Hypocretin (orexin) peptides are involved in the regulation of energy balance and pituitary hormone release. Narcolepsy is a sleep disorder characterized by disruption of hypocretin neurotransmission. Pituitary LH secretion is diminished in hypocretin deficient animal models and intracerebroventricular administration of hypocretin-1 activates the hypothalamo-pituitary gonadal axis in rats. We evaluated whether hypocretin deficiency affects gonadotropin release in humans. To this end, we deconvolved 24 h serum concentrations of LH and FSH in 7 hypocretin deficient narcoleptic males (N) and 7 controls (C), matched for age, body mass index and gender. Basal plasma concentrations of testosterone, estradiol and sex hormone binding globulin were similar in both groups. Mean 24 h LH concentration was significantly lower in narcolepsy patients (3.0 ± 0.4 (N) vs. 4.2 ± 0.3 (C) U/L, P=0.01), which was primarily due to a reduction of pulsatile LH secretion (23.5 ± 1.6 (N) vs. 34.3 ± 4.9 (C) U/L/24 h, P=0.02). The orderliness of LH and FSH secretion, quantitated by the approximate entropy statistic, was greater in patients than in controls. In contrast, all other features of FSH release were similar in narcoleptics and controls. Also, LH and FSH secretions in response to intravenous administration of 100 µg GnRH were similar in patients and controls. These data indicate that endogenous hypocretins are involved in the regulation of the hypothalamo-pituitary gonadal axis activity in humans. In particular, reduced LH release in the face of normal pituitary responsivity to GnRH stimulation in narcoleptic men suggests that hypocretins promote endogenous GnRH secretion.