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Original Article |
Departments of Obstetrics and Gynecology (L.M.-P., R.K., H.M., J.S.T.) and Clinical Chemistry (A.R.), University Hospital of Oulu, FIN-90014 Oulu, Finland; and Department of Medicine (I.V.), University Hospital of Kuopio, FIN-70211 Kuopio, Finland
Address all correspondence and requests for reprints to: Dr. Juha Tapanainen, Department of Obstetrics and Gynecology, University Hospital of Oulu, P.O. Box 5000, FIN-90014 University of Oulu, Oulu, Finland. E-mail: juha.tapanainen{at}oulu.fi.
Metformin, an insulin-sensitizing drug, has been shown to improve ovarian function and glucose metabolism in obese women with polycystic ovary syndrome (PCOS), but its effects and possible benefits in nonobese PCOS subjects are not well known. Seventeen nonobese (body mass index < 25 kg/m2) women with PCOS were randomized to receive either metformin (500 mg twice daily for 3 months, then 1000 mg twice daily for 3 months; n = 8) or ethinyl estradiol (EE, 35 µg)-cyproterone acetate (CA, 2 mg) oral contraceptive pills (EE-CA; n = 9). Waist to hip ratio; serum concentrations of sex steroids, glucose, and insulin during a 75-g oral glucose tolerance test; early phase insulin and C-peptide secretion; and insulin sensitivity using a euglycemic hyperinsulinemic clamp were assessed at baseline and at 3 and 6 months of treatment. Metformin did not have any effect on glucose tolerance or insulin sensitivity, but fasting insulin concentrations decreased from 44.4 ± 5.1 (SE) to 29.8 ± 4.3 pmol/liter (P = 0.03), the waist to hip ratio decreased from 0.78 ± 0.01 to 0.75 ± 0.01 (P = 0.01), and hepatic insulin clearance increased during the treatment. Furthermore, metformin decreased serum testosterone levels from 2.7 ± 0.3 to 2.0 ± 0.2 nmol/liter (P = 0.01) and improved menstrual cyclicity. EE-CA did not have any significant effect on glucose tolerance, serum insulin levels, or insulin sensitivity, but it increased slightly the body mass index (P = 0.09) and significantly serum leptin concentrations (P < 0.001) and decreased serum testosterone levels from 2.1 ± 0.2 to 1.4 ± 0.2 nmol/liter (P = 0.03). In conclusion, EE-CA seems to be an efficient mode of therapy for hyperandrogenic symptoms associated with PCOS, but its possible negative effects on insulin and glucose metabolism also have to be taken into consideration in nonobese subjects. Metformin improved hyperandrogenism, hyperinsulinemia, and menstrual cyclicity, most likely through its positive effect on insulin clearance and abdominal adiposity. Thus, similarly to obese PCOS women, nonobese PCOS subjects with anovulation may also benefit from metformin treatment.
This research was supported by grants provided by the University of Oulu, the Finnish Gynecological Association, the Sigrid Jusélius Foundation, and the Academy of Finland.
Abbreviations: A, Androstenedione; AUGgluc, glucose area under the curve; AUCins, insulin area under the curve; BMI, body mass index; CA, cyproterone acetate; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; EE, ethinyl estradiol; FAI, free androgen index; FFA, free fatty acid; HDL, high-density lipoprotein; IGFBP, IGF binding protein; IGT, impaired glucose tolerance; OC, oral contraceptives; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; RQ, respiratory quotient; S-LDL, serum low-density lipoprotein; T, testosterone; WHR, waist to hip ratio.
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