilitate ovulation. Clomiphene (Clomid) is an oral fertility agent. There are also several injectable gonadotropin preparations that can be used when clomiphene fails.

Surgical therapy
In the past, ovarian wedge resection, a procedure whereby a portion of the ovary is removed and the ovary sewn back together, resulted in a significant reduction in LH and androgen production, reestablishment of regular menses in over 75% of patients and a pregnancy rate of about 60%. However, pelvic adhesive disease, which was often severe, occurred in about 30% of patients. There is probably no longer an indication for wedge resection by laparotomy, although electrosurgical incisions, or "ovarian drilling," has become relatively common place. Success rates of microcautery vary by operator and, while adhesion formation may be considerably less, it is still common.

Anti-diabetic agents
By treating the insulin resistance, PCOS may be also treated, possibly reversed. It is still very unsettled which PCOS patient may derive benefit from these medications. With some PCOS patients these medications have successfully restored normal menstruation and fertility, even the absence of the insulin resistance. They may be a useful alternative when other therapies have failed, or benefit appears to exceed risk. These agent are:

Metformin (Glucophage)
An FDA advisory subcommittee voted unaminously in March 1994 that Metformin be approved for the treatment of insulin resistance and type 2 (insulin resistant) diabetes that cannot be controlled by diet alone. It had the strong endorsement of the American Diabetes Association and is presently used in over 80 countries. By September 1996 over one million U.S. patients had been prescribed the medication. Use is predicted to sharply rise. Metformin enhances the body's sensitivity to insulin and inhibits glucose production from the liver without the risk of hypoglycemia. It does not lower blood glucose levels, but acts to improve the body's sensitivity to insulin without affecting insulin secretion. Some patients have shown weight loss, improved lipid profiles, lowering of blood pressure, return of menstruation, and pregnancy.

Metformin appears to have an excellent safety profile and is generally well tolerated. Gastrointestinal upset and a tendency toward looser stools, or more frequent bowel movements, are the most frequent side effects. These are common in the first month and can be reduced by starting at lower doses and increasing. These side-effects are also more commonly experienced after a fatty meal, or dessert. Lactic acidosis, a rare and potentially fatal condition, has been associated with Metformin use. The reported incidence of lactic acidosis is 3 /100,000 patients using the drug for 1 year. Almost all cases occurred in older patients with other significant diseases and risk factors. A relative disadvantage of Metformin therapy may be the postponement of more aggressive fertility therapy. The usual dose is 500 mg. three times daily.

Troglitazone (Rezulin)
Troglitazone is an anti-diabetic agent not related to either the sulfonylureas (Diabeta, Diabenase, Tolinase), or Metformin. It was introduced in 1997 for treatment of type 2 diabetes and it was recently reported that there were over one million users. Justification for its use is the same as described above for Metformin. In contrast to Metformin, troglitazone appears to work by directly affecting insulin production. Blood glucose is lowered by improving the body's response to insulin. Troglitazone appears to be clearly better tolerated than Metformin, i.e. less GI distress. A repeated warning has been issued by the FDA regarding the potential of serious liver damage. Liver function testing should be followed monthly for the first eight months, then every two months. The usual dose is 400 to 600 mg once daily.

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