At puberty, pulsatile secretion of hormones initiates sexual maturation of the gonads. The G-protein-coupled receptor GPR54 is crucially involved in the initiation of puberty, along with its ligand metastin. Mice lacking GPR54 fail to undergo puberty and have immature reproductive organs and low levels of sex steroids and gonadotrophic hormones, but have normal levels of gonadotrophin-releasing hormone in the hypothalamus. In humans, several cases of hypogonadism have been ascribed to mutations in GPR54. Production of metastin and, to a lesser extent, GPR54 are negatively regulated by testosterone and oestrogen, and injecting GPR54 ligands can increase hormone secretion in rodents. Thus, GPR54 is required for normal functioning of the hypothalamic-pituitary-gonadal axis, probably at the level of gonadotrophin-releasing-hormone secretion.