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Obese Patients with Polycystic Ovary Syndrome: Evidence that Metformin Does Not Restore Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Ovarian Steroids

Division of Endocrinology (C.A.E., J.C.M.) and Center for Research in Reproduction (C.A.E., A.B.B., K.H., M.B.G., J.C.M.), University of Virginia Health System, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: John C. Marshall, M.D., Center for Research in Reproduction, University of Virginia Health System, Box 800391, Charlottesville, Virginia 22908. E-mail: jcm9h{at}virginia.edu.

Women with polycystic ovary syndrome (PCOS) have reduced GnRH sensitivity to suppression by ovarian steroids, which can be ameliorated by androgen blockade. We studied nine PCOS women and nine controls to determine whether metformin could change feedback inhibition by estradiol (E₂) and progesterone (P). LH was measured every 10 min, and FSH, E₂, P, and testosterone (T) were measured every 2 h. Frequently sampled iv glucose tolerance test was performed at the end of each admission. After the first admission, metformin (500 mg, three times a day) was started. The second admission occurred on d 8–11 of the next menstrual cycle in controls and on d 28 in PCOS patients. Patients subsequently took E₂ and P for 1 wk until the third admission.

At baseline, PCOS women had higher T, free T, androstenedione, and estrone. After 4 wk of metformin, controls had a slight reduction in total T, but free T was unchanged. However, PCOS patients had reduced insulin, T, and E₂, and increased LH mean/amplitude and FSH. After ovarian steroids, controls had a greater reduction in LH pulse frequency than PCOS (61 vs. 25%). These results suggest that the beneficial effects of metformin on ovulatory function in obese PCOS women are probably not mediated by enhanced hypothalamic sensitivity.

This work was supported by National Institute of Child Health and Human Development, National Institutes of Health, through Cooperative Agreement U54-HD-28934 as part of the Specialized Cooperative Centers Program in Reproduction Research, by HD-34179 (to J.C.M.), by General Clinical Research Center Grant M-01-RR-00847, and by Eli Lilly Pituitary Scholarship (to C.A.E.).

Abbreviations: BMI, Body mass index; CV, coefficient of variation; E₂, estradiol; FSIGT, frequently sampled iv glucose tolerance test; P, progesterone; PCOS, polycystic ovary syndrome; Si, sensitivity index; T, testosterone; tid, three times a day.

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