Exogenous Estradiol Improves Gonadotropin Sensitivity in Obese Women

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 515-547-Female Reproductive Endocrinology
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-544
Alex Joel Polotsky*, Huayu Liu, Nichole E Carlson, Andrew P Bradford, Jennifer Lesh, Justin Chosich and Nanette Santoro
University of Colorado Denver
Prior studies of ovulatory women indicate an obesity-related deficit in gonadotropins and LH pulse amplitude suggesting a pituitary defect (1). Estrogen exerts an inhibitory effect on LH and FSH responsiveness to GnRH directly at the pituitary (2).

Objective: To examine gonadotropin sensitivity to estrogen negative feedback in eumenorrheic (non-PCOS) obese women.  We conducted testing in the early follicular phase (CD 3-5) before and after 1 month of transdermal estradiol (E2) administration.

Methods: 11 obese (BMI, 36.7±1.3 kg/m2) and 10 normal weight (BMI, 21.2±0.5 kg/m2) women underwent 8-hour, q10 min blood sampling sessions, with a 75 ng/kg bolus of GnRH given at 6 hours. At the completion of baseline studies, a 0.1 mg/day transdermal E2patch was applied starting with day 1 of the subsequent menses. The patch was applied for the entire subsequent menstrual cycle or up to 40 days (if there was no menses). If no menses occurred, oral progesterone was given for 10 days. LH & FSH were assayed by immunofluorometric assay (DELFIA, PerkinElmer). LH pulsatility was evaluated using a modified Santen-Bardin method (3). Group means were compared using t tests.

Results: Obese and normal weight women were of similar age (29.4±1.9 vs. 32.5±1.8 years, respectively, p=0.25). At baseline, obese women exhibited reduced unstimulated LH secretion as compared to controls (mean LH: 2.5±0.2 IU/L vs. 5.2±0.8 IU/L, respectively, p<0.01; LH pulse amplitude:1.1±0.2 IU/L vs.2.7±0.5 IU/L, respectively, p=0.03), but no difference in LH pulse frequency.

Following transdermal E2, LH pulse amplitude increased by 20.3% in the obese but decreased by 14.6% in the normal weight controls (incremental change after E2: +0.47±0.22 vs. -0.54±0.42 IU/L, respectively, p =0.048). Similarly, following transdermal E2, maximum response of FSH to GnRH increased by 21.8% in the obese but decreased by 44.5% in the normal weight controls (incremental change after E2: +0.5±0.5 IU/L vs. -1.6±0.4 IU/L, respectively, p<0.01).

While maximum LH response to GnRH was greater in the controls vs. obese at baseline, incremental changes in LH pituitary responsiveness to GnRH after E2 demonstrated an increase in LH responsiveness in the obese but a decrease in the controls, similar to FSH trends after E2, but did not reach significance.

Conclusions: Obesity modulates gonadotropin sensitivity to E2 and responsiveness to GnRH in women.  The effect of exogenous E2 on FSH responsiveness to GnRH in obesity is greater than on LH responsiveness.  These results suggest that negative feedback by E2 is altered in obese women, and implicates the pituitary gonadotrope as a functionally important locus for mediating the impact of obesity on female reproduction.  The mechanisms behind recovery of reduced LH pulse amplitude and FSH responsiveness by exogenous E2 should be explored as a potential treatment to ameliorate the suppression of the HPO axis in obese women.

(1) Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab. 2007;92:2468-73. (2) Shaw ND, Histed SN, Srouli SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women.J Clin Endocrinol Metab. 2010;95:1955-61. (3) Santen RJ, Bardin CW. Episodic luteinizing hormone secretion in man. Pulse analysis, clinical interpretation, physiologic mechanisms. J Clin Invest. 1973;52:2617-28.

Disclosure: AJP: Principal Investigator, Bayer, Inc.. NS: Investigator, Bayer, Inc., Consultant, Menogenix. Nothing to Disclose: HL, NEC, APB, JL, JC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Bayer Droegemueller Award in Clinical Research (grant# 7347); U54 HD058155 Center for the Study of Reproductive Biology; UL1 RR025780 (University of Colorado CTRC)