Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function

Identification of novel neurohormones that regulate the reproductive axis is essential for the progress of neuroendocrinology. The decapeptide gonadotropin-releasing hormone (GnRH) is the primary factor responsible for the hypothalamic control of gonadotropin secretion. Gonadal sex steroids and inhibin modulate gonadotropin secretion via feedback from the gonads, but a neuropeptide that directly inhibits gonadotropin secretion was unknown in vertebrates until 2000 when a hypothalamic dodecapeptide serving this function was discovered in quail. Because of its action on cultured pituitary in quail, it was named gonadotropin-inhibitory hormone (GnIH). GnIH acts on the pituitary and on GnRH neurons in the hypothalamus via a novel G protein-coupled receptor (GPR147). GPR74 may also be a possible candidate GnIH receptor. GnIH decreases gonadotropin synthesis and release, inhibiting gonadal development and maintenance. Melatonin stimulates the expression and release of GnIH via melatonin receptors expressed by GnIH neurons. GnIH actions and interactions with GnRH seem common not only to several avian species, but also to mammals. Thus, GnIH is considered to have an evolutionarily conserved role in controlling vertebrate reproduction, and GnIH homologs have also been identified in the hypothalamus of mammals. As in birds, mammalian GnIH homologs act to inhibit gonadotropin release in several species. More recent evidence in birds and mammals indicates that GnIH may operate at the level of the gonads as an autocrine/paracrine regulator of steroidogenesis and gametogenesis. Importantly, GnIH in birds and mammals appears to act at all levels of the hypothalamo-pituitary-gonadal (HPG) axis, and possibly over different time-frames (minutes-days). Thus, GnIH and its homologs appear to act as key neurohormones controlling vertebrate reproduction. The discovery of GnIH has enabled us to understand and manipulate vertebrate reproduction from an entirely new perspective.