Neuroendocrine Control Of Reproduction Research Articles

Neuroactive steroids in the neuroendocrine control of food intake, metabolism, and reproduction.

Neuroactive steroids are a type of steroid hormones produced within the nervous system or in peripheral glands and then transported to the brain to exert their neuromodulatory effects. Neuroactive steroids have pleiotropic effects, that include promoting myelination, neuroplasticity, and brain development. They also regulate important physiological functions, such as metabolism, feeding, reproduction, and stress response. The homoeostatic processes of metabolism and reproduction are closely linked and mutually dependent. Reproductive events, such as pregnancy, bring about significant changes in metabolism, and metabolic status may affect reproductive function in mammals. In females, the regulation of reproduction and energy balance is controlled by the fluctuations of oestradiol and progesterone throughout the menstrual cycle. Neurosteroids play a key role in the neuroendocrine control of reproduction. The synthesis of neuroestradiol and neuroprogesterone within the brain is a crucial process that facilitates the release of GnRH and LH, which in turn, regulate the transition from oestrogen-negative to oestrogen-positive feedback. In addition to their function in the reproductive system, oestrogen has a key role in the regulation of energy homoeostasis by acting at central and peripheral levels. The oestrogenic effects on body weight homoeostasis are primarily mediated by oestrogen receptors-α (ERα), which are abundantly expressed in multiple brain regions that are implicated in the regulation of food intake, basal metabolism, thermogenesis, and brown tissue distribution. The tight interplay between energy balance and reproductive physiology is facilitated by shared regulatory pathways, namely POMC, NPY and kisspeptin neurons, which are targets of oestrogen regulation and likely participate in different aspects of the joint control of energy balance and reproductive function. The aim of this review is to present a summary of the progress made in uncovering shared regulatory pathways that facilitate the tight coupling between energy balance and reproductive physiology, as well as their reciprocal interactions and the modulation induced by neurosteroids.

Back to the basics: Neuroendocrine control of reproduction

Back to the basics: Neuroendocrine control of reproduction

Transcriptomic signatures associated with underlying rapid changes in the early phase brain of bi-directional sex change in Trimma okinawae.

Teleost fish exhibit remarkable sexual plasticity and divergent developmental systems, including sequential hermaphroditism. One of the more fascinating models of sexual plasticity is socially controlled sex change, which is often observed in coral reef fish. The Okinawa rubble goby, Trimma okinawae, is a bi-directional sex-changing fish. It can rapidly change sex in either direction based on social circumstances. Although behavioural and neuroendocrine sex change occurs immediately and is believed to trigger gonadal changes, the underlying mechanisms remain poorly understood. In this study, we conducted a de novo transcriptome analysis of the T. okinawae brain and identified genes that are differentially expressed between the sexes and genes that were immediately controlled by social stimulation implicating sex change. Several genes showed concordant expression shifts regardless of the sex change direction and were associated with histone modification in nerve cells. These genes are known to function in the neuroendocrine control of reproduction in nerve cells. Overall, we identified genes associated with the initiation of sex change, which provides insight into the regulation of sex change and sexual plasticity.

Kisspeptin stimulates oocyte maturation, and food deprivation modulates the abundance of kisspeptin system in zebrafish gonads

Kisspeptin is a hormone involved in the neuroendocrine control of reproduction in fish. We hypothesized that kisspeptin stimulates oocyte maturation and modulates other reproductive hormones in zebrafish; and the gonadal kisspeptin system in zebrafish is affected during energy unavailability. The main goals of this research were to test in vitro effects of kisspeptin on oocyte maturation and mRNA abundance in zebrafish ovarian follicles and determine how short-term feed restriction affects kisspeptin and its receptors in zebrafish testis and ovary. This study demonstrates the presence of kisspeptin and its receptors in zebrafish (Danio rerio) gonads and its direct action on ovarian follicles in vitro. Kisspeptin (10 ng/mL) induced oocyte maturation, as indicated by germinal vesicle break down at 18- and 24- hours post-treatment. Kisspeptin significantly increased the abundance of mRNAs encoding reproductive hormones and its receptors in zebrafish oocytes. This suggests that kisspeptin-10 affects ovarian functions by modulating other hormones. Reproduction is a process that requires energy. Therefore, whether energy availability affects the kisspeptin system in zebrafish gonads was determined. Food deprivation modulated kisspeptin expression differently in zebrafish testis and ovary. Kiss2 and kiss1ra were upregulated while kiss1rb was downregulated in the testis post-food deprivation. Meanwhile, no changes in kiss in the ovary were found after food deprivation. However, kiss1rb was downregulated in unfed fish at 3- and 7-days post-food deprivation. Overall, our results suggest sex- and tissue-specific changes in the gonadal abundance of the kisspeptin system in zebrafish. The fine tuning of reproduction during energy fluctuations in fish is likely mediated via changes in hormones, including kisspeptin as shown in this research.

