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

Infertility Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00413179
• Other study ID #: FWH19970383H
• Status: Completed
• Phase: Phase 3
• First received: December 18, 2006
• Last updated: December 18, 2006
• Start date: December 1997
• Est. completion date: April 2003

Study information

• Verified date: December 2006
• Source: Wilford Hall Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 56
• Est. completion date: April 2003
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 40 Years

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Anovulation
• Hyperandrogenism
• Infertility
• Oligoovulation
• Polycystic Ovary Syndrome

Intervention

Drug:
• Metformin

• Clomiphene citrate

• Placebo

Locations

Country	Name	City	State
United States	Wiford Hall Medical Center	Lackland AFB	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Wilford Hall Medical Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pregnancy Rates
Primary	Ovulation Rates
Secondary	Pregnancy Outcome