Endogenous opioids and hypogonadism in human obesity

Abstract

Massively obese males often show symptoms of hypogonadism, but the mechanism for this is unclear. Increased endogenous opioid inhibition of the hypothalamic GnRH pulse generator resulting in insufficient stimulation of the pituitary gonadotroph has been proposed as a possible mechanism. If this hypothesis is correct, obese males should be more sensitive to the LH-elevating effects of the opiate antagonist, naloxone, than men of normal weight and gonadal status. This study investigated the etiology of obesity-related hypogonadism by examining luteinizing hormone (LH) and follicle stimulating hormone (FSH) responses to gonadotropin-releasing hormone (GnRH) and to infusions of saline or naloxone. Subjects were five obese (201 ± 14% IBW) and five normal weight (control) (97 ± 4% IBW) males. Before treatment, obese males had significantly ( p < 0.05) lower testosterone levels than control subjects (307 ± 72 vs. 597 ± 49 ng/ dl), whereas estradiol, androstenedione, and dehydroepiandrosterone levels were not different between the two groups. Both groups showed equivalent elevations in LH (fourfold to sixfold) in response to GnRH stimulation, but obese patients had significantly lower basal ( p < 0.05) and GnRH-stimulated ( p < 0.01) FSH levels. Infusions of naloxone (but not saline) led to significant ( p < 0.01) increases in LH above preinfusion baseline levels (20.5 ± 2.8% in obese and 28.6 ± 6.3% in controls). In control subjects, integrated LH levels during naloxone infusion were not significantly elevated above those found during saline infusion, while obese subjects exhibited a 43% augmentation of integrated LH (31.0 ± 5.3 ng/ ml during naloxone vs. 21.7 ± 1.8 ng/ ml during saline, p < 0.05). Furthermore, analysis of LH pulsatility by cycle detection analysis demonstrated a 51% increase in LH pulse frequency of obese subjects from 0.45 ± 0.04 pulses/ h during saline infusion to 0.68 ± 0.13 pulses/ h during naloxone treatment ( p < 0.05). These data suggest that the hypogonadism found in massively obese males may be due, in part, to increased tonic inhibition, mediated via endogenous opioids, of the hypothalamic GnRH pulse generator.