ENDOGENOUS OPIOIDS AND HYPOGONADISM IN HUMAN OBESITY

Massively obese males often show symptoms of hypogonadism, but the mec hanism for this is unclear. Increased endogenous opioid inhibition of the hypothalamic GnRH pulse generator resulting in insufficient stimul ation of the pituitary gonadotroph has been proposed as a possible mec hanism. If this hypothesis is correct, obese males should be more sens itive 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 gonad otropin-releasing hormone (GnRH) and to infusions of saline or naloxon e. Subjects were five obese (201 +/- 14% IBW) and five normal weight ( control) (97 +/- 4% IBW) males. Before treatment, obese males had sign ificantly (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 g roups. Both groups showed equivalent elevations in LH (fourfold to six fold) in response to GnRH stimulation, but obese patients had signific antly lower basal (p < 0.05) and GnRH-stimulated (p < 0.01) FSH levels . Infusions of naloxone Glut not saline) led to significant (p < 0.01) increases in LH above preinfusion baseline levels (20.5 +/- 2.8% in o bese and 28.6 +/- 6.3% in controls). In control subjects, integrated L H levels during naloxone infusion were not significantly elevated abov e 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, analysi s of LH pulsatility by cycle detection analysis demonstrated a 51% inc rease in LH pulse frequency of obese subjects from 0.45 +/- 0.04 pulse /h during saline infusion to 0.68 +/- 0.13 pulses/h during naloxone tr eatment (p < 0.05). These data suggest that the hypogonadism found in massively obese males may be due, in part, to increased tonic inhibiti on, mediated via endogenous opioids, of the hypothalamic GnRH pulse ge nerator.