Metformin Improves Hypothalamic Progesterone Insensitivity in Hyperandrogenic Girls

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 548-560-Hyperandrogenic Disorders
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-559
Christine Michele Burt Solorzano*1, Jessicah S. P. Collins2, Jennifer P Beller3, Amy Denise Anderson2, Ruchi Bhabhra1, Christopher Rolland McCartney2 and John C Marshall2
1Division of Endocrinology, University of Virginia, Charlottesville, VA, 2University of Virginia, Charlottesville, VA, 3Glens Falls Hospital, Queensbury, NY
The GnRH pulse generator in PCOS has decreased sensitivity to suppression by estradiol (E2) and progesterone (P). Adolescent hyperandrogenemia often precedes adult PCOS. In our studies, 50% of hyperandrogenic (HA) girls have reduced hypothalamic P sensitivity, similar in degree to that observed in adult PCOS women (1). Girls with decreased P sensitivity have higher fasting insulin, suggesting that insulin excess may partly mediate reduced sensitivity. We thus hypothesized that metformin would improve hypothalamic P sensitivity in HA girls by lowering insulin levels.

We assessed the effect of metformin on P suppression of LH (GnRH) pulse frequency in HA girls (n = 6, Tanner stage 5, mean age 15.2 ± 0.3 SEM). Girls had q 10 min LH sampling overnight and 75-g oral glucose tolerance testing (OGTT) the next morning. They received 7 days of oral E2/P, then repeated overnight LH sampling. Girls took metformin (1000 mg BID) for 10 weeks and then repeated the OGTT and LH sampling before and after E2/P. Results are presented as mean ± SEM. The percent change of LH pulse number divided by day 7 P level was used to assess hypothalamic P sensitivity (10.3 ± 7.7 in NW Tanner 3-5 girls [1]).

At baseline, 5 of 6 HA girls were P-insensitive similar to adult PCOS (2). P sensitivity increased overall (3.54 ± 0.95 pre- vs. 5.53 ± 1.34 post-) and improved in 5/6 after metformin (2 girls moved to normal range) (1). Although fasting insulin levels did not improve (27.0 ± 6.6 vs. 27.5 ± 8.2 mIU/ml), metformin reduced AUC insulin during OGTT by 25% (12903 ± 2546 vs. 9631 ± 3490 mIU/mL). Morning free testosterone (T) decreased 20% (46.2 ± 10.0 vs. 37.4 ± 10.3 pmol/L) after metformin. Sex hormone binding globulin was unchanged after metformin (18.7 ± 6.4 vs 20.3 ± 8.1 nmol/L), suggesting decreased free T was due to less total T production.

These results suggest that metformin modestly improves hypothalamic P sensitivity. Fasting insulin did not change, but stimulated insulin and morning free T improved by 20-25% in HA girls. Over a longer period of treatment, we speculate that metformin may provide an even greater benefit for P sensitivity in HA girls. Further studies are needed to delineate mechanisms by which metformin improves hypothalamic P sensitivity.

(1) Blank SK, McCartney CR, Chhabra S, Helm KD, Eagleson CA, Chang RJ, Marshall JC. J Clin Endocrinol Metab  2009; 94:2360. (2) Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. J Clin Endocrinol Metab 1998; 83:582.

Nothing to Disclose: CMB, JSPC, JPB, ADA, RB, CRM, JCM

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Sources of Research Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)/National Institute of Health (NIH) K23HD070854-01 (CBS); through cooperative agreement U54HD28934 as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research at NICHD/NIH (CBS, CRM, JCM); NICHD/NIH F32 HD066855 (JC); National Institute of Diabetes and Digestive and Kidney Diseases/NIH T32 DK07646 (JB, AA, RB).