title: Disruption of the hypothalamic luteinizing hormone pulsing mechanism in aging men.
abstract: The incremental nature of neuroendocrine aging suggests that subtle system dysregulation may precede overt axis failure. The present analyses unmask threefold disruption of pulsatile gonadotropin-releasing hormone (GnRH)-luteinizing hormone (LH) secretion in the aging male. First, by way of random effects-based deconvolution analysis, we document an elevated daily GnRH-LH pulse frequency in healthy older men [namely, mean (+/-SE) 23 +/- 1 (older) vs. 15 +/- 1 (young) LH secretory bursts/24 h, P < 0.001] and lower mean LH pulse mass [3.73 +/- 0.58 (older) vs. 5.46 +/- 0.66 (young) IU/l, P = 0.038]. However, total LH secretion rates and two-compartment LH elimination kinetics were comparable in the two age cohorts. Second, using the approximate entropy statistic, we show an equivalently random order-dependent succession of LH interpulse-interval lengths in young and older men, but a marked age-related deterioration of the ad seriatim regularity of LH pulse mass series in older individuals (P = 0.0057). Third, by modeling GnRH pulse-generator output as a Weibull renewal process (generalized Gamma density) to emulate loosely coupled GnRH neuronal oscillators, we identify an age-related reduction in the frequency-independent and order-independent variability of GnRH-LH interpulse-interval sets (P = 0.08). These findings indicate that the GnRH-LH pulsing mechanism in healthy older men maintains an increased mean frequency and lower amplitude of bursting activity, a reduced uniformity of serial LH pulse-mass values, and an impaired variability among interpulse-interval lengths. Thereby, the foregoing order-dependent and order-independent alterations in GnRH-LH signal generation in the aging human suggest a general framework for exploring subtle disruption of time-sensitive regulation of other neurointegrative systems.
authors.affiliation: Department of Statistics, University of Virginia, Charlottesville, VA 22903, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Keenan
authors.forename: J D
authors.initials: JD
authors.lastname: Veldhuis
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D019277:Entropy; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism; D006801:Humans; D007031:Hypothalamus / Q000254:growth & development*; D007700:Kinetics; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007987:Gonadotropin-Releasing Hormone; D007986:Luteinizing Hormone