Cj. Glueck et al., Metformin-induced resumption of normal menses in 39 of 43 (91%) previouslyamenorrheic women with the polycystic ovary syndrome, METABOLISM, 48(4), 1999, pp. 511-519
In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) wit
h fasting hyperinsulinemia (greater than or equal to 20 mu U/mL), our aim w
as to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), wh
ich reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, all
owing resumption of regular normal menses. A second aim was to assess the e
ffects of weight loss versus other Metformin-induced effects on ovarian fun
ction, and to determine if there were different responses to Metformin betw
een 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 t
he plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (P
AI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 h
ad normal hemoglobin A1C (HgA1C); only three (7%) had type 2 diabetes melli
tus. 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%) resu
med normal menses. The percentage of women resuming normal menses did not d
iffer 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 ent
ry 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 Metf
ormin, the median fasting serum insulin decreased from 26 mu U/mL to 22 (P
= .019), testosterone decreased from 61 ng/dL to 47 (P = .003), and estradi
ol increased from 41 pg/mL to 71 (P = .0001). Metformin-induced improvement
s in ovarian function were independent of weight loss (testosterone decreas
e, P < .002; estradiol increase, P < .0004). The change in response variabl
es 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 lo
st 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. Al
though the pretreatment fasting serum insulin was not significantly correla
ted with testosterone (r = .24, P = .13) or androstenedione (r = .27, P = .
09), on Metformin, the change in insulin correlated positively with the cha
nge in testosterone (r = .35, P = .047) and with the change in androstenedi
one (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 t
he PAI-1 gene and were also more likely to have high PAI-Fx (greater than o
r equal to 22 U/mL, 28% v 3%, chi(2) = 10.1, P = .001). Metformin reduces t
he endocrinopathy of PCOS, allowing resumption of normal menses in most (91
%) previously amenorrheic women with PCOS. Copyright (C) 1999 by W.B. Saund
ers Company.