Functional Hypogonadotropic Hypogonadism in Men: Underlying Neuroendocrine Mechanisms and Natural History

Abstract Context After completion of puberty a subset of men experience functional hypogonadotropic hypogonadism (FHH) secondary to excessive exercise or weight loss. This phenomenon is akin to hypothalamic amenorrhea (HA) in women, yet little is known about FHH in men. Objective To investigate the neuroendocrine mechanisms, genetics, and natural history underlying FHH. Design Retrospective study in an academic medical center. Participants Healthy postpubertal men presenting with symptoms of hypogonadism in the setting of excessive exercise (>10 hours/week) or weight loss (>10% of body weight). Healthy age-matched men served as controls. Interventions Clinical assessment, biochemical and neuroendocrine profiling, body composition, semen analysis, and genetic evaluation of genes known to cause isolated GnRH deficiency. Main Outcome Measures Reproductive hormone levels, endogenous GnRH-induced LH pulse patterns, and rare genetic variants. Results Ten men with FHH were compared with 18 age-matched controls. Patients had significantly lower body mass index, testosterone, LH, and mean LH pulse amplitudes yet normal LH pulse frequency, serum FSH, and sperm counts. Some patients exhibited nocturnal, sleep-entrained LH pulses characteristic of early puberty, and one FHH subject showed a completely apulsatile LH secretion. After decreased exercise and weight gain, five men with men had normalized serum testosterone levels, and symptoms resolved. Rare missense variants in NSMF (n = 1) and CHD7 (n = 1) were identified in two men with FHH. Conclusions FHH is a rare, reversible form of male GnRH deficiency. LH pulse patterns in male FHH are similar to those observed in women with HA. This study expands the spectrum of GnRH deficiency disorders in men.

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Predictors of Primary Care Referral to Bariatric Surgery or Weight Loss Medicine at a Major Academic Medical Center

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2020.07.055 ◽

2020 ◽

Vol 231 (4) ◽

pp. S27-S28

Author(s):

Jacob Nudel ◽

Susanna W.L. de Geus ◽

Jayakanth Srinivasan ◽

Jonathan Woodson ◽

Donald Thomas Hess

Keyword(s):

Bariatric Surgery ◽

Primary Care ◽

Weight Loss ◽

Medical Center ◽

Academic Medical Center ◽

Academic Medical

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Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2013-2809 ◽

2014 ◽

Vol 99 (3) ◽

pp. 861-870 ◽

Cited By ~ 80

Author(s):

Valerie F. Sidhoum ◽

Yee-Ming Chan ◽

Margaret F. Lippincott ◽

Ravikumar Balasubramanian ◽

Richard Quinton ◽

...

Keyword(s):

Medical Center ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Academic Medical Center ◽

Brain Magnetic Resonance Imaging ◽

Magnetic Resonance Imaging Scan ◽

Event Analysis ◽

Neurokinin B ◽

Olfactory Bulbs ◽

History Of

Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieves activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: The objective of this study was to determine the natural history of reversal and to identify associated phenotypes and genotypes. Design, Setting, and Subjects: This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center. Main Outcome Measures: History of spontaneous fertility, regular menses, testicular growth, or normalization of serum sex steroids, LH secretory profiles, brain imaging findings, and sequences of 14 genes associated with IHH were reviewed. Results: Of 308 patients with IHH, 44 underwent reversal. Time-to-event analysis estimated a lifetime incidence of reversal of 22%. There were no differences in the rates of cryptorchidism, micropenis, or partial pubertal development in patients with reversal vs IHH patients without reversal. Fifteen patients with reversal (30%) had Kallmann syndrome (IHH and anosmia); one had undetectable olfactory bulbs on a brain magnetic resonance imaging scan. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared with a cohort of IHH patients without reversal (10% vs 3%, P = .044), had comparable frequencies of mutations in FGFR1, PROKR2, and GNRHR, and had no mutations in KAL1. Five men did not sustain their reversal and again developed hypogonadotropism. Conclusions: Reversal of IHH may be more widespread than previously appreciated and occurs across a broad range of genotypes and phenotypes. Enrichment for mutations that disrupt neurokinin B signaling in patients who reversed indicates that, despite the importance of this signaling pathway for normal pubertal timing, its function is dispensable later in life. The occurrence of reversal in a patient with no olfactory bulbs demonstrates that these structures are not essential for normal reproductive function. Patients with IHH require lifelong monitoring for reversal and, if reversal occurs, subsequent relapse also may occur.

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GNRH1 Variants in Congenital Hypogonadotropic Hypogonadism: Single-center experience and Systematic Literature Review

Neuroendocrinology ◽

10.1159/000521558 ◽

2021 ◽

Author(s):

Virendra A. Patil ◽

Anurag Ranjan Lila ◽

Nalini Shah ◽

Alka V. Ekbote ◽

Ravikumar Shah ◽

...

Keyword(s):

Literature Review ◽

World Literature ◽

Medical Center ◽

Hypogonadotropic Hypogonadism ◽

Academic Medical Center ◽

Missense Mutations ◽

Single Center Experience ◽

The World ◽

Pubmed Search ◽

Reproductive Phenotype

Objective: As GNRH1 genotype-phenotype correlation in CHH is not well-studied, we aim to describe the GNRH1 variants in our CHH cohort and present a systematic review as well as genotype-phenotype analysis of all mutation-positive cases reported in the world literature. Design: Retrospective study of GNRH1 mutation-positive patients from a western-Indian center. PRISMA guidelines-based PubMed search of published literature of all GNRH1 mutation-positive patients Setting: Academic medical center. Patient(s): Two probands from our cohort and 19 probands from the world literature. Intervention(s): None Main Outcome Measure(s): Demographic details, clinical presentation, biochemistry, imaging, treatment details, and genotypic data were recorded. Result(s): Two probands in our cohort carried two novel pathogenic biallelic GnRH variants (p.Glu24Leu, c.238-2A>G). Both had a severe reproductive phenotype. We report successful gonadotropin therapy and fertility in one proband. We included 19 probands from 12 studies after the literature review. Ten CHH probands (inclusive two from this study) with biallelic GNRH1 variants had severe reproductive phenotype, low gonadotropins levels, low/normal prolactin, normal pituitary imaging, and no extra-reproductive phenotype. Of seven biallelic variants reported, three were frameshift, two were splice-site and two were missense mutations. All of them were pathogenic/likely pathogenic without oligogenicity. Of seven monoallelic GNRH1 variants reported in eleven probands, four had non-reproductive phenotype, three were Benign/Likely Benign, four were oligogenic. Conclusion(s): GNRH1 biallelic variants lead to severe reproductive phenotype, with low gonadotropin levels without non-reproductive features or oligogenicity. However, the role of GNRH1 monoallelic variants in CHH pathophysiology for reported variants remains questionable.

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