Human Reproduction, Vol. 18, No. 8, 1618-1625,
August 2003
© 2003 European Society of Human Reproduction and Embryology
Pioglitazone and metformin in obese women with polycystic ovary syndrome not optimally responsive to metformin
Cholesterol Center, Jewish Hospital, ABC Building, 3200 Burnet Avenue, Cincinnati, OH 45229, USA
1 To whom correspondence should be addressed. e-mail: glueckch{at}healthall.com
BACKGROUND: In an observational study of 13 women with polycystic ovary syndrome (PCOS) not optimally responsive to metformin diet, we assessed the efficacy and safety of addition of pioglitazone. We also compared these 13 women to 26 women with PCOS, who were responsive to metformin diet, matched by age and by pre- treatment menstrual history and not different by obesity categories. METHODS: Prospectively, as outpatients, with diet constant [1500–2000 calorie (depending on entry body mass index), 26% protein, 44% carbohydrate, 30% fat], metformin (2.55 g/day) was given for 12 months to 39 women, 13 not optimally responsive, 26 responsive to metformin diet, followed by addition of pioglitazone (45 mg/day) for 10 months in the 13 non-responders. Outcome measures included changes in sex hormones, insulin, insulin resistance (IR), insulin secretion, high density lipoprotein cholesterol, weight, and menstrual status. RESULTS: In 13 non-responders, on metformin diet, median serum insulin fell (21 to 16 µIU/ml, P < 0.05) and insulin secretion fell from 251 to 200 (P < 0.01); weight, dehydroepiandrosterone sulphate (DHEAS), testosterone and IR were unchanged (P 
0.07). Compared with 14% pre- treatment, on metformin diet, expected menses occurred 46% of the time at 3 months (P = 0.05), 38% at 6 months (P = 0.07), 27% at 9 months, and 24% at 12 months. In 26 responders, on metformin diet, median weight fell (93 to 87 kg), testosterone fell (50 to 32 ng/dl), insulin fell (26 to 16 µIU/ml), IR fell (5.32 to 3.45) and insulin secretion fell (351 to 271) (P 
0.017 for all). The occurrence of expected menses in the 26 responders was 2.5-fold higher than in the 13 non-responders (P < 0.0001). In 11 non-responders, on pioglitazone + metformin diet over 10 months versus antecedent metformin diet, DHEAS fell (211 to 171 µg/dl, P = 0.02), insulin fell (16 to 10 µIU/ml, P = 0.001), IR fell (3.37 to 1.73, P = 0.002), insulin secretion fell (217 to 124, P = 0.004), sex hormone-binding globulin rose (31 to 43 nmol/l, P = 0.006), and HDL cholesterol rose (38 to 42 mg/dl, P = 0.003). On pioglitazone + metformin diet, the occurrence of expected menses was 2-fold higher than on metformin diet (P < 0.0001). CONCLUSIONS: In women with PCOS who failed to respond optimally to metformin, when pioglitazone was added, insulin, glucose, IR, insulin secretion, and DHEAS fell, HDL cholesterol and sex hormone-binding globulin rose, and menstrual regularity improved, without adverse side-effects.
Key words: insulin resistance/metformin/pioglitazone/polycystic ovary syndrome
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