Progesterone Suppression of Luteinizing Hormone Pulse Frequency in Adolescent Girls With Hyperandrogenism: Effects of Metformin

Abstract

Context: Polycystic ovary syndrome (PCOS) and adolescent hyperandrogenism (HA) are characterized by rapid luteinizing hormone (LH) pulse frequency. This partly reflects impaired gonadotropin-releasing hormone pulse generator (hypothalamic) sensitivity to progesterone (P4) negative feedback. We assessed whether metformin may improve P4 sensitivity in adolescent HA, for which it is prescribed widely. Objective: To test the hypothesis that metformin improves hypothalamic P4 sensitivity in adolescent HA. Design: Nonrandomized, interventional trial. Setting: Academic clinical research unit. Participants: Ten adolescent girls with HA. Intervention: The girls underwent LH sampling every 10 minutes for 11 hours, at study baseline and after 7 days of oral P4 and estradiol (E2). Participants then took metformin (1 g twice daily) for 9.4 to 13.7 weeks, after which participants again underwent frequent LH sampling before and after 7 days of oral P4 and E2 (while continuing metformin). Total and free testosterone (T) and fasting insulin were assessed at each admission. At admissions 1 and 3, 2-hour oral glucose tolerance tests were performed. Main Outcome Measure: Metformin-related change in hypothalamic P4 sensitivity index [percent change in LH pulse frequency (before vs after P4 and E2) divided by day 7 P4 level]. Results: Free T levels decreased by 29% with metformin (P = 0.0137). Measures of hyperinsulinemia and P4 sensitivity index did not significantly change with metformin use. Conclusion: Short-term metformin use improved biochemical hyperandrogenemia, but did not improve hypothalamic sensitivity to P4 suppression, in adolescent girls.