Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone
Vandermolen DT,Ratts VS,Evans WS,Stovall DW,Kauma SW,Nestler JE
Published February 15, 2001Fertility and Sterility, 75(2), 310-315
Vandermolen, D. T., Ratts, V. S., Evans, W. S., Stovall, D. W., Kauma, S. W., & Nestler, J. E. (2001). Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertility and Sterility, 75(2), 310-315. https://doi.org/10.1016/s0015-0282(00)01675-7
Vandermolen DT, Ratts VS, Evans WS, Stovall DW, Kauma SW, Nestler JE. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001;75(2):310-315. doi:10.1016/s0015-0282(00)01675-7
Vandermolen, David T., et al. "Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone." Fertility and Sterility, vol. 75, no. 2, 2001, pp. 310-315.
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Department of Obstetrics and Gynecology, Medical College of Virginia, Virginia Commonwealth University, Richmond, USA.
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RRM Academy Synopsis
Metformin raised ovulation and pregnancy in clomiphene-resistant PCOS
Adding metformin to clomiphene increased ovulation and pregnancy in women with polycystic ovary syndrome (PCOS) that had resisted clomiphene, a 27-woman randomized trial found. More than 7 out of 10 women on metformin ovulated, against fewer than 3 out of 10 on placebo. More than 5 out of 10 on metformin conceived, against under 1 out of 10 on placebo.
Key Findings
Ovulation occurred in 9 of 12 women (75%) taking metformin plus clomiphene, against 4 of 15 women (27%) taking placebo plus clomiphene (P=.02).
Pregnancy occurred in 6 of 11 women (55%) in the metformin group and 1 of 14 women (7%) in the placebo group (P=.02).
Of the 8 women who ovulated in response to metformin and clomiphene, 6 conceived (75%). Across their 28 ovulatory cycles, 21% (6 of 28) ended in pregnancy.
In the metformin group, 2 of 6 pregnancies ended in miscarriage and 4 produced healthy term infants. The single placebo pregnancy produced a healthy term infant. All 7 pregnancies were singletons.
After 7 weeks, women taking metformin showed no significant shift in blood insulin, androgens, LH or FSH relative to women taking placebo.
Interpretation
This double-blind, placebo-controlled trial enrolled 27 women aged 18 to 35 with PCOS who had not ovulated on clomiphene. PCOS has since been renamed polyendocrine metabolic ovarian syndrome (PMOS). Enrollment required each woman's partner to have a normal semen analysis. Average body mass index was high in both groups. The authors propose metformin worked in part through improved insulin sensitivity. The authors note that findings may not apply to all clomiphene-resistant women, especially those with lower body weight. The findings support larger studies of metformin in clomiphene-resistant PCOS.
RRM Context
Restorative reproductive medicine seeks the cause of ovulation failure. The authors cite findings that women with PCOS who do not ovulate on clomiphene show more insulin resistance. They also cite earlier work that metformin improves insulin sensitivity. Partners of the women had a normal semen analysis. Restorative care evaluates both partners before treatment.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone.
Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC.
Interventions
Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC.
Main Outcome Measures
Ovulation and pregnancy rates.
Results
In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant.
Conclusions
In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.
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