The neuroendocrine physiology of kisspeptin in the human

Kisspeptin is a 54-amino acid peptide, encoded by the KiSS-1 gene, which activates the G protein-coupled receptor GPR54. Recent evidence suggests the kisspeptin/GPR54 system is a key regulator of reproduction. GPR54-deficient mice have abnormal sexual development. Central or peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis in animal models. This review discusses the evidence that kisspeptin also plays a key role in human reproduction. Inactivating GPR54 mutations cause normosmic hypogonadotrophic hypogonadism in humans. Mutations which increase GPR54 signaling are associated with gonadotrophin-dependent premature puberty. Acute intravenous administration of kisspeptin to healthy human male volunteers potently increased plasma LH levels and significantly increased plasma FSH and testosterone without side effects. Plasma kisspeptin is found at low concentrations in the circulation of men and non-pregnant women, but is markedly increased in pregnancy. The placenta is believed to be the source of these high levels of circulating kisspeptin. The kisspeptin-GPR54 system is also implicated in tumour biology. Consistent with this role, plasma kisspeptin concentrations are elevated in patients with abnormal proliferation of placental tissue (gestational trophoblastic neoplasia or GTN) at presentation and fall after treatment with chemotherapy. The kisspeptin/GPR54 system therefore appears to play an important role in the regulation of reproduction in humans. Kisspeptin represents a novel tool for the manipulation of the HPG axis in humans and plasma kisspeptin may be a novel tumour marker in patients with GTN.