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. 2022 Nov 21;13:951938. doi: 10.3389/fendo.2022.951938

Figure 1.

Figure 1

Distinct populations of kisspeptin neurons in the hypothalamus; kisspeptin neurons in the arcuate nucleus (ARC KP-neurons) and rostral periventricular area of the third ventricle (RP3V KP-neurons) which includes anteroventral periventricular (AVPV) nucleus. ARC KP-neurons exhibit episodic activity that induce pulsatile GnRH and LH secretion through oestradiol (E2) mediated negative-feedback and are known as the ‘GnRH pulse generator’ depicted on the right. Synchronisation of these neurons is driven by NKB and dynorphin; NKB stimulates whereas dynorphin inhibits kisspeptin release (not shown). Peripheral factors are depicted [glutamate (stimulatory), leptin (stimulatory) and CRH (inhibitory)] acting at the level of the brain to regulate kisspeptin output. By contrast RP3V KP-neurons induce an LH surge through E2 mediated positive-feedback and ovulation depicted on the left. Oestrogen receptor α (ERα) is responsible for mediating both negative and positive feedback from E2. ERα can signal either by translocation to the nucleus and recruitment of cofactors to oestrogen response element (ERE) (classical pathway), or by recruitment of other transcription factors not via the ERE (non-classical pathway). Notably, E2-induced positive feedback occurs via the classical pathway, whereas negative feedback is mediated via the non-classical pathway. Oestrogen receptor β (ERβ) has been shown to potentiate E2 positive feedback in the RP3V in the presence of high E2 levels and has an inhibitory effect on ERα in the AVPV in the presence of low E2 levels. Regardless of E2 levels, the ratio of ERα:ERβ is twice as high in the ARC as in the AVPV.ARC, arcuate nucleus; AVPV, anteroventral periventricular nucleus; CRH, corticotrophin-releasing hormone; E2, oestradiol; ERα, oestrogen receptor α; ERβ, oestrogen receptor β; ERE, oestrogen response element; FSH, follicle-stimulating hormone; GnRH, gonadotrophin releasing hormone; KISS1R, kisspeptin receptor; LH, luteinising hormone; NKB, neurokinin B; RP3V, rostral periventricular area of the third ventricle.