Coming of age in the kisspeptin era: sex differences, development, and puberty

Abstract

The status of the neuroendocrine reproductive axis differs dramatically during various stages of development, and also differs in several critical ways between the sexes, including its earlier pubertal activation in females than males and the presence of neural circuitry that generates preovulatory hormone surges in females but not males. The reproductive axis is controlled by various hormonal and neural pathways that converge upon forebrain gonadotropin-releasing hormone (GnRH) neurons, and many of the critical age and sex differences in the reproductive axis likely reflect differences in the "upstream" circuits and factors that regulate the GnRH system. Recently, the neural kisspeptin system has been implicated as an important regulator of GnRH neurons. Here I discuss the evidence supporting a critical role of kisspeptin signaling at different stages of life, including early postnatal and pubertal development, as well as in adulthood, focusing primarily on information gleaned from mammalian studies. I also evaluate key aspects of sexual differentiation and development of the brain as it relates to the Kiss1 system, with special emphasis on rodents. In addition to discussing recent advances in the field of kisspeptin biology, this paper will highlight a number of unanswered questions and future challenges for kisspeptin investigators, and will stress the importance of studying the kisspeptin system in both males and females, as well as in multiple species.

Fig. 1

Kiss1 neurons project to and stimulate GnRH neurons, acting at either GnRH cell bodies (AVPV/PeN neurons) or GnRH fiber terminals in the median eminence (ARC neurons). Kiss1 neurons express sex steroid receptors and are differentially regulated by gonadal steroids. E₂’s stimulation of Kiss1 expression in the AVPV/PeN and inhibition of Kiss1 in the ARC appears to underlie steroid-mediated positive and negative feedback, respectively. ER = estrogen receptors. Kiss1R = kisspeptin receptor.

Fig. 2

Sex-specific pattern of gonadal steroid secretion in early development in rodents. In perinatal males, but not females, there is an acute surge of testosterone (T) which organizes the development of the brain to be male-like. In females, the absence of circulating postnatal sex steroids results in sexually-dimorphic brain circuits developing to be female-like.

Fig. 3

Sex-specific pattern of Kiss1 gene expression in the AVPV/PeN of adult male and female mice that were gonadectomized and treated with similar levels of E₂. As in rats, adult female mice have significantly more Kiss1 neurons in this region than adult males. 3V = third ventricle.

Fig. 4

The reproductive circuits of prepubertal (PND 16–18) male mice are suppressed by both gonadal steroids and gonadal steroid-independent factors. In contrast, reproductive circuits in prepubertal females and adults of both sexes are predominantly suppressed by gonadal steroids. Gonadectomy (removing hormone negative feedback) therefore increases ARC Kiss1 levels in adults and prepubertal females, but not prepubertal males (who still have gonad-independent restraint mechanisms present). It is unknown if this sex difference relates to sex differences in pubertal maturation.