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Kisspeptin and gpr-54 mediate negative steroid feedback within the HPG axis.

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It has been known for many years that the HPG axis is under the control of steroid hormone feedback from the gonads. Steroid hormone levels fluctuate across the cycle in females (Almond and Dial, 1990; Gill et al., 2002; Karsch and Evans, 1996; Moenter et al., 2003). However, the mediator of steroid hormone feedback has remained elusive for many years, as GnRH neurons only possess estrogen receptor β (ERβ) which does not play a role in feedback (Herbison and Pape, 2001). Therefore, neurons upstream of the GnRH neuron, which possess estrogen receptor α (ERα), progesterone receptor (PR) and androgen receptor (AR) have been sought as possible mediators of steroid effects on GnRH release. Kisspeptin neurons express ERα, PR and AR and therefore have the potential to relay feedback effects on the GnRH neuron. Regulation of KiSS-1 expression is likely be a mediator of negative feedback in mouse (Smith et al., 2005a; Smith et al., 2005b), rat (Adachi et al., 2007), ewe (Franceschini et al., 2006; Goodman et al., 2007; Smith et al., 2006b) and human (Rance, 2008). Evidence now suggests that reduced activity of kisspeptin neurons in the ARC of rodents, primates and sheep is responsible for translating estrogen negative feedback to GnRH neurons. OVX female and castrated male mice (Smith et al., 2005a; Smith et al., 2005b), sheep (Pompolo et al., 2006; Smith et al., 2006b) and rhesus monkeys (Rometo et al., 2007; Shibata et al., 2007) have an increased level of KiSS-1 mRNA in the neurons compared to controls (Table 3). Also, if estrogen replacement is given to OVX female or testosterone is given to castrated male mice, sheep and rats, then KiSS-1 mRNA levels are reduced to control levels (Pompolo et al., 2006; Rometo et al., 2007; Shibata et al., 2007; Smith et al., 2006b; Smith et al., 2006c; Smith et al., 2005b). This suggests that steroids are negatively regulating KiSS-1 mRNA in the ARC, hence reducing stimulation of GnRH neurons. KiSS-1 mRNA regulation by steroids is specifically mediated via the ERα isoform as PPT, a specific inhibitor for this isoform blocks the reduction of neuronal mRNA in the ARC, but DPN an ERβ specific inhibitor does not affect these mRNA levels (Bateman and Patisaul, 2008). Also ERα -/- mice do not have any steroid negative feedback on KiSS-1 mRNA levels in the hypothalamus (Smith et al., 2005a).

This negative regulation of kisspeptin by steroids was also revealed by KiSS-1 mRNA regulation across the rat’s ovarian cycle in the ARC (Table 3), where levels increased at diestrus when estrogen levels are low and decreased at proestrus when estrogen levels are elevated (Adachi et al., 2007). Further evidence for negative feedback is derived from females at the time of menopause, when estrogen is low due to reduced follicle numbers in humans and rhesus monkeys. At this time, a rise in KiSS-1 mRNA and in turn LH is seen accompanied by cellular hypertrophy, similar to the rise in OVX female rhesus monkey (Kim et al., 2008; Rance, 2008; Rometo et al., 2007), which is thought to be due to the lack of negative feedback from the follicles.

However, kisspeptin cannot be the only factor effecting GnRH secretion, since in the gpr-54 knockout mouse, there are still basal pulses of LH (Colledge, 2009; Seminara et al., 2003). It has been shown that KiSS-1 co-localises with two other ERα, PR and AR positive peptidergic neurons; the dynorphin A neuron and the neurokinin B neuron (Goodman et al., 2007). Recently, a mutation in the neurokinin B receptor in man has also been shown to affect the HPG axis and reproduction. Therefore, it is possible that they work in concert to regulate negative feedback and the HPG axis in the ARC (Topaloglu et al., 2009). However, this may not be the case in mice, where neurokinin B knockouts do not display a reproductive phenotype (Nordquist et al., 2008; Siuciak et al., 2007).

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