title: Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes.
abstract: BACKGROUND
  Idiopathic hypogonadotropic hypogonadism (IHH) with normal smell (normosmic IHH) or anosmia (Kallmann syndrome) is associated with defects in the production or action of GnRH. Accordingly, most IHH patients respond to physiological pulsatile GnRH replacement by normalizing serum LH, FSH, and testosterone (T) levels and achieving gametogenesis; some patients, however, show atypical responses. Interestingly, several IHH-associated genes are expressed in multiple compartments of the hypothalamic-pituitary-gonadal axis.
  
  
  OBJECTIVE
  The aim of the study was to investigate whether the clinical, biochemical, or genetic characteristics of IHH men with atypical responses to GnRH indicate alternative or additional defects in the hypothalamic-pituitary-gonadal axis.
  
  
  METHODS
  We studied 90 IHH men undergoing long-term pulsatile GnRH treatment over 30 yr.
  
  
  METHODS
  We conducted a retrospective study of response to GnRH at a Clinical Research Center.
  
  
  METHODS
  Physiological regimens of pulsatile s.c. GnRH were administered for at least 12 months. Dose-response studies using i.v. GnRH pulses assessed the pituitary LH response.
  
  
  METHODS
  We measured serum T, LH, FSH, and inhibin B levels, sperm in ejaculate, and determined the sequence of IHH-associated genes.
  
  
  RESULTS
  Twenty-six percent of subjects displayed atypical responses to GnRH: 1) 10 remained hypogonadotropic and hypogonadal, demonstrating pituitary and testicular defects; 2) eight achieved spermatogenesis and normal T but only with hypergonadotropism, indicating impaired testicular responsiveness to gonadotropins; and 3) five remained azoospermic despite achieving adult testicular volumes and normal hormonal profiles, suggesting primary defects in spermatogenesis. Mutations were identified only in KAL1 across groups.
  
  
  CONCLUSIONS
  In addition to hypothalamic GnRH deficiency, IHH men can have primary pituitary and/or testicular defects, which are unmasked by GnRH replacement.
authors.affiliation: Harvard Reproductive Endocrine Sciences Center and the Reproductive Endocrine Unit of the Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Gerasimos P
authors.initials: GP
authors.lastname: Sykiotis
authors.forename: Xuan-Huong
authors.initials: XH
authors.lastname: Hoang
authors.forename: Magdalena
authors.initials: M
authors.lastname: Avbelj
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Hayes
authors.forename: Apisadaporn
authors.initials: A
authors.lastname: Thambundit
authors.forename: Andrew
authors.initials: A
authors.lastname: Dwyer
authors.forename: Margaret
authors.initials: M
authors.lastname: Au
authors.forename: Lacey
authors.initials: L
authors.lastname: Plummer
authors.forename: William F
authors.initials: WF
authors.lastname: Crowley
authors.forename: Nelly
authors.initials: N
authors.lastname: Pitteloud
mesh_terms: D000328:Adult; D053713:Azoospermia / Q000235:genetics; D004247:DNA / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000235:genetics; D012739:Gonadal Steroid Hormones / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000627:therapeutic use; D006062:Gonadotropins / Q000172:deficiency* / Q000235:genetics; D020249:Hormone Replacement Therapy; D006801:Humans; D007006:Hypogonadism / Q000151:congenital* / Q000235:genetics / Q000473:pathology*; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology; D007031:Hypothalamus / Q000473:pathology*; D017436:Kallmann Syndrome / Q000150:complications / Q000235:genetics; D008297:Male; D009154:Mutation / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics; D010902:Pituitary Gland / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013076:Sperm Count; D013091:Spermatogenesis / Q000187:drug effects; D013737:Testis / Q000473:pathology*
chemical_list: C076266:ANOS1 protein, human; D016326:Extracellular Matrix Proteins; D012739:Gonadal Steroid Hormones; D006062:Gonadotropins; D009419:Nerve Tissue Proteins; D007987:Gonadotropin-Releasing Hormone; D004247:DNA
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