Trial Information

The Effect of Metformin Added to Clomiphene Citrate on Pregnancy Rates in Hyperandrogenic, Chronic Oligoovulatory or Anovulatory Women: A Randomized Trial

Women with polycystic ovary syndrome (PCOS), defined as chronic oligoovulation or
anovulation and hyperandrogenism, are primarily treated with clomiphene citrate as first
line therapy if they desire pregnancy. However, women with PCOS have lower than expected
pregnancy rates in response to clomiphene citrate. Approximately 20% of women with PCOS are
resistant to clomiphene citrate. Subjects with chronic oligoovulation or anovulation and
hyperandrogenism will ovulate 80% of the time, but pregnancy occurs in only 40%. The ideal
initial treatment regimen for women with PCOS who desire pregnancy has not been determined.

Metformin (Glucophage; Bristol-Myers Squibb, Princeton, NJ) is an insulin sensitizer and
lowers serum insulin and androgen levels. Numerous case studies, case series, retrospective
studies, and non-placebo controlled prospective studies, have suggested an improvement in
insulin sensitivity, spontaneous menses, ovulatory response and pregnancies when metformin
was given alone or prior to initiation of ovulation inducing agents in women with chronic
anovulation and hyperandrogenism.

However, there has been conflicting evidence in the literature regarding the effect of
metformin alone or in combination with ovulation inducing agents regarding ovulation and
pregnancy rates in prospective, randomized trials. Therefore, it remains unknown if the use
of metformin plus clomiphene citrate in non-selected, infertility patients with PCOS
improves ovulation and pregnancy rates compared to the use of clomiphene citrate alone.

Women with a history of infertility and diagnosed with hyperandrogenic, oligoovulatory or
anovulatory cycles as the sole etiology for their infertility were randomized to receive
clomiphene citrate 50 mg days 5-9, plus metformin 500 mg three times daily versus clomiphene
plus placebo. The dose of clomiphene was increased up to a maximum dose of 250 mg in a
step-wise fashion until ovulation was confirmed with an ovulation predictor kit. Once
ovulation was confirmed the subjects continued the ovulatory dose of clomiphene for 6
ovulatory cycles or until conception. Metformin or placebo was started on cycle day one and
discontinued 8 days after the LH surge and/or by cycle day 21. A positive HCG, ovulation
rates and pregnancy outcome were the outcome measures.