The neuroendocrine regulation of the mammalian reproductive axis

William Colledge reports on the meeting from April 2013 in Boston, USA here. This issue of Experimental Physiology has four reports from the speakers at the Physiological Society-sponsored symposium on The Neuroendocrine Regulation of the Mammalian Reproductive Axis at the Experimental Biology Meeting in Boston in April 2013. Reproduction is a key characteristic of living organisms and is essential for survival of the species. As Charles Darwin wrote in The Origin of the Species, ‘Multiply, vary, let the strongest live and the weakest die.’ In mammals, the capacity for reproduction involves co-ordinated communication between the hypothalamus, the anterior pituitary and the gonads (the hypothalamic–pituitary–gonadal axis). It has been recognized since the 1970s that a small population of gonadotrophin-releasing hormone (GnRH) neurons in the hypothalamus are critical for regulation of the mammalian reproductive axis. Puberty involves functional activation of these neurons, resulting in pulsatile GnRH release that stimulates gonadotrophic hormone production from the anterior pituitary and subsequent gonadal maturation (Fig. 1). In the last decade, there have been significant advances in our understanding of the hierarchical pathways that regulate GnRH release. In particular, the peptides and signalling pathways that modulate GnRH neuronal activity have been identified. One of the most important neuropeptides are the kisspeptins, encoded by the Kiss1 gene and synthesized by distinct neuronal populations in the arcuate (ARC) and the anteroventral periventricular (AVPV) regions of the hypothalamus (Fig. 1). Kisspeptins signal through a G-protein-coupled receptor (GPR54, now renamed KISS1R) expressed by GnRH neurons to stimulate GnRH release. The two populations of kisspeptin neurons respond differently to estradiol feedback from the ovary to regulate the oestrous cycle in female rodents. Kisspeptin expression in the ARC neurons is negatively regulated by estradiol, which is thought to regulate the tonic release of GnRH. Kisspeptin expression in the AVPV neurons is positively regulated by estradiol, which is required for generating the preovulatory GnRH/luteinizing hormone (LH) surge (Clarkson et al. 2008). This symposium brought together experts in the kisspeptin field to provide detailed reviews of the clinical, genetic, molecular and electrophysiological aspects of the neuroendocrine control of mammalian reproduction. Integration of kisspeptin neurons in the female hypothalamic–pituitary–gonadal axis Kisspeptin neurons are found in the arcuate (ARC) and the anteroventral periventricular (AVPV) regions of the hypothalamus and act directly on gonadotrophin-releasing hormone (GnRH) neurons to stimulate GnRH release. The GnRH is secreted into the hypophyseal portal system and stimulates gonadotrophs in the anterior pituitary to release gonadotrophic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)] into the bloodstream. The gonadotrophic hormones stimulate oogenesis and ovulation, and estradiol from the ovary acts in long feedback loops on the kisspeptin neurons to control GnRH release. For simplicity, not all hormonal feedback loops are shown. Stephanie Seminara from Harvard Medical School (Boston, MA, USA) has played a major role in identifying the link between kisspeptin signalling and fertility. Her seminal work showed that some patients with failure of pubertal maturation carry mutations in the kisspeptin receptor, KISS1R (Seminara et al. 2003). Her symposium article (Lippincott et al. 2013) reviews the genetic mutations that result in clinical cases of hypogonadotrophic hypogonadism. These mutations have been important in defining the pathways governing GnRH ontogeny and physiology. Stephanie Seminara highlights the frequency with which some of these patients show spontaneous reversal of their reproductive defect and how this may provide an insight into the different roles of neuropeptides in the initiation of puberty. In particular, she discusses the incidence of reversal in patients with mutations in KISS1R compared with the neurokinin B pathway, which also regulates GnRH release in humans, and compares these clinical phenotypes with those of mice carrying the same mutations. Although the neurokinin B mutations seem to show species differences in fertility, this may simply represent two ends of a spectrum, and detailed phenotypic analyses can highlight the conservation of function between the species. Ulrich Boehm from the University of