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

Phase 3
18 Years
40 Years
Not Enrolling
Polycystic Ovary Syndrome, Anovulation, Oligoovulation, Infertility, Hyperandrogenism

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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.

Inclusion Criteria:

- Married

- Hyperandrogenic women 18-40 years old who desired fertility and who demonstrated
chronic anovulation or oligoovulation

- Had patent fallopian tubes and whose partners had normal semen analyses were eligible
for enrollment in the study.

Exclusion Criteria:

- Androgen secreting tumours

- Diabetes mellitus

- Thyroid abnormalities

- Hyperprolactinemia

- Adult onset congenital adrenal hyperplasia

- Diminished ovarian reserve

- Subjects who used hormonal medications two months prior to the start of the trial.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Outcome Measure:

Pregnancy Rates

Principal Investigator

Randal D Robinson, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Wilford Hall Medical Center and Brooke Army Medical Center


United States: Institutional Review Board

Study ID:




Start Date:

December 1997

Completion Date:

April 2003

Related Keywords:

  • Polycystic Ovary Syndrome
  • Anovulation
  • Oligoovulation
  • Infertility
  • Hyperandrogenism
  • Polycystic Ovarian Syndrome
  • Chronic Anovulation
  • Chronic Oligoovulation
  • Infertility
  • Hyperandrogenism
  • Metformin
  • Ovulation induction
  • Anovulation
  • Infertility
  • Polycystic Ovary Syndrome
  • Hyperandrogenism



Wiford Hall Medical Center Lackland AFB, Texas  78236