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

Lookup NU author(s): Dr Richard Quinton

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Abstract

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.


Publication metadata

Author(s): Sidhoum VF, Chan YM, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, Dwyer A, Pitteloud N, Hayes FJ, Hall JE, Martin KA, Boepple PA, Seminara SB

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2014

Volume: 99

Issue: 3

Pages: 861-870

Print publication date: 19/12/2013

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society

URL: http://dx.doi.org/10.1210/jc.2013-2809

DOI: 10.1210/jc.2013-2809


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Funding

Funder referenceFunder name
Harvard University
Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources)
HL-102923Lung GO Sequencing Project
HL-102924Women's Health Initiative Sequencing Project
HL-102926Seattle GO Sequencing Project
HL-103010Heart GO Sequencing Project
HL-102925Broad GO Sequencing Project
M01-RR-01066Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health)
R01 HD015788National Institutes of Health
U54 HD028138National Institutes of Health
UL1 RR025758Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health)
UL1TR000170Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Advancing Translational Sciences, National Institutes of Health)

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