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Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome

Legro, Richard S.; Barnhart, Huiman X.; Schlaff, William D.; Carr, Bruce R.; Diamond, Michael P.; Carson, Sandra A.; Steinkampf, Michael P.; Coutifaris, Christos; McGovern, Peter G.; Cataldo, Nicholas A.; Gosman, Gabriella G.; Nestler, John E.; Giudice, Linda C.; Leppert, Phyllis C.; Myers, Evan R.

Obstetrical & Gynecological Survey: June 2007 - Volume 62 - Issue 6 - p 386-388
doi: 10.1097/01.ogx.0000265909.61668.01
Gynecology: Normal and Abnormal Menstrual Cycles

Polycystic ovary syndrome (PCOS) may be the commonest cause of female infertility. In addition to anovulation, early pregnancy loss, and later complications of pregnancy, obesity—which is common in women with PCOS—has been implicated. Small-scale trials suggest that treatment with an insulin sensitizer such as metformin, alone or combined with clomiphene citrate, is at least equal to, and possibly superior to clomiphene alone as treatment for infertility. This randomized, placebo-controlled trial evaluated both of these agents, alone and combined, in 626 infertile women diagnosed as having PCOS. Extended-release metformin was given in a maximum dose of 1 gm daily, and clomiphene concurrently in a dose of 50 mg daily, starting on menstrual day 3. The dose of clomiphene was doubled if necessary. Treatment continued for up to six cycles over 30 weeks. Baseline variables were similar in all treatment groups.

Rates of live birth were 22.5% in clomiphene-treated patients, 7.2% with metformin therapy, and 26.8% with combination therapy. The differences between the metformin group and the clomiphene and combined treatment groups were significant. Combined therapy was not significantly more effective than clomiphene alone. Similar results were obtained when adjusting for body mass index. Among secondary outcomes, ovulation rates were significantly higher with combined treatment than in either of the single-drug groups, but this did not translate into increased live births. Rates of conception and of live births per ovulatory cycle were significantly higher in the clomiphene and combined drug groups than with metformin alone. There were no multiple pregnancies in the metformin group. There were no notable group differences in rates of first-trimester pregnancy loss. Compared to metformin-treated women, those given clomiphene or combined therapy had significant increases in sex hormone-binding globulin levels and decreased free androgen indices. Serious adverse events—mostly pregnancy complications—were most frequent in the clomiphene and combined treatment groups. Gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group.

These findings fail to support the view that extended-release metformin, alone or combined with clomiphene citrate, improves live birth rates in previously infertile women with PCOS. Clomiphene alone seems preferable as first-line treatment for these patients despite a risk of multiple births. Combining the two drugs does not further increase the chances of a live birth.

For the Cooperative Multicenter Reproductive Medicine Network; Pennsylvania State University College of Medicine, Hershey; Duke University Medical Center, Durham, North Carolina; University of Colorado, Denver; University of Texas Southwestern Medical Center, Dallas; Wayne State University, Detroit, Michigan; Baylor College of Medicine, Houston, Texas; University of Alabama, Birmingham; University of Pennsylvania School of Medicine, Philadelphia; University of Medicine and Dentistry of New Jersey, Newark; Stanford University, Stanford, California; University of Pittsburgh, Pittsburgh, Pennsylvania; Virginia Commonwealth University School of Medicine, Richmond; University of California at San Francisco; and National Institute of Child Health and Human Development, Bethesda, Maryland

N Engl J Med 2007;356:551–566

Copyright © 2007 Wolters Kluwer Health, Inc. All rights reserved.