Saarland School of Medicine (Homburgh, Germany) uses sophisticated transgenic mouse models to extend our understanding of the physiology of kisspeptin neurons. In female mice, oestrogen acts as a regulator of GnRH secretion by an indirect mechanism, because GnRH neurons do not express the oestrogen receptor α (ERα). It is now known that sex steroid feedback to GnRH neurons is mediated by kisspeptin neurons, which express the ERα and show oestrogen-dependent changes in kisspeptin expression (Fig. 1). Ulrich Boehm's symposium article (Kumar & Boehm, 2013) summarizes the effects of ablating the ERα specifically in kisspeptin neurons. He has shown that conditional gene ablation of ERα in kisspeptin neurons advances vaginal opening/puberty in female mice, suggesting that kisspeptin neurons may act as a brake to precocious puberty (Mayer et al. 2010). These mice are still sterile as adults, however, with disrupted oestrous cycles, indicating that oestrogen signalling in kisspeptin neurons is required for normal fertility. Transgenic mice that cannot produce kisspeptin neuropeptides are sterile (for review, see Colledge et al. 2013). In contrast, female mice in which kisspeptin neurons have been chronically ablated by tissue-restricted expression of a diphtheria toxin undergo puberty at the normal time and are fertile (Mayer & Boehm, 2011). Ulrich Boehm suggests that compensatory changes during brain development prior to postnatal day 20 might overcome the loss of kisspeptin neurons. In support of this, it was shown that acute ablation of kisspeptin neurons in adult female mice causes infertility, possibly because neuronal compensation cannot occur once brain development is complete. The nature of these compensatory changes remains to be established, but these data raise the interesting possibility of kisspeptin-independent pathways stimulating GnRH release to maintain fertility. Martin Kelly from the Oregon Health and Science University (Portland, USA) is an expert electrophysiologist who has studied the biophysical properties of GnRH neurons for several years. His article (Kelly et al. 2013) describes his latest work on characterizing the electrophysiological and molecular properties of kisspeptin neurons in guinea-pigs and mice and defining the ion channels that regulate their pacemaker activity. Pacemaker neurons control the rhythmic activity of neuronal networks by intrinsic burst firing of action potentials. This rhythm is associated with important physiological functions, including the control of breathing, sleep patterns and arousal. Martin Kelly is particularly interested in the pacemaker activity of kisspeptin neurons, which may co-ordinate the synchronous activity of the kisspeptin neuronal network to drive pulsatile GnRH release. He has shown that with appropriate stimulation, kisspeptin neurons in the ARC have burst-firing activity, which is generated by the activity of HCN (hyperpolarization-activated cyclic nucleotide-gated) and T-type calcium (Cav3) channels. As discussed by Martin Kelly, the ability of AVPV kisspeptin neurons to exhibit burst-firing activity is not as clearly defined and is probably influenced by the stage of the oestrous cycle and estradiol levels in the animals. An important part in dissecting the control pathways that regulate the reproductive axis is to map the neuronal circuitry associated with kisspeptin neurons. Shel-Hwa Yeo presented neuronal tracing experiments that she carried out at the University of Otago (New Zealand) to map the projections of kisspeptin neurons to other parts of the hypothalamus (Yeo & Herbison, 2011). Her article describes the use of anterograde and retrograde tracers to map kisspeptin neuronal circuitry in the hypothalamus (Yeo, 2013). She shows that kisspeptin neurons from both the ARC and AVPV regions project to the preoptic area of the hypothalamus, where the majority of the GnRH neurons are found. She also highlights that kisspeptin neurons project to several other regions of the brain, suggesting that they may control a variety of limbic functions as well as the central regulation of reproduction. The symposium provided a fantastic overview of the role of kisspeptins in regulating the mammalian reproductive axis and generated lively discussions between the audience and the speakers. It is hoped that the summary articles from the speakers, which cover a range of research areas in the field, will provide a useful source of information for anyone interested in mammalian reproductive physiology.

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