Hypogonadotropic hypogonadism and GNRH1 mutations in mice and humans

The neuropeptide gonadotropin-releasing hormone (GnRH) plays a key regulatory role in mammalian reproduction. It is synthesized by hypothalamic neurons and released from nerve endings into the portal circulation. After binding to membrane GnRH type 1 receptors on gonadotropic cells of the anterior pituitary, it stimulates the synthesis and release of luteinizing hormone and follicle-stimulating hormone. These two peptides travel through the general circulation to the gonads, where they stimulate the synthesis and secretion of sex steroid hormones and trigger gametogenesis. The discovery in 1977 of a hypogonadal mouse lacking GnRH (hpg mice) and, in 1986, that the gnrh1 gene was deleted in this mouse, suggested that GNRH1 mutations might also cause human congenital idiopathic (or isolated) hypogonadotropic hypogonadism. This was finally demonstrated in 2009.