Multiple gonadotropin-releasing hormone systems in non-mammalian vertebrates: Ontogeny, anatomy, and physiology.

Three paralogous genes for gonadotropin-releasing hormone (GnRH; gnrh1, gnrh2, and gnrh3) and GnRH receptors exist in non-mammalian vertebrates. However, there are some vertebrate species in which one or two of these paralogous genes have become non-functional during evolution. The developmental migration of GnRH neurons in the brain is evolutionarily conserved in mammals, reptiles, birds, amphibians, and jawed teleost fish. The three GnRH paralogs have specific expression patterns in the brain and originate from multiple sites. In acanthopterygian teleosts (medaka, cichlid, etc.), the preoptic area (POA)-GnRH1 and terminal nerve (TN)-GnRH3 neuronal types originate from the olfactory regions. In other fish species (zebrafish, goldfish and salmon) with only two GnRH paralogs (GnRH2 and GnRH3), the TN- and POA-GnRH3 neuronal types share the same olfactory origin. However, the developmental origin of midbrain (MB)-GnRH2 neurons is debatable between mesencephalic or neural crest site. Each GnRH system has distinctive anatomical and physiological characteristics, and functions differently. The POA-GnRH1 neurons are hypophysiotropic in nature and function in the neuroendocrine control of reproduction. The non-hypophysiotropic GnRH2/GnRH3 neurons probably play neuromodulatory roles in metabolism (MB-GnRH2) and the control of motivational state for sexual behavior (TN-GnRH3).

Gonadotropin-releasing hormone (GnRH) measurements in pituitary portal blood: A history.

Much about the neuroendocrine control of reproduction is inferred from changes in the episodic release of luteinizing hormone (LH), as measured in samples of peripheral blood. This, however, assumes that LH precisely mirrors gonadotropin-releasing hormone (GnRH) release from the hypothalamus. Because GnRH is not measurable in peripheral blood, characterization of the relationship between these two hormones required the simultaneous measurement of GnRH and LH in pituitary portal and peripheral blood, respectively. Here, we review the history of why and how portal blood collection was developed, the aspects of the true output of the central component of the hypothalamic-pituitary-gonadal axis that this methodology helped clarify, and conditions under which the pituitary fails to serve as an adequate bioassay for the release pattern of GnRH.

Role of insulin in the neuroendocrine control of reproduction.

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin-resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin-responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player.

Gonadectomy and Blood Sampling Procedures in the Small Size Teleost Model Japanese Medaka (Oryzias latipes).

Sex steroids, produced by the gonads, play an essential role in brain and pituitary tissue plasticity and in the neuroendocrine control of reproduction in all vertebrates by providing feedback to the brain and pituitary. Teleost fishes possess a higher degree of tissue plasticity and variation in reproductivestrategies compared to mammals and appear to be useful models to investigate the role of sex steroids and the mechanisms by which they act. The removal of the main source of sex steroid production using gonadectomy together with blood sampling to measure steroid levels has been well-established and fairly feasible in bigger fish and is a powerful technique to investigate the role and effects of sex steroids. However, these techniques raise challenges when implemented in small size teleost models. Here, we describe the step-by-step procedures of gonadectomy in both males and female Japanese medaka followed by blood sampling. These protocols are shown to be highly feasible in medaka indicated by a high survival rate, safety for the life span and phenotype of the fish, and reproducibility in terms of sex steroid clearance. The use of these procedures combined with the other advantages of using this small teleost model will greatly improve the understanding of feedback mechanisms in the neuroendocrine control of reproduction and tissue plasticity provided by sex steroids in vertebrates.

Reproductive health in women with type 2 diabetes mellitus.

