Aromatase Inhibition Ameliorates Decreased LH Output Found in Obese Women

Kelsey Jones,Alex J Polotsky,Nanette Santoro,Andrew P Bradford,Justin Chosich,Sarah Ryan,Nichole E Carlson

doi:10.1007/s43032-019-00105-5

Abstract

In obese ovulatory women, serum luteinizing Hormone (LH) and follicle stimulating hormone (FSH) are lowered compared with normal weight women. This relative hypogonadotropic hypogonadism represents a potential etiology for overall decreased fertility in obesity. The objective was to determine if administration of an aromatase inhibitor (AI) to ovulating obese women would normalize LH and FSH by interrupting estradiol negative feedback. Letrozole (2.5–5 mg) was given daily to 22 women, 12 obese and 10 normal weight, for 7 days. On the last day of administration, 8 h of blood sampling was done every 10 min before and after a bolus of GnRH at 4 h. We obtained data from 21 ovulatory women (10 normal weight and 11 obese) who had undergone a similar protocol of frequent blood sampling but no aromatase inhibitors (AI) treatment. Serum LH and FSH levels and pulse characteristics were measured. Treatment with AI only significantly affected obese women. Further, in women with obesity, LH secretion, prior to the GnRH bolus, was significantly higher in AI treated compared with non-treated (p = 0.011). AI treatment doubled LH pulse amplitude in obese women (p = 0.004). In response to aromatase inhibition, LH secretion in ovulatory women with obesity is increased and similar to levels found in untreated normal weight women. The increase in LH pulse amplitude indicates that the AI effect is mediated at the level of the pituitary. Our results suggest that the hypogonadotropic phenotype of simple obesity is subject to modulation by interruption of estradiol negative feedback.

Highlights

Obesity makes it more difficult for women to conceive, whether through natural or assisted methods
aromatase inhibitor (AI)-treated NW had higher average levels of Luteinizing hormone (LH) (6.9 IU/L, 95% CI 4.0, 9.6) compared with normal weight non-AItreated women (4.76 IU/L, 95% CI 3.39, 6.69), statistical significance was not reached (p = 0.11)
With GnRH stimulation, average mean peak LH was 1.5 times higher in AI-treated NW women compared with non-treated NW women (20.50 IU/L, 95% CI 13.68, 30.74 vs. 13.45 IU/ L, 95% CI 8.80, 20.57; p = 0.16)

Summary

Introduction

Obesity makes it more difficult for women to conceive, whether through natural or assisted methods. Obesity is known to affect the hypothalamic-pituitary-ovarian axis, oocyte quality, and overall fertility [1,2,3]. Luteinizing hormone (LH) is produced by the pituitary gonadotropes and is essential for ovulation. Cellular mechanisms involve the theca cells in the ovary, whereby products of these cells permit the granulosa cells to produce estrogens. Estrogens provide negative feedback on pituitary LH secretion through the mid-follicular phase. In an ovulatory obese woman, both LH and FSH are consistently demonstrated to be reduced with a corresponding reduction in estrogen and progesterone production by the ovary after ovulation.

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