Figure 3 The hypothalamic–pituitary–gonadal axis Figure 3 | The hypothalamic–pituitary–gonadal axis. The cell bodies of neuroendocrine neurons releasing gonadotropin-releasing hormone (GnRH) are scattered throughout the preoptic region of the hypothalamus at the ventral surface of the brain and send their neuronal processes to the median eminence, where GnRH is released into the pituitary portal blood vessels for delivery to the anterior pituitary. There, GnRH stimulates the secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Blood-borne LH and FSH act on target cells in the gonads (depicted here as the ovary) to direct the production of gametes, as well as the secretion of steroid hormones (for example, oestrogens in females). Within the brain, gonadal steroids influence GnRH secretion via neuroendocrine feedback loops. The oestrogen receptor-α (ERα)-expressing kisspeptin neurons seem to have crucial roles in mediating these feedback mechanisms. In contrast to the direct action of kisspeptin on GnRH cells, leptin, a circulating metabolic hormone involved in energy homeostasis signalling, is believed to indirectly regulate LH release as GnRH neurons do not express the leptin receptor (LepR). The population of neuronal nitric oxide synthase (nNOS)-expressing cells residing in the organum vasculosum laminae terminalis (OVLT) and median preoptic nucleus (MePO) and surrounding GnRH cell bodies (tuning their neuronal excitability) probably mediate the effects of leptin and control leptin-induced GnRH release, thus fine-tuning LH release, as nNOS cells of the OVLT and MePO do express LepR. In parallel, the same population of nNOS cells also expresses, in addition to ERα and N-methyl-D-aspartate receptor (NMDAR), the kisspeptin receptor (GPR54) and are surrounded by kisspeptin fibres, which suggests that nNOS cells can directly receive kisspeptin signals. nNOS neurons could thus have a vital role in relaying both neuronal and hormonal homeostatic cues to GnRH neurons. ARH, arcuate nucleus of the hypothalamus; AVPV, anteroventral periventricular nucleus. Chachlaki, K. et al. (2017) The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus Nat. Rev. Endocrinol. doi:10.1038/nrendo.2017.69