As type 2 diabetes mellitus (T2DM) reaches epidemic proportions in the developed world and the age at diagnosis decreases, more women of reproductive age are being affected. In this article, we provide a synoptic view on potential mechanisms and relevant factors underlying menstrual cycle disorders and fertility issues in women with T2DM. The article discusses the function of the hypothalamic-pituitary-ovarian (HPO) axis, the central role of the hypothalamus in the homeostasis of this system, the central modulators of the axis, and the peripheral metabolic signals involved in neuroendocrine control of reproduction. The available literature on the relationship between T2DM and the female reproductive lifespan, menstrual cycle disorders, fertility issues, and gestational health in women with T2DM are also discussed. The data so far indicate that there is a "U-shaped" relationship between menarche, menopause, and T2DM, both early and late menarche/menopause being risk factors for T2DM. Hyperglycemia and its consequences may be responsible for the effects of T2DM on reproductive health in women, but the exact mechanisms are not as yet fully understood; thus, more studies are needed in order to identify factors causing disruption of the HPO axis.

¿Qué sabemos de los esteroides sexuales y las gonadotropinas en la reproducción de teleósteos neotropicales?

Esta revisión provee un resumen general de las investigaciones realizadas en los últimos 10 años acerca de los esteroides sexuales (17β-Estradiol, Testosterona, 11 Ketotestosterona y 17α, 20β-DHP), las gonadotropinas (Fsh y Lh) y sus principales reguladores (GnRH1-3 y GnIH1-3); y su respectiva función en la modulación de la reproducción. Específicamente sobre el eje Hipotálamo – Pituitaria – Gónada (HPG), en teleósteos modelo y neotropicales (Astyanax altiparanae, Steindachneridion parahybae, Salminus hillarii, Centropomus undecimalis). Mostramos que el papel regulador de éstos continúa siendo tema de discusión, pues varía en función de múltiples características, entre ellas, las estrategiareproductivas de la especie en cuestión y/o las condiciones en las que éstas son mantenidas durante el estudio. Históricamente, se ha descrito que la Fsh actúa en las fases tempranas de la reproducción, estimulando la biosíntesis de estradiol y testosterona necesarios para la gametogénesis; mientras la Lh está implicada en las fases finales del ciclo reproductivo (maduración final de los gametos y desove). Sin embargo, en especies con desarrollo asincrónico y desove múltiple, la Lh se produce durante todo el ciclo en paralelo con la Fsh, sugiriendo la necesidad de ambas hormonas en la gametogénesis y maduración final. Adicionalmente, investigaciones recientes en especies con comportamiento migratorio reproductivo, han evidenciado una disminución significativa en la expresión del ARNm de la subunidad β de Lh (lhb) cuando los individuos son mantenidos en cautiverio, lo que podría ocasionar alguna disfunción reproductiva bajo los actuales sistemas de cultivo, considerado hoy el gran problema de la acuicultura contemporánea. Desafortunadamente, los estudios de estos tópicos en especies suramericanas son aún incipientes, por lo que se hace necesario centrar las investigaciones hacia el esclarecimiento del control neuroendocrino de la reproducción en especies nativas, más aún cuando estas especies son mantenidas en cautiverio.

Gonadotropin-inhibitory hormone in teleosts: New insights from a basal representative, the eel

Since its discovery in birds, gonadotropin-inhibitory hormone (GnIH) has triggered investigation in the other groups of vertebrates. In the present study, we have identified a single gnih gene in the European eel (Anguilla anguilla), a representative species of a basal group of teleosts (Elopomorphs). We have also retrieved a single gnih gene in Osteoglossomorphs, as well as in more recently emerged teleosts, Clupeocephala. Phylogeny and synteny analyses allowed us to infer that one of the two gnih paralogs emerged from the teleost-specific whole genome duplication (TWGD or 3R), would have been lost shortly after the 3R, before the emergence of the basal groups of teleosts. This led to the presence of a single gnih in extant teleosts as in other vertebrates. Two gnih paralogs were still found in some teleost species, such as in salmonids, but resulting from the additional whole genome duplication that specifically occurred in this lineage (4R). Eel gnih was mostly expressed in the diencephalon part of the brain, as analyzed by quantitative real-time PCR. Cloning of eel gnih cDNA confirmed that the sequence of the GnIH precursor encoded three putative mature GnIH peptides (aaGnIH-1, aaGnIH-2 and aaGnIH-3), which were synthesized and tested for their direct effects on eel pituitary cells in vitro. Eel GnIH peptides inhibited the expression of gonadotropin subunits (lhβ, fshβ, and common a-subunit) as well as of GnRH receptor (gnrh-r2), with no effect on tshβ and gh expression. The inhibitory effect of GnIH peptides on gonadotropic function in a basal teleost is in agreement with an ancestral inhibitory role of GnIH in the neuroendocrine control of reproduction in vertebrates.

