Gonadal and Nongonadal Regulation of Sex Differences in Hypothalamic Kiss1 Neurones

Abstract

In vertebrates, physiology and behaviour, including aspects relating to reproduction and puberty, often vary between animals of the opposite sex. The neuroendocrine reproductive axis is governed by various hormonal and neural pathways that converge upon forebrain gonadotrophin-releasing hormone (GnRH) neurones (1). GnRH neurones direct the activation of the rest of the reproductive axis by stimulating the pituitary to synthesise and secrete gonadotrophins [luteinising hormone (LH) and follicle-stimulating hormone (FSH)], which regulate the gonads. GnRH neurones themselves do not appear to be sexually dimorphic, indicating that sex differences in the control of the reproductive axis likely reflect key sex differences in the afferent neural circuits and factors that regulate the GnRH system. However, many of the sexually-dimorphic factors that influence reproductive status have remained poorly defined. The newly-discovered kisspeptin system has recently been implicated as an important regulator of GnRH neurones, both in development and adulthood, and sex differences in the kisspeptin system may relate to sex differences in reproductive function. Here, the recent evidence that supports an important role of kisspeptin signalling in the control of the reproductive axis is reviewed, as well as how this relates to sexual differentiation of reproductive physiology. The roles of kisspeptin signalling in puberty and adulthood have already been extensively reviewed (2-4) and the focus herein is primarily on the latest findings connecting sexual differentiation and the kisspeptin system, specifically in rodent animal models. Journal of NeuroendocrinologyCorrespondence to: A. S. Kauffman, Department of Reproductive Medicine, Center for Chronobiology, University of California, San Diego, 9500 Gilman Drive, #0674 La Jolla, CA 92093, USA (e-mail: akauffman@ucsd.edu).The brains of males and females differ anatomically and physiologically, including sex differences in neurone size or number, synapse morphology and specific patterns of gene expression. Brain sex differences may underlie critical sex differences in physiology or behaviour, including several aspects of reproduction, such as the timing of sexual maturation (earlier in females than males) and the ability to generate a preovulatory gonadotrophin surge (in females only). The reproductive axis is controlled by afferent pathways that converge upon forebrain gonadotrophin-releasing hormone (GnRH) neurones, but GnRH neurones are not sexually dimorphic. Although most reproductive sex differences probably reflect sex differences in the upstream circuits and factors that regulate GnRH secretion, the key sexually-dimorphic factors that influence reproductive status have remained poorly defined. The recently-identified neuropeptide kisspeptin, encoded by the Kiss1 gene, is an important regulator of GnRH secretion, and Kiss1 neurones in rodents are sexually dimorphic in specific hypothalamic populations, including the anteroventral periventricular nucleus-periventricular nucleus ...

Fibroblast Growth Factor Signaling Deficiencies Impact Female Reproduction and Kisspeptin Neurons in Mice1

“…Also unexpectedly, these mice have more KP-ir neurons in their AVPV/PeV throughout all ages examined, including during the period approximating pubertal onset (PND 30). In female rodents, elevated numbers of AVPV/PeV KP-ir neurons correlate with pubertal onset [25] and the ability to generate the ovulatory LH surge [27]. Thus, the increased number of KP-ir neurons in compound hypomorphs could drive early VO.…”

Sex differences in developmental programming models

“…Sexual maturity is reached earlier in females than in males, an effect that is preserved across a range of species from mice to humans, and may be correlated with expression of kisspeptin in the hypothalamus (Clarkson & Herbison 2006, Kauffman 2010. There is a marked difference in developmental programming of offspring phenotypes when measured before and after puberty.…”

Serum kisspeptin concentrations are negatively correlated with body mass index in adolescents with anorexia nervosa and amenorrhea

“…the pancreas, liver, small intestine, ovaries, adipose tissue and adrenal glands. 8,9 Kisspeptin has been associated with the GnRH induced secretion of LH 10 and, indeed, our patients with typical AN manifested significantly lower LH serum levels compared to controls, hence kisspeptin serum concentrations were expected to be significantly decreased in the former. Although serum levels of kisspeptin in the amenorrheic adolescents with typical AN were lower than those in the healthy normally menstruating adolescents, these differences were not statistically significant, as theoretically assumed.…”