Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System
Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System
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DOI：
10.1210/jc.2013-2809
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发表时间：
2014-03-01
影响因子：
5.8
通讯作者：
Seminara, Stephanie B.
中科院分区：
文献类型：
--
作者：
Sidhoum, Valerie F.;Chan, Yee-Ming;Seminara, Stephanie B.
目的：本研究的目的是确定逆转的自然历史，并确定相关的表型和基因类型。设计、背景和对象：这是一个在学术医学中心评估的IHH患者的临床、生化和遗传特征的回顾。主要观察指标：自然生育史、月经规律、睾丸发育或血清性类固醇激素正常化、黄体生成素分泌、脑成像、发现结果：308例IHH患者中，44例逆转。事件发生时间分析估计终生逆转发生率为22%。发生逆转的患者与未逆转的IHH患者相比，隐睾症、小阴茎或部分青春期发育的发生率没有差异。15名反转患者(30%)有Kallmann综合征(IHH和嗅觉障碍)；1名患者在脑磁共振成像扫描中检测不到嗅球。与未逆转的IHH患者相比，发生逆转的受试者富含影响神经激动素B信号的突变(10%比3%，P=.044)，在FGFR1、PROKR2和GNRHR中有相似的突变频率，在KAL1中没有突变。5名男性的逆转没有持续，再次发展为促性腺激素减退。结论：IHH逆转可能比以前所认识的更广泛，发生在广泛的基因和表型中。在逆转的患者中，对扰乱神经激动素B信号的突变的丰富表明，尽管这一信号通路对于正常的青春期时间选择很重要，但它的功能在以后的生活中是可有可无的。没有嗅球的患者出现反转表明，这些结构对正常生殖功能并不是必不可少的。患有IHH的患者需要终身监测逆转情况，如果发生逆转，随后也可能复发。
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.