Do insulin-sensitizing drugs increase ovulation rates for women with PCOS?

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Clinical Inquiries

Do insulin-sensitizing drugs increase ovulation rates for women with PCOS?

J Fam Pract. 2005 February;54(2):156-178

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References

1. Lord JM, Flight I, Norman RJ. Metformin in polycystic ovary syndrome: systematic review and meta-analysis. BMJ 2003;327:951-953.

2. Lord JM, Flight I, Norman RJ. Insulin-sensitizing drugs (metformin, troglitazone, rosiglitazone, pioglitazone, Dchiro-inositol) for polycystic ovary syndrome. In The Cochrane Library, 2004;3, accessed on October 22, 2004.

3. Kashyap S, Wells GA, Rosenwaks Z. Insulin-sensitizing agents as primary therapy for patients with polycystic ovary syndrome. Human Reproduction 2004;19:2474-2483.

4. Harborne L, Fleming R, Lyall H, Norman J, Sattar N. Descriptive review of the evidence for the use of metformin in polycystic ovary syndrome. Lancet 2003;361:1894-1901.

5. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 2001;86:1626-1632.

6. Ehrmann DA, Schneider DJ, Sobel BE, et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2108-2116.

7. Brettenthaler N, De Geyter C, Huber PR, Keller U. Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004;89:3835-3840.

8. Shobokshi A, Shaarawy M. Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy. J Soc Gynecol Investig 2003;10:99-104.

9. Ghazeeri G, Kutteh WH, Bryer-Ash M, Haas D, Ke RW. Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome. Fertil Steril 2003;79:562-566.

10. American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin no 41. Polycystic ovary syndrome. 2002.

11. AACE Medical guidelines for clinical practice for the diagnosis and treatment of hyperandrogenic disorders. Endocr Pract 2001;7:121-134.

Less information exists on the role of TZDs and ovarian function in PCOS. Studies of the most researched drug in the class, troglitazone (Rezulin), report improvements in ovulation rates and metabolic markers of PCOS.^5,6 Troglitazone has been taken off of the market due to hepatotoxicity, but results from a RCT of 40 patients with PCOS reported that the use of pioglitazone (Actos) for 3 months increased normal regular cycles and ovulations over placebo (41.2% vs 5.6%; P<.02).⁷ No liver effects were noted, but caution must be taken since these drugs are pregnancy class C. Two small RCTs studied the use of rosiglitazone (Avandia) in combination with clomiphene and reported improvements in menstrual regularity⁸ (92% with combination therapy achieved improved menstrual cycles vs 68% with rosiglitazone alone; OR=0.185) and both spontaneous and clomiphene-induced ovulation rates (52% of clomiphene-resistant women ovulated after rosiglitazone therapy and 77% vs 33% ovulated with combination therapy vs rosiglitazone alone, P=.04).⁹ Further research is needed to determine the clinical effects of the thiazolidinediones.

Recommendations from Others

The American College of Obstetricians and Gynecologists guideline on diagnosis and management of PCOS reports that interventions that improve insulin sensitivity, including weight loss, use of metformin, and use of TZDs are useful for improving ovulatory frequency for women with PCOS.¹⁰ The recommendation is based on good and consistent scientific evidence (SOR: A). They also note that insulin-sensitizing agents may improve many risk factors for diabetes and cardiovascular disease, but this recommendation is based on limited evidence (SOR: B). Finally, they recommend, based on expert opinion (SOR: C), that caution be used with these agents because their effects on early pregnancy are unknown, even though metformin appears to be safe.

The American Association of Clinical Endocrinologists recommends using metformin 850 mg twice daily to treat the hyperandrogenic state of PCOS.¹¹ The use of TZDs is less clear due to limited evidence and risks of teratogenicity.

CLINICAL COMMENTARY

For those trying to conceive, the tried-andtrue medication is clomiphene
Linda French, MD
Department of Family Practice Michigan State University, East Lansing

I tend to think of women with PCOS as falling into 2 camps, those actively trying to conceive and those who are not. Those who are not can often get benefits for their menstrual cycles and hyperandrogenism with birth control pills. For those trying to conceive, the tried-and-true first-line medication is clomiphene.

Metformin has been figuring prominently in the literature as adjunct or second-line therapy for infertility for women with PCOS. It is also an accepted treatment for hirsutism. So, for women with PCOS, metformin is a treatment that bridges the 2 camps. I look forward to seeing head-to-head trials of metformin, clomiphene, and both therapies for induction of ovulation.

Evidence-based answers from the Family Physicians Inquiries Network

Do insulin-sensitizing drugs increase ovulation rates for women with PCOS?

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