Extended-Release Metformin Does Not Reduce the Clomiphene Citrate Dose Required to Induce Ovulation in Polycystic Ovary Syndrome

The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 3124-3127
The Endocrine Society
Nicholas A. Cataldo, Huiman X. Barnhart, Richard S. Legro, Evan R. Myers, William D. Schlaff, Bruce R. Carr, Michael P. Diamond, Sandra A. Carson, Michael P. Steinkampf, Christos Coutifaris, Peter G. McGovern, Gabriella Gosman, John E. Nestler, Linda C. Giudice for the Reproductive Medicine Network1
Context: When used for ovulation induction, higher doses of clomiphene may lead to antiestrogenic 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: Our objective was to determine if cotreatment with extended-release metformin (metformin XR) can lower the threshold dose of clomiphene needed to induce ovulation in women with PCOS.

Design: A secondary analysis of data from the National Institute of Child Health and Human Development Cooperative Multicenter Reproductive Medicine Network prospective, double-blind, placebo-controlled multicenter clinical trial, Pregnancy in Polycystic Ovary Syndrome, was performed.

Setting: Study volunteers at multiple academic medical centers were included.

Participants: Women with PCOS and elevated serum testosterone who were randomized to clomiphene alone or with metformin (n = 209 in each group) were included in the study.

Interventions: Clomiphene citrate, 50 mg daily for 5 d, was increased to 100 and 150 mg in subsequent cycles if ovulation was not achieved; half also received metformin XR, 1000 mg twice daily. Treatment was for up to 30 wk or six cycles, or until first pregnancy.

Main Outcome Measures: Ovulation was confirmed by a serum progesterone more than or equal to 5 ng/ml, drawn prospectively every 1–2 wk.

Results: The overall prevalence of at least one ovulation after clomiphene was 75 and 83% (P = 0.04) for the clomiphene-only and clomiphene plus 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: Metformin XR does not reduce the lowest dose of clomiphene that induces ovulation in women with PCOS.

Stanford University School of Medicine (N.A.C., L.C.G.), Stanford, California 94305; Duke University School of Medicine (H.X.B., E.R.M.), Durham, North Carolina 27701; Pennsylvania State University School of Medicine (R.S.L.), Hershey, Pennsylvania 17033; University of Colorado (W.D.S.), Denver, Colorado 80218; University of Texas Southwestern Medical Center (B.R.C.), Dallas, Texas 75235; Wayne State University (M.P.D.), Detroit, Michigan 48202; Baylor College of Medicine (S.A.C.), Houston, Texas 77030; University of Alabama at Birmingham (M.P.S.), Birmingham, Alabama 35294; University of Pennsylvania School of Medicine (C.C.), Philadelphia, Pennsylvania 19104; University of Medicine and Dentistry of New Jersey (P.G.M.), Newark, New Jersey 07101-1709; University of Pittsburgh (G.G.), Pittsburgh, Pennsylvania 15260; and Department of Medicine (J.E.N.), Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298-0565

Address all correspondence and requests for reprints to: Richard S. Legro, M.D., Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, Pennsylvania 17033. E-mail: [email protected].

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