KLUCZOWA ROLA KISSPEPTYN W REGULACJI PROCESÓW ROZRODCZYCH SAMIC

Odkrycie kisspeptyn zrewolucjonizowało wiedzę dotyczącą neuroendokrynnnej kontroli rozmnażania ssaków. Nadrzędnym elementem nadzorującym wydzielanie hormonów steroidowych przez gonady są zlokalizowane w podwzgórzu neurony produkujące gonadoliberynę, sterujące działaniem osi podwzgórze-przysadka mózgowa-gonady (PPG). Jednak odkrycie kisspeptyn i ich receptora (KISS1R) wykazało, że niewątpliwie kisspetyny pełną kluczową rolę w regulacji tej osi. Na szczególną uwagę zasługuje regulacja rozrodu u samic ssaków, obejmująca ujemne i dodatnie sprzężenia zwrotne, owulację, implantację zarodka, ciążę i laktację. Wykazano, że to właśnie system KISS-1/KISS1R bierze udział w zarządzaniu zmianami hormonalnymi obserwowanymi w tych procesach. Ponadto, kisspeptyny są zaangażowane w odbieranie, a także przekazywanie informacji ze środowiska zewnętrznego do osi PPG. Chociaż kisspeptyny zlokalizowano głównie w mózgu, liczne badania sugerują ich lokalną produkcję w jajniku, co oprócz znaczenia fizjologicznego jest istotne również w rozwoju patologii układu rozrodczego.

17β-Estradiol Increases Arcuate KNDy Neuronal Sensitivity to Ghrelin Inhibition of the M-Current in Female Mice

Obesity and anorexia result in dysregulation of the hypothalamic–pituitary–gonadal axis, negatively impacting reproduction. Ghrelin, secreted from the stomach, potentially mediates negative energy states and neuroendocrine control of reproduction by acting through the growth hormone secretagogue receptor (GHSR). GHSR is expressed in hypothalamic arcuate (ARC) Kisspeptin/Neurokinin B (Tac2)/Dynorphin (KNDy) neurons. Ghrelin is known to inhibit the M-current produced by KCNQ channels in other ARC neurons. In addition, we have shown 17β-estradiol (E2) increases Ghsr expression in KNDy neurons 6-fold and increases the M-current in NPY neurons. We hypothesize that E2 increases GHSR expression in KNDy neurons to increase ghrelin sensitivity during negative energy states. Furthermore, we suspect ghrelin targets the M-current in KNDy neurons to control reproduction and energy homeostasis. We utilized ovariectomized Tac2-EGFP adult female mice, pretreated with estradiol benzoate (EB) or oil vehicle and performed whole-cell-patch-clamp recordings to elicit the M-current in KNDy neurons using standard activation protocols in voltage-clamp. Using the selective KCNQ channel blocker XE-991 (40 µM) to target the M-current, oil- and EB-treated mice showed a decrease in the maximum peak current by 75.7 ± 13.8 pA (n = 10) and 68.0 ± 14.7 pA (n = 11), respectively. To determine the actions of ghrelin on the M-current, ghrelin was perfused (100 nM) in oil- and EB-treated mice resulting in the suppression of the maximum peak current by 58.5 ± 15.8 pA (n = 9) and 59.2 ± 11.9 pA (n = 9), respectively. KNDy neurons appeared more sensitive to ghrelin when pretreated with EB, revealing that ARC KNDy neurons are more sensitive to ghrelin during states of high E2.

Modeling and high-throughput experimental data uncover the mechanisms underlying Fshb gene sensitivity to gonadotropin-releasing hormone pulse frequency

Neuroendocrine control of reproduction by brain-secreted pulses of gonadotropin-releasing hormone (GnRH) represents a longstanding puzzle about extracellular signal decoding mechanisms. GnRH regulates the pituitary gonadotropin's follicle-stimulating hormone (FSH) and luteinizing hormone (LH), both of which are heterodimers specified by unique β subunits (FSHβ/LHβ). Contrary to Lhb, Fshb gene induction has a preference for low-frequency GnRH pulses. To clarify the underlying regulatory mechanisms, we developed three biologically anchored mathematical models: 1) parallel activation of Fshb inhibitory factors (e.g. inhibin α and VGF nerve growth factor-inducible), 2) activation of a signaling component with a refractory period (e.g. G protein), and 3) inactivation of a factor needed for Fshb induction (e.g. growth differentiation factor 9). Simulations with all three models recapitulated the Fshb expression levels obtained in pituitary gonadotrope cells perifused with varying GnRH pulse frequencies. Notably, simulations altering average concentration, pulse duration, and pulse frequency revealed that the apparent frequency-dependent pattern of Fshb expression in model 1 actually resulted from variations in average GnRH concentration. In contrast, models 2 and 3 showed "true" pulse frequency sensing. To resolve which components of this GnRH signal induce Fshb, we developed a high-throughput parallel experimental system. We analyzed over 4,000 samples in experiments with varying near-physiological GnRH concentrations and pulse patterns. Whereas Egr1 and Fos genes responded only to variations in average GnRH concentration, Fshb levels were sensitive to both average concentration and true pulse frequency. These results provide a foundation for understanding the role of multiple regulatory factors in modulating Fshb gene activity.

The potential regulatory mechanisms of the gonadotropin-releasing hormone in gonadotropin transcriptions identified with bioinformatics analyses

BackgroundThe regulation of gonadotropin synthesis and release by gonadotropin­releasing hormone (GnRH) plays an essential role in the neuroendocrine control of reproduction. However, the mechanisms underlying gonadotropin regulation by GnRH pulse frequency and amplitude are still ambiguous. This study aimed to explore the molecular mechanisms and biological pathways associated with gonadotropin synthesis by GnRH pulse frequencies and amplitudes.MethodsUsing GSE63251 datasets downloaded from the Gene Expression Omnibus (GEO), differentially expressed genes (DEGs) were screened by comparing the RNA expression from the GnRH pulse group, the GnRH tonic group and the control group. Pathway enrichment analyses of DEGs was performed, followed by protein-protein interaction (PPI) network construction. Furthermore, sub-network modules were constructed by ClusterONE and GO function and pathways analysed by DAVID. In addition, the relationship between the metabolic pathways and the GnRH pathway was verified in vitro.ResultsIn total, 531 common DEGs were identified in GnRH groups, including 290 up-regulated and 241 down-regulated genes. DEGs predominantly enriched in 16 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including 11 up-regulated pathways (signallingsignallingmetabolic pathways, signallingand GnRH signalling pathway) and 5 down-regulated pathways (type II diabetes mellitus). Moreover, FBJ osteosarcoma oncogene (FOS) and jun proto-oncogene (JUN) had higher connectivity degrees in the PPI network. Three modules in the PPI were identified with ClusterONE. The genes in module 1 were significantly enriched in five pathways, including signallingthe insulin resistance and GnRH signalling pathway. The genes in modules 2 and 3 were mainly enriched in metabolic pathways and steroid hormone biosynthesis, respectively. Finally, knockdown leptin receptor (LEPR) and insulin receptor (INSR) reversed the GnRH-modulated metabolic related-gene expression.ConclusionsThe present study revealed the involvement of GnRH in the regulation of gonadotropin biosynthesis and metabolism in the maintenance of reproduction, achieved by bioinformatics analyses. This, indicates that the GnRH signalling pathway played a central linkings role in reproductive function and metabolic balance. In addition, the present study identified the difference response between GnRH pulse and GnRH tone, indicated that abnormal GnRH pulse and amplitude may cause disease, which may provide an improved understanding of the GnRH pathway and a new insight for disease diagnosis and treatment.

Expanding the Role of Tachykinins in the Neuroendocrine Control of Reproduction.

Reproductive function is driven by the hormonal interplay between the gonads and brain-pituitary axis. Gonadotropin-releasing hormone (GnRH) is released in a pulsatile manner, which is critical for the attainment and maintenance of fertility, however, GnRH neurons lack the ability to directly respond to most regulatory factors, and a hierarchical upstream neuronal network governs its secretion. We and others proposed a model in which Kiss1 neurons in the arcuate nucleus (ARC), so called KNDy neurons, release kisspeptin (a potent GnRH secretagogue) in a pulsatile manner to drive GnRH pulses under the coordinated autosynaptic action of its cotransmitters, the tachykinin neurokinin B (NKB, stimulatory) and dynorphin (inhibitory). Numerous genetic and pharmacological studies support this model; however, additional regulatory mechanisms (upstream of KNDy neurons) and alternative pathways of GnRH secretion (kisspeptin-independent) exist, but remain ill defined. In this aspect, attention to other members of the tachykinin family, namely substance P (SP) and neurokinin A (NKA), has recently been rekindled. Even though there are still major gaps in our knowledge about the functional significance of these systems, substantial evidence, as discussed below, is placing tachykinin signaling as an important pathway for the awakening of the reproductive axis and the onset of puberty to physiological GnRH secretion and maintenance of fertility in adulthood.

