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.

Trial registration: ClinicalTrials.gov NCT01427595.

Copyright © 2017 Endocrine Society

Figures

Figure 1.

Study schematic. Arrows indicate overnight CRU admissions for frequent blood sampling to measure LH levels. Participants took E2 (1 mg daily) and P4 (0.5 mg/kg three times daily) between admissions 1 and 2 and again between admissions 3 and 4. After admission 2, the metformin dose was increased weekly by 500 mg/d until participants were using 1000 mg twice daily. *75 g OGTT performed at 7:00 am on the days of discharge from admissions 1 and 3.

Figure 2.

Metformin-related changes in P4 sensitivity index. (A) Open circles represent the numbered participant’s hypothalamic sensitivity to P4 suppression at baseline (premetformin); that is, percent reduction in LH pulse frequency at admission 2 compared with admission 1 (y-axis) as a function of achieved P4 concentration assessed during admission 2 (x-axis). Closed circles represent the participant’s hypothalamic sensitivity to P4 suppression after metformin; that is, percent reduction in pulse frequency (admission 4 vs admission 3) as a function of achieved P4 concentration during admission 4. Arrows connecting these circles indicate the directionality of the change in pulse frequency after metformin treatment of an individual participant. Participant 9 had a 60% increase in LH pulse frequency. (B) Change in P4 sensitivity index with metformin treatment. Each participant’s metformin-related change in P4 sensitivity index (pre- vs postmetformin treatment) is represented by an open circle containing the participant’s number. The dashed line indicates no change in sensitivity.

Figure 3.

Metformin-related changes in selected parameters. Metformin-related changes in (A) weight, (B) total T, (C) SHBG, and (D) free T levels. Metformin-related changes in (E) insulin and (F) glucose responses to oral glucose ingestion. Data from admission 1 (mean ± standard error of the mean) are shown in open squares; data from admission 3 are shown in closed squares.