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Special Issue "Molecular Background of Male and Female Central Hypogonadism 2.0"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 31 March 2022.

Special Issue Editors

Dr. Rossella Cannarella
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Interests: genetics of male infertility; female infertility; pituitary gland; adrenal gland; osteoporosis; transitional age; diabetes; thyroid gland
Special Issues, Collections and Topics in MDPI journals
Dr. Rosita Angela Condorelli
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Interests: male infertility; female infertility; pituitary gland; osteoporosis; transitional age; diabetes; thyroid gland
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Sandro La Vignera
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
Interests: male infertility; female infertility; osteoporosis; transitional age; diabetes; thyroid gland; male sexual disorders
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Central hypogonadism (CH) is a disorder that affects the hypothalamic–pituitary axis with congenital or acquired mechanisms. Ever since Sanger sequencing was developed, various genes have been implicated in the pathogenesis of congenital CH. Since 1991, when the key role of the KAL1 gene in the migration of GnRH-secreting neurons into the hypothalamus and olfactory nerve development was initially reported, Kallmann syndrome (KS) has been defined as a genetic disease leading to congenital CH associated with hyposmia/anosmia. Today, about 30 genes have been shown to be involved in the pathogenesis of CH, and it has become clear that gene mutations can cause CH with or without hyposmia/anosmia, thus making the classification into normosmic KS and normosmic CH obsolete. Furthermore, some gene mutations also seem to be implicated in the pathogenesis of late-onset hypogonadism, thus suggesting that genetic CH may be more frequent than expected. This Special Issue of the International Journal of Molecular Sciences aims to gather studies describing recent advances in the genetic background of CH and offer an updated and evidence-based classification of genetic CH. Evaluation of previous and current research will likely broaden our knowledge of genetic CH, including its epidemiology.

Prof. Dr. Aldo E. Calogero
Dr. Rossella Cannarella
Dr. Rosita Angela Condorelli
Prof. Dr. Sandro La Vignera
Guest Editors

Manuscript Submission Information

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Keywords

  • Central hypogonadism
  • Puberty delay
  • Kallmann syndrome
  • Normosmic hypogonadism
  • Late-onset hypogonadism
  • Infertility
  • Genetics
  • GnRH neurons

Published Papers (3 papers)

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Research

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Article
Anti-Müllerian Hormone, Growth Hormone, and Insulin-Like Growth Factor 1 Modulate the Migratory and Secretory Patterns of GnRH Neurons
Int. J. Mol. Sci. 2021, 22(5), 2445; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052445 - 28 Feb 2021
Cited by 2 | Viewed by 636
Abstract
Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone [...] Read more.
Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5–150 ng/mL), GH (3–1000 ng/mL), or IGF1 (1.5–150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty. Full article
(This article belongs to the Special Issue Molecular Background of Male and Female Central Hypogonadism 2.0)
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Review

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Review
The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency
Int. J. Mol. Sci. 2021, 22(17), 9425; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179425 - 30 Aug 2021
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Abstract
Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step [...] Read more.
Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis. Full article
(This article belongs to the Special Issue Molecular Background of Male and Female Central Hypogonadism 2.0)
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Review
Mechanisms of Central Hypogonadism
Int. J. Mol. Sci. 2021, 22(15), 8217; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158217 - 30 Jul 2021
Viewed by 626
Abstract
Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired [...] Read more.
Reproductive function depends upon an operational hypothalamo–pituitary–gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy. Full article
(This article belongs to the Special Issue Molecular Background of Male and Female Central Hypogonadism 2.0)
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