title: Reversal and relapse of hypogonadotropic hypogonadism: resilience and fragility of the reproductive neuroendocrine system.
abstract: BACKGROUND
  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.
  
  
  METHODS
  This was a retrospective review of clinical, biochemical, and genetic features of patients with IHH evaluated at an academic medical center.
  
  
  METHODS
  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.
authors.affiliation: Harvard Center for Reproductive Endocrine Sciences and Reproductive Endocrine Unit (V.F.S., Y.-M.C., M.F.L., R.B., L.P., A.D., N.P., F.J.H., J.E.H., K.A.M., P.A.B., S.B.S.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Division of Endocrinology (Y.-M.C.), Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115; and Department of Endocrinology (R.Q.), Institute for Human Genetics, University of Newcastle-upon-Tyne, Newcastle-upon-Tyne NE1 3BZ, United Kingdom.
authors.forename: Valerie F
authors.initials: VF
authors.lastname: Sidhoum
authors.forename: Yee-Ming
authors.initials: YM
authors.lastname: Chan
authors.forename: Margaret F
authors.initials: MF
authors.lastname: Lippincott
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Balasubramanian
authors.forename: Richard
authors.initials: R
authors.lastname: Quinton
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwyer
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Hayes
authors.forename: Janet E
authors.initials: JE
authors.lastname: Hall
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Martin
authors.forename: Paul A
authors.initials: PA
authors.lastname: Boepple
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Seminara
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000453:epidemiology / Q000503:physiopathology* / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009490:Neurosecretory Systems / Q000502:physiology*; D012008:Recurrence; D012074:Remission Induction; D012098:Reproduction / Q000502:physiology*; D012189:Retrospective Studies; D055815:Young Adult