Sexual differentiation and the Kiss1 system: hormonal and developmental considerations

Abstract

The nervous system (both central and peripheral) is anatomically and physiologically differentiated between the sexes, ranging from gender-based differences in the cerebral cortex to motoneuron number in the spinal cord. Although genetic factors may play a role in the development of some sexually differentiated traits, most identified sex differences in the brain and behavior are produced under the influence of perinatal sex steroid signaling. In many species, the ability to display an estrogen-induced luteinizing hormone (LH) surge is sexually differentiated, yet the specific neural population(s) that allows females but not males to display such estrogen-mediated "positive feedback" has remained elusive. Recently, the Kiss1/kisspeptin system has been implicated in generating the sexually dimorphic circuitry underlying the LH surge. Specifically, Kiss1 gene expression and kisspeptin protein levels in the anteroventral periventricular (AVPV) nucleus of the hypothalamus are sexually differentiated, with females displaying higher levels than males, even under identical hormonal conditions as adults. These findings, in conjunction with accumulating evidence implicating kisspeptins as potent secretagogues of gonadotropin-releasing hormone (GnRH), suggest that the sex-specific display of the LH surge (positive feedback) reflects sexual differentiation of AVPV Kiss1 neurons. In addition, developmental kisspeptin signaling via its receptor GPR54 appears to be critical in males for the proper sexual differentiation of a variety of sexually dimorphic traits, ranging from complex social behavior to specific forebrain and spinal cord neuronal populations. This review discusses the recent data, and their implications, regarding the bi-directional relationship between the Kiss1 system and the process of sexual differentiation.

Figure 1

Model of the sex steroid-mediated development of the sexually-dimorphic preovulatory LH surge in rodents. The presence of androgens at the time of birth, such as occurs in normal males or in females given an exogenous perinatal treatment of testosterone, results in the development of a male-like AVPV, which includes the absence (or low levels) of Kiss1 neurons. This low level of Kiss1 in the AVPV correlates with the inability of males and androgenized females to display an LH surge in adulthood (in response to exogenous estradiol and progesterone treatment). In contrast, females lack androgen secretion in early perinatal development, and thus have high levels of Kiss1 in the AVPV as adults, correlating with their ability to show an LH surge. It should be noted that this rodent model of sexually-differentiated Kiss1 population in the AVPV may differ in sheep and primates in which positive feedback signaling in females is likely derived from neurons (perhaps kisspeptin cells) in the medial basal hypothalamus (a region including the ARC) rather than the more anterior AVPV/POA region.