GnRH, anosmia and hypogonadotropic hypogonadism – Where are we?

Forni, Paolo E.; Wray, Susan

doi:10.1016/j.yfrne.2014.09.004

Cited by 104 publications

(100 citation statements)

References 193 publications

(280 reference statements)

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“…Data from the past few years suggest that GnRH neurons originate from both the neural crest and ectodermal progenitors, and migrate in close association with growing axons of olfactory and/or terminal nerves. 15,16 Once in the hypothalamus, GnRH neurons detach from their axonal guides, disperse further into the brain parenchyma and stop migrating. At birth, GnRH neurons have reached their final destination in the brain and many of them project into the median eminence, where they release the GnRH decapeptide from their axon terminals into the hypophyseal portal vasculature.…”

Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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“…This syndrome arises from mutations in genes such as NELF, CHD7, KAL1, FGFR1, FGF8, WDR11, PROK2, PROKR2 and SEMA-3A that primarily alter olfactory development and, consequently, impede GnRH neuron migration from the olfactory placode into the hypothalamus 7,212,213 . Although the absence of GnRH neurons in the human hypothalamus has only been demonstrated for KAL1 mutations to date 214 , animal models indicate that other Kallmann-related mutations will probably result from the same defect 7 .…”

Section: Hypogonadotropic Hypogonadismmentioning

confidence: 99%

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

2016

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The gonadotropin-releasing hormone (GnRH) neuronal network generates pulse and surge modes of gonadotropin secretion critical for puberty and fertility. The arcuate nucleus kisspeptin neurons that innervate the projections of GnRH neurons in and around their neurosecretory zone are key components of the pulse generator in all mammals. By contrast, kisspeptin neurons located in the preoptic area project to GnRH neuron cell bodies and proximal dendrites and are involved in surge generation in female rodents (and possibly other species). The hypothalamic-pituitary-gonadal axis develops embryonically but, apart from short periods of activation immediately after birth, remains suppressed through a combination of gonadal and non-gonadal mechanisms. At puberty onset, the pulse generator reactivates, probably owing to progressive stimulatory influences on GnRH neurons from glial and neurotransmitter signalling, and the re-emergence of stimulatory arcuate kisspeptin input. In females, the development of pulsatile gonadotropin secretion enables final maturation of the surge generator that ultimately triggers the first ovulation. Representation of the GnRH neuronal network as a series of interlocking functional modules could help conceptualization of its functioning in different species. Insights into pulse and surge generation are expected to aid development of therapeutic strategies ameliorating pubertal disorders and infertility in the clinic.

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“…About 800–1,200 GnRH neurons are scattered throughout the forebrain of a mouse [61]. This poses a challenge for molecular studies of GnRH neurons in vivo.…”

Section: Introductionmentioning

confidence: 99%

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

Lainez

Coss²

2019

Neuroendocrinology

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Background: The mechanisms whereby neuroinflammation negatively affects neuronal function in the hypothalamus are not clear. Our previous study determined that obesity-mediated chronic inflammation elicits sex-specific impairment in reproductive function via reduction in spine density in gonadotropin-releasing hormone (GnRH) neurons. Neuroinflammation and subsequent decrease in GnRH neuron spine density was specific for male mice, while protection in females was independent of ovarian estrogens. Methods: To examine if neuroinflammation-induced cytokines can directly regulate GnRH gene expression, herein we examined signaling pathways and mechanisms in males in vivo and in GnRH-expressing cell line, GT1–7. Results: GnRH neurons express cytokine receptors, and chronic or acute neuroinflammation represses GnRH gene expression in vivo. Leukemia inhibitory factor (LIF) in particular represses GnRH expression in GT1–7 cells, while other cytokines do not. STAT3 and MAPK pathways are activated following LIF treatment, but only MAPK pathway, specifically p38α, is sufficient to repress the GnRH gene. LIF induces cFOS that represses the GnRH gene via the -1,793 site in the enhancer region. In vivo, following high-fat diet, cFOS is induced in GnRH neurons and neurons juxtaposed to the leaky blood brain barrier of the organum vasculosum of the lamina terminalis, but not in the neurons further away. Conclusion: Our results indicate that the increase in LIF due to neuroinflammation induces cFOS and represses the GnRH gene. Therefore, in addition to synaptic changes in GnRH neurons, neuroinflammatory cytokines directly regulate gene expression and reproductive function, and the specificity for neuronal targets may stem from the proximity to the fenestrated capillaries.

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GnRH, anosmia and hypogonadotropic hypogonadism – Where are we?

Cited by 104 publications

References 193 publications

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

Control of puberty onset and fertility by gonadotropin-releasing hormone neurons

Leukemia Inhibitory Factor Represses GnRH Gene Expression via cFOS during Inflammation in Male Mice

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