Lateral hypothalamic orexin and melanin-concentrating hormone neurons provide direct input to gonadotropin-releasing hormone neurons in the human.

Hypophysiotropic projections of gonadotropin-releasing hormone (GnRH)-synthesizing neurons form the final common output way of the hypothalamus in the neuroendocrine control of reproduction. Several peptidergic neuronal systems of the medial hypothalamus innervate human GnRH cells and mediate crucially important hormonal and metabolic signals to the reproductive axis, whereas much less is known about the contribution of the lateral hypothalamic area to the afferent control of human GnRH neurons. Orexin (ORX)- and melanin-concentrating hormone (MCH)-synthesizing neurons of this region have been implicated in diverse behavioral and autonomic processes, including sleep and wakefulness, feeding and other functions. In the present immunohistochemical study, we addressed the anatomical connectivity of these neurons to human GnRH cells in post-mortem hypothalamic samples obtained from autopsies. We found that 38.9 ± 10.3% and 17.7 ± 3.3% of GnRH-immunoreactive (IR) perikarya in the infundibular nucleus of human male subjects received ORX-IR and MCH-IR contacts, respectively. On average, each 1 mm segment of GnRH dendrites received 7.3 ± 1.1 ORX-IR and 3.7 ± 0.5 MCH-IR axo-dendritic appositions. Overall, the axo-dendritic contacts dominated over the axo-somatic contacts and represented 80.5 ± 6.4% of ORX-IR and 76.7 ± 4.6% of MCH-IR inputs to GnRH cells. Based on functional evidence from studies of laboratory animals, the direct axo-somatic and axo-dendritic input from ORX and MCH neurons to the human GnRH neuronal system may convey critical metabolic and other homeostatic signals to the reproducive axis. In this study, we also report the generation and characterization of new antibodies for immunohistochemical detection of GnRH neurons in histological sections.

Editorial: advances in neuroscience: the BRAIN initiative and implications for neuroendocrinology.

Editorial: advances in neuroscience: the BRAIN initiative and implications for neuroendocrinology.

Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes.

The neuroendocrine control of reproduction in mammals is governed by a neural hypothalamic network of nearly 1500 gonadotropin-releasing hormone (GnRH) secreting neurons that modulate the activity of the reproductive axis across life. Congenital hypogonadotropic hypogonadism (HH) is a clinical syndrome that is characterized by partial or complete pubertal failure. HH may result from inadequate hypothalamic GnRH axis activation, or a failure of pituitary gonadotropin secretion/effects. In man, several genes that participate in olfactory and GnRH neuronal migration are thought to interact during the embryonic life. A growing number of mutations in different genes are responsible for congenital HH. Based on the presence or absence of olfaction dysfunction, HH is divided in two syndromes: HH with olfactory alterations [Kallmann syndrome (KS)] and idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH). KS is a heterogeneous disorder affecting 1 in 5000 males, with a three to fivefold of males over females. KS is associated with mutations in KAL1, FGFR1/FGF8, FGF17, IL17RD, PROK2/PROKR2, NELF, CHD7, HS6ST1, FLRT3, SPRY4, DUSP6, SEMA3A, NELF, and WDR11 genes that are related to defects in neuronal migration. These reproductive and olfactory deficits include a variable non-reproductive phenotype, including sensorineural deafness, coloboma, bimanual synkinesis, craniofacial abnormalities, and/or renal agenesis. Interestingly, defects in PROKR2, FGFR1, FGF8, CHD7, DUSP6, and WDR11 genes are also associated with normosmic IHH, whereas mutations in KISS1/KISSR, TAC3/TACR3, GNRH1/GNRHR, LEP/LEPR, HESX1, FSHB, and LHB are only present in patients with normosmic IHH. In this paper, we summarize the reproductive, neurodevelopmental, and genetic aspects of HH in human pathology.

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).

The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction.