Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome

Abstract

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (≥ 20 μU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G 5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); only three (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1 ± 5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups ( P < .1) or among dose groups ( P > .1). The body mass index (BMI) decreased from 36.4 ± 7 Kg/m 2 at study entry to 35.1 ± 6.7 on Metformin ( P = .0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 μU/mL to 22 ( P = .019), testosterone decreased from 61 ng/dL to 47 ( P = .003), and estradiol increased from 41 pg/mL to 71 ( P = .0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P < .002; estradiol increase, P < .0004). The change in response variables on Metformin did not differ ( P > .05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not ( P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose ( P < .05), which increased 6 mg/dL in those who lost the least weight on Metformin versus those in the 60th to 80th percentile for weight loss, in whom glucose decreased 33 mg/dL. Although the pretreatment fasting serum insulin was not significantly correlated with testosterone ( r = .24, P = .13) or androstenedione ( r = .27, P = .09), on Metformin, the change in insulin correlated positively with the change in testosterone ( r = .35, P = .047) and with the change in androstenedione ( r = .48, P = .01). Patients were more likely than normal controls (83% v 64%, P = .016) to be heterozygous or homozygous for 4G polymorphism of the PAI-1 gene and were also more likely to have high PAI-Fx (≥22 U/mL, 28% v 3%, χ 2 = 10.1, P = .001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.