Kisspeptin-neuron control of LH pulsatility and ovulation

Abstract

Feedback from oestradiol (E2) plays a critical role in the regulation of major events in the physiological menstrual cycle including the release of gonadotrophins to stimulate follicular growth, and the mid-cycle luteinising hormone (LH) surge that leads to ovulation. E2 predominantly exerts its action via oestrogen receptor-alpha (ERα), however, as gonadotrophin releasing hormone (GnRH) neurons lack ERα, E2-feedback is posited to be indirectly mediated via upstream neurons. Kisspeptin (KP) is a neuropeptide expressed in hypothalamic KP-neurons that control GnRH secretion and plays a key role in the central mechanism regulating the hypothalamic-pituitary-gonadal (HPG) axis. In the rodent arcuate (ARC) nucleus, KP is co-expressed with Neurokinin B and Dynorphin; and thus, these neurons are termed ‘Kisspeptin-Neurokinin B-Dynorphin’ (KNDy) neurons. ARC KP-neurons function as the ‘GnRH pulse generator’ to regulate GnRH pulsatility, as well as mediating negative feedback from E2. A second KP neuronal population is present in the rostral periventricular area of the third ventricle (RP3V), which includes anteroventral periventricular (AVPV) nucleus and preoptic area neurons. These RP3V KP-neurons mediate positive feedback to induce the mid-cycle luteinising hormone (LH) surge and subsequent ovulation. Here, we describe the role of KP-neurons in these two regions in mediating this differential feedback from oestrogens. We conclude by considering reproductive diseases for which exploitation of these mechanisms could yield future therapies.

Luteinizing hormone stimulates ingression of mural granulosa cells within the mouse preovulatory follicle

“…LH release was stimulated by intraperitoneal injection of kisspeptin (Owen et al, 2021), a neuropeptide that causes gonadotropin releasing hormone to be secreted from the hypothalamus, which in turn causes release of LH into the bloodstream (Stevenson et al, 2022). The rise in serum LH peaks ~1.5 hours after kisspeptin injection and is comparable in amplitude and duration to the endogenous LH surge (Owen et al, 2021).…”

“…Except as indicated, LH release was stimulated by intraperitoneal injection of kisspeptin into ∼25 day old mice that had been injected 44 hours previously with eCG to stimulate follicle growth and LH receptor expression [36]. Kisspeptin is a neuropeptide that causes gonadotropin releasing hormone to be secreted from the hypothalamus, which in turn causes release of LH into the bloodstream [40]. The rise in serum LH peaks ∼1.5 hours after kisspeptin injection and is comparable in amplitude and duration to the endogenous LH surge [36].…”

Single neonatal estrogen implant sterilizes female animals by decreasing hypothalamic KISS1 expression

“…ARC Kisspeptin neurons primarily serve the role of GnRH pulse generator, while AVPV Kisspeptin neurons induce the mid-cycle LH surge and subsequent ovulation 19 . In the adult, these separate populations show differential regulation by E2 72 .…”

“…GnRH is transported into the pituitary via the portal vein where it stimulates the synthesis and secretion of gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH), which enter the circulation for delivery to the gonads. LH and FSH stimulate gonadal steroidogenesis, primarily estradiol (E2) production in females, and ultimately regulate growth and release of the germ cells (oocytes) 19 . This stepwise pathway of hormonal stimulation is essential for not only development of the female reproductive system but also for regulatory maintenance of oocyte maturation, ovulation, successful fertilization and pregnancy.…”

Assessing hypothalamic pituitary gonadal function in reproductive disorders

“…Kisspeptin neurons are expressed in two discrete hypothalamic nuclei, namely the arcuate nucleus (ARC) (homologous to the infundibular nucleus in humans) and the rostral periventricular area of the third ventricle (RP3V) [ 10 ]. In several animal species, kisspeptin neurons in the ARC co-express neurokinin B and dynorphin providing autocrine/paracrine regulation of GnRH secretion and are thus collectively known as ‘KNDy neurons’ [ 11 ].…”