Adding metformin to a clomifene citrate regimen did not significantly increase the probability of ovulating or becoming pregnant in women who had polycystic ovary disease and were treated with clomifene citrate alone.
This conclusion was based on results of a trial conducted at 20 Dutch hospitals where 228 women were randomized to receive either clomifene citrate (Clomid) in combination with metformin (Glucophage) or clomifene citrate with a placebo (BMJ 2006;doi:10.1136/bmj.38867. 631551.55). The researchers, led by Etelka Moll, registrar for obstetrics and gynecology at the center for reproductive medicine at Academic Medical Center, Amsterdam, found comparable ovulation rates in the two groups, the primary outcome measure, and no statistically significant differences in pregnancy, spontaneous abortion, and clomifene resistance rates, the secondary outcome measures.
“The effects of metformin on ovulation may not be sufficiently strong to improve on the already high ovulation rates with clomifene citrate in these women,” the authors wrote.
Of the 111 women in the clomifene citrate plus metformin group, 64% ovulated. Of the 114 in the clomifene citrate plus placebo group, 72% ovulated. In the metformin group, 40% had an ongoing pregnancy, compared with 46% in the clomifene and placebo group. Spontaneous abortions occurred in 12% of the metformin group and 11% of the control group. None of these differences was statistically significant.
The authors note that their trial population was less obese than women evaluated in previous studies of the combined therapy, reflecting a normal range of women with polycystic ovary syndrome (PCOS)—around 35%–60% of such women are obese. Lean women are less likely to benefit from insulin sensitizers such as metformin because they are less insulin resistant.
Patients in the metformin group were significantly more likely to drop out of the study due to side effects, the authors said.
Clomifene citrate stimulates ovulation by increasing follicle-stimulating hormone and luteinizing hormone levels. Of women with PCOS treated with clomifene citrate, 75% will ovulate. Metformin, which potentiates insulin action, stimulates ovulation by reducing insulin and androgen levels.