A genetic basis of congenital isolated hypogonadotropic hypogonadism (CHH) can be defined in almost 50% of cases, albeit not necessarily the complete genetic basis. Next-generation sequencing (NGS) techniques have led to the discovery of a great number of loci, each of which has illuminated our understanding of human gonadotropin-releasing hormone (GnRH) neurons, either in respect of their embryonic development or their neuroendocrine regulation as the "pilot light" of human reproduction. However, because each new gene linked to CHH only seems to underpin another small percentage of total patient cases, we are still far from achieving a comprehensive understanding of the genetic basis of CHH. Patients have generally not benefited from advances in genetics in respect of novel therapies. In most cases, even genetic counselling is limited by issues of apparent variability in expressivity and penetrance that are likely underpinned by oligogenicity in respect of known and unknown genes. Robust genotype-phenotype relationships can generally only be established for individuals who are homozygous, hemizygous or compound heterozygotes for the same gene of variant alleles that are predicted to be deleterious. While certain genes are purely associated with normosmic CHH (nCHH) some purely with the anosmic form (Kallmann syndrome-KS), other genes can be associated with both nCHH and KS-sometimes even within the same kindred. Even though the anticipated genetic overlap between CHH and constitutional delay in growth and puberty (CDGP) has not materialised, previously unanticipated genetic relationships have emerged, comprising conditions of combined (or multiple) pituitary hormone deficiency (CPHD), hypothalamic amenorrhea (HA) and CHARGE syndrome. In this review, we report the current evidence in relation to phenotype and genetic peculiarities regarding 60 genes whose loss-of-function variants can disrupt the central regulation of reproduction at many levels: impairing GnRH neurons migration, differentiation or activation; disrupting neuroendocrine control of GnRH secretion; preventing GnRH neuron migration or function and/or gonadotropin secretion and action.

Genetics of congenital hypogonadotropic hypogonadism: peculiarities and phenotype of an oligogenic disease

Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that ultimately affect the release of kisspeptin, which modulates gonadotropin-releasing hormone (GnRH) release from GnRH neurons to control the reproductive axis. The presence of sufficient energy reserves is critical to achieve successful reproduction. Consequently, metabolic factors impose a very tight control over kisspeptin synthesis and release. This Review offers a synoptic overview of the different steps in which kisspeptin neurons are subjected to metabolic regulation, from early developmental stages to adulthood. We cover an ample array of known mechanisms that underlie the metabolic regulation of KISS1 expression and kisspeptin release. Furthermore, the novel role of kisspeptin neurons as active players within the neuronal circuits that govern energy balance is discussed, offering evidence of a bidirectional role of these neurons as a nexus between metabolism and reproduction.

Metabolic regulation of kisspeptin - the link between energy balance and reproduction.

A healthy nutritional state is required for all aspects of reproduction and is signaled by the adipokine leptin. Leptin acts in a relatively narrow concentration range: too much or too little will compromise fertility. The leptin signal timing is important to prepubertal development in both sexes. In the brain, leptin acts on ventral premammillary neurons which signal kisspeptin (Kiss1) neurons to stimulate gonadotropin releasing hormone (GnRH) neurons. Suppression of Kiss1 neurons occurs when agouti-related peptide neurons are activated by reduced leptin, because leptin normally suppresses these orexigenic neurons. In the pituitary, leptin stimulates production of GnRH receptors (GnRHRs) and follicle-stimulating hormone at midcycle, by activating pathways that derepress actions of the messenger ribonucleic acid translational regulatory protein Musashi. In females, rising estrogen stimulates a rise in serum leptin, which peaks at midcycle, synchronizing with nocturnal luteinizing hormone pulses. The normal range of serum leptin levels (10-20 ng/mL) along with gonadotropins and growth factors promote ovarian granulosa and theca cell functions and oocyte maturation. In males, the prepubertal rise in leptin promotes testicular development. However, a decline in leptin levels in prepubertal boys reflects inhibition of leptin secretion by rising androgens. In adult males, leptin levels are 10% to 50% of those in females, and high leptin inhibits testicular function. The obesity epidemic has elucidated leptin resistance pathways, with too much leptin in either sex leading to infertility. Under conditions of balanced nutrition, however, the secretion of leptin is timed and regulated within a narrow level range that optimizes its trophic effects.

The Importance of Leptin to Reproduction.

