title: Two-week pulsatile gonadotropin releasing hormone infusion unmasks dual (hypothalamic and Leydig cell) defects in the healthy aging male gonadotropic axis.
abstract: OBJECTIVE
  To examine the possibility that lower serum bioavailable testosterone concentrations, without increased LH release, in healthy older men, reflects hypothalamic GnRH deficiency.
  
  
  METHODS
  We used a randomized, double-blind, placebo-controlled design.
  
  
  METHODS
  We treated each of five young (ages 20-34 years) and five older (ages 60-78 years) men with 2 weeks of randomized infusions of saline or pulsatile GnRH (100 ng/kg i.v. every 90 min).
  
  
  RESULTS
  At baseline (saline infusion), older men had more LH pulses (young compared with old, 10 +/- 0.6 compared with 15 +/- 1, P = 0.0026) per 24h, reduced fractional LH pulse amplitude (219 +/- 17% compared with 167 +/- 40%, P = 0.0376), and more disorderly hormone release as judged by approximate entropy (ApEn) (LH, P < or = 0.0001; testosterone, P < or = 0.0047). In response to pulsatile i.v. GnRH infusions, serum 24-h LH concentrations (measured by immunoradiometric assay (IRMA)), increased equivalently in young and older men (to 7.3 +/- 1.2 and 7.2 +/- 1.8 IU/l respectively). GnRH treatment also normalized LH pulse frequency and amplitude, ApEn, and plasma biologically active LH (pooled) concentrations. In contrast, 24-h testosterone concentrations failed to increase equivalently in older men (young compared with old, 869 +/- 88 compared with 517 +/- 38 ng/dl, P = 0.0061), reflecting lower testosterone peak maxima (995 +/- 108 compared with 583 +/- 48 ng/dl, P = 0.0083) and interpeak nadirs (750 +/- 87 compared with 427 +/- 26 ng/dl, P = 0.0073).
  
  
  CONCLUSIONS
  We have demonstrated that, in older men, successful reconstitution of 24-h pituitary (bioactive) LH output and pulsatile (IRMA) LH release patterns could be achieved by a fixed exogenous GnRH pulse signal, thereby implicating altered endogenous hypothalamic GnRH release in the relative hypogonadotropism of aging. The failure of testosterone concentrations to increase concomitantly points to a simultaneous Leydig cell defect. We conclude that aging in men is marked by a dual defect in the central nervous system-pituitary-Leydig cell axis.
authors.affiliation: McGuire VA Medical Center, Richmond, Virginia, USA. Mulligan.Thomas_M@Richmond.VA.GOV
authors.forename: T
authors.initials: T
authors.lastname: Mulligan
authors.forename: A
authors.initials: A
authors.lastname: Iranmanesh
authors.forename: R
authors.initials: R
authors.lastname: Kerzner
authors.forename: L W
authors.initials: LW
authors.lastname: Demers
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D018592:Cross-Over Studies; D003687:Dehydroepiandrosterone / Q000097:blood; D004311:Double-Blind Method; D005640:Follicle Stimulating Hormone / Q000097:blood; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D007031:Hypothalamus / Q000378:metabolism* / Q000503:physiopathology; D007260:Infusion Pumps; D007262:Infusions, Intravenous; D007265:Inhibins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D007985:Leydig Cells / Q000378:metabolism*; D007986:Luteinizing Hormone / Q000097:blood / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000503:physiopathology; D011388:Prolactin / Q000097:blood; D013739:Testosterone / Q000097:blood / Q000378:metabolism
chemical_list: D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D003687:Dehydroepiandrosterone; D007265:Inhibins; D007334:Insulin-Like Growth Factor I; D011388:Prolactin; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone