KatCarney

Should we use insulin sensitizers to treat infertility in women with refractory PCOS?

Contemporary OB/GYN, March, 2000, by John E. Nestler

Yes. When weight loss is not an option, insulin sensitizers may be worth trying.

Women with polycystic ovary syndrome (PCOS) who are refractory to ovulation induction with clomiphene citrate have few remaining therapeutic options. They can proceed to ovulation induction with gonadotropins and, should that fail, in vitro fertilization (IVF). These therapies are associated with substantial side effects, such as multiparity and ovarian hyperstimulation syndrome, and are extremely costly.

A novel therapeutic approach emerges from the observation that most women with PCOS suffer from insulin resistance and compensatory hyperinsulinemia, and from evidence that strongly suggests that the elevated circulating insulin concentration impedes ovulation. For example, it has been shown in obese women with PCOS that the magnitude of obesity (and hence presumably hyper-insulinemia) correlates directly with the failure to ovulate in response to clomiphene, or with the need for multiple courses and progressively increasing doses of clomiphene.

Therefore, in obese women with PCOS, efforts to induce weight loss through diet and exercise may increase the success of clomiphene induction. This is likely a result of the attendant improvement in peripheral insulin sensitivity and reduction in plasma insulin concentration.

Many obese women with PCOS, however, do not lose weight and weight loss is not an option for nonobese women with PCOS. In these settings, it is worthwhile to consider the use of "insulin-sensitizing" drugs to improve peripheral insulin sensitivity and reduce the plasma insulin concentration.

Experience with insulin sensitizers

Metformin is the insulin-sensitizing drug that has been assessed most comprehensively in women with PCOS. In multiple studies, metformin was shown to decrease serum androgens in both obese [1,2] and lean [3] women with PCOS, to enhance the frequency of spontaneous ovulation, [1,4,5] and to improve the ovulation response to clomiphene induction. [5] One multi-center study, conducted in the United States and abroad, critically assessed the effects of pretreatment with metformin for 5 weeks on spontaneous ovulation (during the 5 weeks of metformin monotherapy) and the response to clomiphene induction (during combined metformin and clomiphene therapy). [5] The dose of clomiphene used was 50 mg daily for 5 days. Of note, half the women in the study had a history of failing prior clomiphene induction.

In this study, spontaneous ovulation was increased by eightfold in the women who received metformin (34%), compared with the women who received placebo (4%). Women who failed to ovulate during the pretreatment phase of the study then underwent clomiphene induction. The ovulation rate in the women who went on to receive both met formin and clomiphene (90%) was tenfold greater than that in the women treated with placebo and clomiphene (8%). The midluteal serum progesterone concentration in the 19 women who responded to combined metformin and clomiphene therapy was 23.8[plus or minus]3.4 ng/mL.

It should be noted that pregnancy was not an outcome measure of this study In the context of the question posed, it is noteworthy that there is an ongoing US multicenter study specifically addressing the utility of metformin for clomiphene induction in women with PCOS who previously proved refractory to clomiphene at a dose of 150 mg. Pregnancy is an outcome measure of this study. Interim results from this ongoing study were presented as an abstract at the October 1999 meeting of the American Society for Reproductive Medicine. The women who were treated with metformin demonstrated higher ovulation and pregnancy rates after induction with clomiphene than women treated with placebo. [6]

Safety concerns

An important question is: "How safe is metformin for ovulation induction?" Metformin is a category B drug, which means that there is no demonstrated teratogenicity in vitro. It is commonly administered to premenopausal diabetic women, and simply discontinued when the women become pregnant. No untoward effects have been documented with this practice. In the 1960s, investigators in South Africa administered metformin to a small group of diabetic women throughout their pregnancies, and there was no evidence of increased teratogenicity. Therefore, metformin appears to be a safe drug for ovulation induction.

A word of caution should be noted about the use of alternative insulin-sensitizing drugs for ovulation induction. Theoretically the thiazolidinedione class of drugs, of which troglitazone is a member, may have undesirable actions when considering ovulation induction. This class of drugs binds to the PPAR-gamma receptor and exerts genomic actions, which raises the issue of possible teratogenicity in vivo. In addition, troglitazone may directly inhibit progesterone production by human granulosa cells, and may independently affect sex steroid metabolism in vivo. Therefore, although troglitazone is also a category B drug, there is some cause for caution in using the drug specifically for ovulation induction.

On balance, given the potential side effects and expense of gonadotropin induction and IVF it seems reasonable to offer a woman with PCOS who has failed clomiphene induction a trial of insulin-sensitizing therapy Based on the literature, a brief period of metforrnin monotherapy (such as 2 to 3 months) might be tried in an attempt to induce spontaneous ovulation and to reduce the circulating insulin concentration. Should ovulation not occur, combined treatment with metformin and clomiphene could follow. Ideally, such therapy would be part of an Institutional Review Board-approved experimental protocol that would yield answers to some of the untested issues concerning this practice. In any case, the women would need to be advised that this is still experimental therapy, and that there are no reported data on pregnancy rates or outcome.

Conclusion

Finally I would note that the question as posed avoids the issue of whether women with PCOS should be administered an insulin-sensitizing drug for ovulation induction before proceeding to clomiphene. This question can be answered only by a head-to-head trial comparing an insulin-sensitizing drug with clomiphene as initial ovulation induction therapy The question as posed also begs a much larger and potentially more important issue: Since most women with PCOS appear to suffer from syndrome X, should all women with PCOS be given a trial of treatment with an insulin-sensitizing drug as first-line therapy after weight loss? That is, PCOS appears to be a metabolic disorder with far-reaching general health concerns (such as increased risk for type 2 diabetes, hypertension, dyslipidemia, and heart disease), and this may be the more important concern in women with PCOS. [7] I believe that a good case could be made for answering this query in the affirmative as well, but perhaps that should be left to another issue of Contemporary OB/GYN.



Dr. Nestler is William G. Blackard Professor of Medicine and Chair, Division of Endocrinology and Metabolism, Medical College of Virginia, Virginia Commonwealth University, Richmond, Va.

REFERENCES

(1.) Moghetti P, Castello R, Negri C, et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: a randomized, double-blind, placebo-controlled 6-month trial, followed by open, long-term clinical evaluation. J Clin Endocrinol Metab. 2000;85:139-146.

(2.) Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction in insulin secretion in women with polycystic ovary syndrome. N Engl J Med. 1996;335: 617-623.

(3.) Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075-4079

(4.) Morin-Papunen LC, Koivunen RM, Ruokonen A, et al. Metformin therapy improves the menstrual pattern with minimal endocrine and metabolic effects in women with polycystic ovary syndrome. Fertil Steril. 1998;69:691-696.

(5.) Nestler JE, Jakubowicz DJ, Evans WS, et al. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med. 1998;338;1876-1880.

(6.) Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory response to clomiphene citrate (CC) in patients resistant to CC alone. Program of the 1999 Annual Meeting of the American Society for Reproductive Medicine. Abstract P-255, p S171.

(7.) Nestler JE. Polycystic ovary syndrome: a disorder for the generalist [editorial]. Fertil Steril. 1998;70:811-812.


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