Puberty is driven by sophisticated neuroendocrine networks that timely activate the brain centers governing the reproductive axis. The timing of puberty is genetically determined; yet, puberty is also sensitive to numerous internal and external cues, among which metabolic/nutritional signals are especially prominent. Compelling epidemiological evidence suggests that alterations of the age of puberty are becoming more frequent; the underlying mechanisms remain largely unknown, but the escalating prevalence of obesity and other metabolic/feeding disorders is possibly a major contributing factor. This phenomenon may have clinical implications, since alterations in pubertal timing have been associated to adverse health outcomes, including higher risk of earlier all-cause mortality. This urges for a better understanding of the neurohormonal basis of normal puberty and its deviations. Compelling evidence has recently documented the master role of hypothalamic neurons producing kisspeptins, encoded by Kiss1, in the neuroendocrine pathways controlling puberty. Kiss1 neurons seemingly participate in transmitting the regulatory actions of metabolic cues on pubertal maturation. Key cellular metabolic sensors, as the mammalian target of rapamycin (mTOR), AMP-activated protein kinase (AMPK) and the fuel-sensing deacetylase, SIRT1, have been recently shown to participate also in the metabolic modulation of puberty. Recently, we have documented that AMPK and SIRT1 operate as major molecular effectors for the metabolic control of Kiss1 neurons and, thereby, puberty onset. Alterations of these molecular pathways may contribute to the perturbation of pubertal timing linked to conditions of metabolic stress in humans, such as subnutrition or obesity and might become druggable targets for better management of pubertal disorders.

/pdf/novel-mechanisms-for-the-metabolic-control-of-puberty-4afxtqylyx.pdf

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition.

Pubertal onset is thought to be timed by an increase in pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin secretion in mammals. The underlying mechanism of pubertal onset in mammals is still an open question. Evidence accumulated in the last 15 years suggests that kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in the hypothalamic arcuate nucleus play a key role in pubertal onset by triggering pulsatile GnRH/gonadotropin secretin in mammals. Specifically, KNDy neurons are now considered a part of GnRH pulse generator, in which neurokinin B facilitates and dynorphin A inhibits, the synchronized discharge of KNDy neurons in autocrine and/or paracrine manners. Kisspeptin serves as a potent secretagogue of GnRH secretion and thus its release is fundamental to pubertal increase in GnRH/gonadotropin secretion in mammals. Proposed mechanisms inhibiting Kiss1 (kisspeptin gene) expression during childhood to juvenile varies from species to species: we envisage that negative feedback action of estrogen plays a key role in the inhibition of Kiss1 expression in KNDy neurons in rodents and sheep, whereas estrogen-independent inhibition of kisspeptin secretion by γ-amino butyric acid or neuropeptide Y are suggested to be responsible for the pre-pubertal suppression of GnRH/gonadotropin secretion in primates. Taken together, the timing of pubertal onset is postulated to be controlled by upstream regulators for kisspeptin biosynthesis and secretion in mammals.

/pdf/central-mechanism-controlling-pubertal-onset-in-mammals-a-43yx3zgaif.pdf

Central Mechanism Controlling Pubertal Onset in Mammals: A Triggering Role of Kisspeptin.

Pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with Adcyap1fl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction in female mice.

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuromodulator implicated in anxiety, metabolism and reproductive behavior. PACAP global knockout mice have decreased fertility and PACAP modulates LH release. However, its source and role at the hypothalamic level remain unknown. We demonstrate that PACAP-expressing neurons of the ventral premamillary nucleus of the hypothalamus (PMVPACAP) project to, and make direct contact with, kisspeptin neurons in the arcuate and AVPV/PeN nuclei and a subset of these neurons respond to PACAP exposure. Targeted deletion of PACAP from the PMV through stereotaxic virally mediated cre- injection or genetic cross to LepR-i-cre mice with PACAPfl/fl mice led to delayed puberty onset and impaired reproductive function in female, but not male, mice. We propose a new, sex-specific role for PACAP-expressing neurons in the PMV in the relay of nutritional state information to regulate GnRH release by modulating the activity of kisspeptin neurons, thereby regulating reproduction. Disclosure statement The authors have nothing to disclose.

https://www.biorxiv.org/content/biorxiv/early/2018/03/02/274860.full.pdf

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

/pdf/pacap-neurons-in-the-ventral-premammillary-nucleus-regulate-2jp3yb4v5b.pdf

Emily Brengle

Papers

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse.

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse

PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse