Insulin-Sensitizing Agents (ISAs) & PCOS: Before you ask for a prescription. . .

Ilene from Pensacola asks:

My gynecologist recently told me that I have polycystic ovary syndrome (PCOS), and that I should try to lose weight before he gives me fertility medications. A friend told me that I should start taking a medicine to help lower my insulin levels. I'm confused about the connection between insulin and PCOS, and why I need to take an insulin-lowering medicine. I am 28 years old, and otherwise in good health.

Dr. Feinberg answers:

What are ISAs? ISAs, also known as insulin-lowering medications, help the body utilize insulin in a more efficient manner. ISAs can provide a real benefit to people with type II diabetes, since such individuals have a limited ability to efficiently produce or utilize insulin.

Why ISAs for PCOS? Most women with PCOS do not have diabetes. However, their pancreas are often pushed to produce excessive quantities of insulin. Elevated insulin levels in the bloodstream (called hyperinsulinemia) can cause the ovaries to overproduce androgens (so-called 'male' hormones) All women normally produce some androgens, but overproduction of androgens can lead to common PCOS symptoms - the lack of ovulation, abnormal or absent menstrual cycles, infertility, unwanted hair growth, and acne. When ISAs are prescribed to women with PCOS, the pancreas gradually produces less insulin, giving the ovaries a chance to function in a normal fashion. Scientific studies have shown significant declines in ovarian androgen levels when women with PCOS take ISAs. Some (but not all) of these women subsequently demonstrated ovulatory menstrual cycles.

What ISAs are available? Several different ISAs are on the market or are under investigation. No ISAs are currently approved by the U.S. Food and Drug Administration (FDA) for non-diabetic women with PCOS. By law, physicians are permitted to prescribe FDA-approved medications for 'off-label' indications, but informed consent and close monitoring are warranted. Detailed information about these ISAs are described in the Physicians' Desk Reference (www.pdr.net), and can be obtained by the manufacturers. ISAs commonly discussed by doctors and patients include:

Glucophage, (metformin, Bristol-Myers Squibb). A popular ISA for type II diabetes, over 15 peer-reviewed scientific publications since 1994 have examined the metabolic impact of Glucophage in women with PCOS. While Glucophage can promote spontaneous ovulation by lowering insulin levels, most women with PCOS also require weight loss and/or the fertility drug clomiphene. Many of these women, however, were previously unresponsive to clomiphene. Taken orally 2 or 3 times per day, Glucophage can cause gastrointestinal upset. Fatal cases of a rare metabolic disorder called lactic acidosis have been reported.

Rezulin, (troglitazone, Sankyo Parke Davis). This once-a-day oral ISA was rising in popularity until the FDA reviewed reports of rare but severe liver toxicity. Fewer scientific publications exist regarding Rezulin and PCOS, but the metabolic impact of this ISA appears favorable. Ovulation and successful pregnancies have been reported with the use of Rezulin alone, or with Rezulin in combination with clomiphene. Studies comparing the efficacy of Rezulin and Glucophage for PCOS have not been carried out.

Avandia, (rosiglitazone, SmithKline Beecham) and Actos, (pioglitazone, Eli Lilly Actos is a registered trademark of Takeda Chemical Industries, Ltd. and is used under license by Takeda Pharmaceuticals America, Inc.). The two newest 'glitazone' ISAs in the U.S. marketplace, these oral medications may offer similar metabolic benefits to Rezulin, with an improved safety profile. Their role in treating PCOS has not been evaluated.

In the pipeline: d-chiro-inositol, a "phosphoglycan" agent that helps improve insulin action. This oral medication is under development by INSMED Pharamceuticals and has been utilized in an experimental protocol for PCOS, as described in a 1999 article in The New England Journal of Medicine.

Should I be taking an ISA? No brief summary article such as this should serve as a substitute for a private consultation with your physician. I have prescribed ISAs in my practice with the goal of promoting ovulation for infertile women with severe PCOS. In many cases, that goal was successfully achieved. However, large-scale controlled scientific clinical studies addressing the efficacy and safety of ISAs for PCOS are lacking. Of particular interest would be studies designed to directly compare ISAs with non-pharmacologic insulin-lowering strategies, such as low carbohydrate diets, weight loss, and exercise. Beyond the short term goal of inducing ovulation for infertile women with PCOS, the longer term benefits and risks of ISAs remain unknown.

References:

Dr. Feinberg is a Board-certified specialist in Reproductive Endocrinology and Infertility, and in Obstetrics and Gynecology. He is the IVF Medical Director for Reproductive Associates of Delaware in Wilmington, DE and is an Associate Professor (Adjunct) in the Department of Obstetrics and Gynecology at Yale University School of Medicine.

Dr. Feinberg would like to answer the numerous questions he receives related to PCOS and fertility. However, the best medical advice you could obtain comes from your personal physician who knows your medical history best. A list of Board-certified reproductive endocrinology and infertility specialists throughout the country can be found at www.socrei.org.