The Effect of Metformin Added to Clomiphene Citrate on Pregnancy Rates in Hyperandrogenic, Chronic Oligoovulatory or Anovulatory Women
Condition: Polycystic Ovary Syndrome; Anovulation; Oligoovulation; Infertility; Hyperandrogenism
MeSH terms: Polycystic Ovary Syndrome; Infertility; Hyperandrogenism; Anovulation
Study type: Interventional
Phase: Phase 3

Summary: 
      The purpose of our study was to conduct a placebo controlled, double-blind randomized trial
      in chronic oligoovulatory or anovulatory , hyperandrogenic, infertility patients comparing
      the effects of adjuvant metformin plus clomiphene citrate to clomiphene citrate plus placebo
      on pregnancy rates and ovulation rates. We hypothesized that combining metformin with
      clomiphene citrate would result in higher ovulation and pregnancy rates in hyperandrogenic
      women who have chronic oligoovulation or anovulation as the sole etiology for their
      infertility and who have unknown responsiveness to clomiphene citrate.
    

Detailed description: 
      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.
    

Intervention name(s): Metformin; Clomiphene citrate; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Metformin; Clomiphene; Enclomiphene; Zuclomiphene
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Polycystic Ovarian Syndrome; Chronic Anovulation; Chronic Oligoovulation; Infertility; Hyperandrogenism; Metformin; Ovulation induction