Clomiphene, Metformin, or Both for Infertility in the Polycystic Ovary Syndrome

Background The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. Methods We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. Results The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combinationtherapy group (P\u3c0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combinationtherapy group (46.0%, P\u3c0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. Conclusions Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. (ClinicalTrials.gov number, NCT00068861.

Flawed experimental design reveals the need for guidelines requiring appropriate positive controls in endocrine disruption research

A study published in Toxicological Sciences (Ryan et al., 2009) illustrates the importance of examining appropriate doses of both the positive control and the test chemical in research on endocrine-disrupting chemicals. For the three low doses of bisphenol A (BPA) that were fed to rats during pregnancy and lactation, there were no effects on female offspring (there were also no effects on male offspring from the same experiment; Howdeshell et al., 2008). A review of the results of the positive control doses makes it clear that the experiment cannot adequately assess the consequences of low-dose exposure to BPA because the animal model is insensitive to low doses of the positive control estrogen. Therefore, conclusions being drawn from this experiment about low-dose responses to any estrogen are invalid, including that of “no harm” from the low doses of BPA that were tested. However, the experiment is important because it highlights the need to apply basic principles of study design, long known and accepted in studies of hormones and hormonally active drugs, to toxicological studies of chemicals with hormonal activity