Fig. 1.

Relationship between KNDy neurons, GnRH neurons, and the heat-defence pathway. KNDy neurones in the infundibular nucleus secrete the neuropeptides Kiss (encoded by the KISS1 gene), NKB (encoded by the TAC3 gene) and Dyn (encoded by the PDYN gene). NKB and Dyn act autosynaptically, stimulating and inhibiting further Kiss release, respectively. Kiss acts on GnRH neurones. GnRH stimulates LH and FSH release from the anterior pituitary which stimulates ovarian sex steroid production. During menopause, lack of oestradiol (E2) negative feedback results in increased expression of KISS1 and TAC3 mRNA but decreased expression of PDYN mRNA. Consequently, KNDy neurones become hypertrophied, as seen by increased size of nuclei/nucleoli and increased Nissl substance. KNDy neurones project to the hypothalamic thermoregulatory centre (the median POA and adjacent MnPO). During menopause, the increase in NKB signalling and overstimulation of KNDy neurons increases activity in the thermoregulatory centre which then becomes hypersensitive to external cues from peripheral sensors, leading to activation of heat dissipation effectors. KNDy kisspeptin–neurokinin B–dynorphin, Kiss kisspeptin, NKB neurokinin B, Dyn dynorphin, GnRH gonadotropin-releasing hormone, LH luteinizing hormone, FSH follicle-stimulating hormone, POA pre-optic area, MnPO median preoptic nucleus, E2 oestradiol, ERα oestrogen receptor alpha, PR progesterone receptor, KISS1 kisspeptin gene, TAC3 tachykinin 3 gene, PDYN prodynorphin gene. The figure was created with BioRender.com