Kisspeptin resets the hypothalamic GnRH clock in men

Abstract

Context: Reproduction in all mammals is controlled by a hypothalamic clock that produces periodic secretory pulses of GnRH, but how the timing of these pulses is determined is poorly understood. The neuropeptide kisspeptin potently and selectively stimulates the secretion of GnRH. Although this property of kisspeptin is well described, the effects of kisspeptin on endogenous GnRH pulse generation remain largely unexplored.

Objective: The objective of the study was to detail the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in men.

Participants: Thirteen healthy adult men participated in the study.

Intervention: The intervention was the administration of a single iv bolus of the C-terminal decapeptide of kisspeptin (amino acids 112-121 of the parent protein).

Results: Kisspeptin induced an immediate LH pulse, regardless of the timing of the previous endogenous pulse. The kisspeptin-induced pulses were on average larger than endogenous pulses (amplitude 5.0 ± 1.0 vs. 2.1 ± 0.3 mIU/ml, P = 0.02). Comparison of the morphology of kisspeptin-induced LH pulses in healthy men with that of GnRH-induced LH pulses in men with isolated GnRH deficiency suggests that a single i.v. bolus of kisspeptin triggered sustained GnRH release lasting approximately 17 min. Furthermore, kisspeptin reset the GnRH pulse generator, as it not only induced an immediate LH pulse but also delayed the next endogenous pulse by an interval approximating the normal interpulse interval.

Conclusions: As the first known agent capable of resetting the hypothalamic GnRH pulse generator, kisspeptin can be used as a physiological tool for studying GnRH pulse generation and opens a door to understanding the mechanisms of biological clocks in general.

Fig. 1.

Effects of kisspeptin on LH secretion. A and B, Representative patterns of LH secretion from two men. C, Average serum LH (upper panel) and distribution of pulses (lower panel) across all 13 subjects. Each box in the lower panel indicates that a subject had a pulse nadir at that time point. Error bars show sem in this and all figures. Arrows, Time of kisspeptin administration; arrowheads, peaks of pulses.

Fig. 2.

Effects of kisspeptin on hormone concentrations. A, Amplitude of LH pulses. B, AUC of LH pulses. C, FSH in 2-h study pools. D, Testosterone in 2-h study pools.

Fig. 3.

Contour of LH pulses induced by administration of GnRH to men with GnRH deficiency and by administration of kisspeptin to healthy men. A, Average LH after an instantaneous bolus, after a 1-, 5-, or 30-min infusion of GnRH or after an instantaneous bolus of kisspeptin. [Adapted with permission with modifications from F. P. Pralong, et al.: Neuroendocrinology 64:247–256, 1996 (18) with permission from S. Karger AG, Basel.] Vertical dashed line, Time of peak LH. B, Average time from nadir to peak of LH pulses. C, Linear regression of time from nadir to peak. D, Time from nadir to peak of endogenous pulses and kisspeptin-induced pulses. Pre, Prekisspeptin pulses; Post, postkisspeptin pulses, excluding the immediate kisspeptin-induced pulse. E, Pharmacokinetics of kisspeptin 112–121 in human plasma in vitro. Dashed line, Lower limit of quantitation.

Fig. 4.

Effects of kisspeptin on pulse intervals. A, Schematic of the predicted result if kisspeptin were to have no effect on the timing of endogenous pulses. Note that this is an idealized schematic and that actual pulse profiles show more variability in pulse intervals. B, The observed result, that kisspeptin delayed the appearance of the next endogenous pulse and prolongs intervals B and B2. C, Observed pulse intervals. Bars, means.