Extended-release metformin does not reduce the clomiphene citrate dose required to induce ovulation in polycystic ovary syndrome.

Author(s): Cataldo NA, Barnhart HX, Legro RS, Myers ER, Schlaff WD, Carr BR, Diamond MP, Carson SA, Steinkampf MP, Coutifaris C, McGovern PG, Gosman G, Nestler JE, Giudice LC, for the Reproductive Medicine Network

Affiliation(s): Stanford University School of Medicine, Stanford, CA (N.A.C., L.C.G.); Duke University School of Medicine, Durham, NC (H.X.B., E.R.M.); Pennsylvania State University School of Medicine, Hershey, PA (R.S.L.); University of Colorado, Denver, CO (W.D.S.); University of Texas Southwestern Medical Center, Dallas, TX (B.R.C.); Wayne State University, Detroit, MI (M.P.D.); Baylor College of Medicine, Houston, TX (S.A.C.); University of Alabama at Birmingham, Birmingham, AL (M.P.S.); University of Pennsylvania School of Medicine, Philadelphia, PA (C.C.); University of Medicine and Dentistry of New Jersey, Newark, NJ (P.G.M.); University of Pittsburgh, Pittsburgh, PA (G.G.); and Department of Medicine, Virginia Commonwealth University School of Medicine, Richmond, VA (J.E.N.).

Publication date & source: 2008-05-27, J Clin Endocrinol Metab., [Epub ahead of print]

Publication type:

Context: When used for ovulation induction, higher doses of clomiphene may lead to anti-estrogenic side effects that reduce fecundity. It has been suggested that metformin in combination with clomiphene can restore ovulation to some clomiphene -resistant anovulators with polycystic ovary syndrome (PCOS). Objective: To determine if co-treatment with extended-release metformin can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS. Design: Secondary analysis of data from the NICHD Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome (PPCOS) Setting: Study volunteers at multiple academic medical centers Participants: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (N=209 in each group) Interventions: Clomiphene citrate, 50 mg daily for 5 days, increased to 100 mg and 150 mg in subsequent cycles if ovulation not achieved; half also received extended-release metformin, 1000 mg twice daily. Treatment was for up to 30 weeks or 6 cycles, or until first pregnancy. Main Outcome Measures: Ovulation was confirmed by a serum progesterone >=5ng/mL, drawn prospectively every 1-2 weeks. Results: The overall prevalence of at least one ovulation after clomiphene was 75% and 83% (P=0.04) for the clomiphene-only and clomiphene+metformin groups, respectively. Using available data from 314 ovulators, the frequency distribution of the lowest clomiphene dose (50, 100, or 150 mg daily) resulting in ovulation was indistinguishable between the two treatment groups. Conclusion: Extended-release metformin does not reduce the lowest dose of clomiphene which induces ovulation in women with PCOS.