Reversal and Relapse of Hypogonadotropic Hypogonadism: Resilience and Fragility of the Reproductive Neuroendocrine System
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. J Clin Endocrinol Metab. 2013 Jan 1:jc20132809. [Epub ahead of print]

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Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit, Department of Medicine, MA General Hospital, Boston, MA 02114.


Context: A subset of patients diagnosed with idiopathic hypogonadotropic hypogonadism (IHH) later achieve activation of their hypothalamic-pituitary-gonadal axis with normalization of steroidogenesis and/or gametogenesis, a phenomenon termed reversal. Objective: To determine the natural history of reversal and to identify associated phenotypes and genotypes. Design, Setting, and Subjects: 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. 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 MRI. Subjects with reversal were enriched for mutations affecting neurokinin B signaling compared to a cohort of IHH patients without reversal (10% vs. 3%, p = 0.048); 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 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.