Women with oligomenorrhea and polycystic ovaries show a high incidence of 
ovulation failure perhaps linked to insulin resistance and related metabolic 
features. A number of reports show that the biguanide metformin improves ovarian 
function. However, in these trials the quality of evidence supporting ovulation 
is suboptimal, and few studies have been placebo-controlled. The aim of our 
study was to use a double-blind, placebo-controlled approach with detailed 
assessment of ovarian activity (two blood samples per week) to assess the 
validity of this therapeutic approach in this group of women. Of the 94 patients 
randomized, 2 withdrew before treatment commenced, 47 received placebo, and 45 
received metformin (850 mg, twice a day). The numbers discontinuing the study 
prematurely were higher in the treatment group (n = 15) than the placebo group 
(n = 5; P < 0.05). The ovulation frequency assessed by the ratio of luteal phase 
weeks to observation weeks was significantly (P < 0.01) higher in the treated 
group (23%) compared with the placebo (13%), and the time to first ovulation was 
significantly (P < 0.05) shorter [23.6 d; 95% confidence interval (CI), 17, 30; 
compared with 41.8 d; 95% CI, 28, 56]. The proportion of patients failing to 
ovulate during the placebo-treatment period was higher (P < 0.05) in the placebo 
group, and the majority of ovulations were characterized by normal progesterone 
concentrations in both groups. The effect of metformin on follicular maturation 
was rapid, because the E2 circulating concentration increased over the first 
week of treatment only in the metformin group. Significant (P < 0.01) weight 
loss (and leptin reduction) was recorded in the metformin group, whereas the 
placebo group actually increased weight (P < 0.05). A significant increase in 
circulating high-density lipoprotein was observed only in the metformin-treated 
group. Metabolic risk factor benefits of metformin treatment were not observed 
in the morbidly obese subgroup of patients (body mass index > 37). No change in 
fasting glucose concentrations, fasting insulin, or insulin responses to glucose 
challenge was recorded after 14-wk metformin or placebo therapy. There was an 
inverse relationship between body mass and treatment efficacy. We show in a 
large randomized placebo-controlled trial that metformin treatment improves 
ovulation frequency in women with abnormal ovarian function and polycystic 
ovaries significantly but to a modest degree, and protracted treatment improves 
cardiovascular risk factors. These data support a beneficial effect of metformin 
in improving ovarian function in women with oligomenorrhea and polycystic 
ovaries.