Aromatase Inhibition Ameliorates Decreased LH Output Found in Obese Women

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.

Keywords: Aromatase inhibitor; FSH; LH; Letrozole; Obesity.

Fig. 1

Hormone curves from subjects representative of AI treated (solid dots) vs. untreated (open dots), and normal weight (blue) vs. obese (orange). A bolus of GnRH was administered at 240 min, as indicated by the vertical gray line. Pulses are represented by asterisks; peaks are represented by diamonds

Fig. 2

Differences in luteinizing hormone by AI treated vs. untreated, and normal weight vs. obese. Bar plots represent the geometric mean, with 95% confidence intervals (vertical lines); horizontal lines with an asterisk represent significant pairwise differences (p < 0.05). Amp, amplitude, calculated as described in materials and methods