Sex Steroids and the Control of the Kiss1 System: Developmental Roles and Major Regulatory Actions

Kisspeptins, encoded by the Kiss1 gene, and their canonical receptor, GPR54 (also termed Kiss1R), are unanimously recognised as essential regulators of puberty onset and gonadotrophin secretion. These key reproductive functions stem from the capacity of kisspeptins to stimulate gonadotrophin-releasing hormone (GnRH) secretion in the hypothalamus, where discrete populations of Kiss1 neurones have been identified. In rodents, two major groups of hypothalamic Kiss1 neurones exist: one present in the arcuate nucleus (ARC) and the other located in the anteroventral periventricular area (AVPV/RP3V). In recent years, numerous signals have been identified as putative modulators of the hypothalamic Kiss1 system. Among them, the prominent role of sex steroids as being important regulators of Kiss1 neurones has been documented in different species and developmental stages, such as early brain sex differentiation, puberty, adulthood and senescence. These regulatory actions are (mainly) conducted via oestrogen receptor (ER)a, which is expressed in almost all Kiss1 neurones, and likely involve both classical and nonclassical pathways. The regulatory effects of sex steroids are nucleus-specific. Thus, sex steroids inhibit the expression of Kiss1/kisspeptin at the ARC, as a mechanism to conduct their negative-feedback actions on gonadotrophin secretion. By contrast, oestrogens enhance Kiss1 expression at the AVPV/RP3V in rodents, suggesting the involvement of this population in the positive-feedback actions of oestradiol to generate the preovulatory surge of gonadotrophins. In addition, sex steroids have been shown to act post-transcriptionally, modulating GnRH/gonadotrophin responsiveness to kisspeptin. Finally, sex steroids also regulate the expression of co-transmitters of Kiss1 neurones, such as neurokinin B, whose mRNA content in the ARC fluctuates in parallel to that of Kiss1 in response to changes in the circulating levels of sex steroids, therefore suggesting the contribution of this neuropeptide in the feedback control of gonadotrophin secretion. In sum, compelling experimental evidence obtained in different mammalian (and non-mammalian) species, including primates, demonstrates that sex steroids are essential regulators of hypothalamic Kiss1 neurones, which in turn operate as conduits for their effects on GnRH neurones. The physiological relevance of such regulatory phenomena is thoroughly discussed.