Amplification of the neurosecretory activity of the GnRH system is the defining neuroendocrine event for sexual maturation. The physiological mechanisms that drive GnRH secretion at puberty have been difficult to identify but the discovery in 2003 that the G protein coupled receptor KISS1R is a key regulator of pubertal development in mice and men has ushered in a new chapter in reproductive neuroendocrinology. KISS1R is activated by endogenous peptides derived from a precursor protein, kisspeptin. Despite kisspeptin's importance in driving the reproductive cascade, relatively few patients with GnRH deficient states and mutations in the kisspeptin pathway have been described. Yet, these cases, coupled with loss-of-function mouse models, provide unique and complementary information into the biological role of this signaling system in the control of GnRH secretion. This article will examine some of the subtleties in genotype-phenotype correlations in both mice and men carrying disabling mutations in the kisspeptin pathway.

Copyright © 2011. Published by Elsevier Ireland Ltd.