Age-dependent regression analysis of male gonadal axis

Daniel M. Keenan, Johannes D. Veldhuis

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


The mechanisms by which aging progressively depletes testosterone (Te) availability in the male are unknown. Accordingly, the objective was to estimate brain gonadotropin-releasing hormone (GnRH) outflow (release and action), which cannot be observed directly, on the basis of downstream effects on pituitary luteinizing hormone (LH) secretion. LH, in turn, feeds forward on (stimulates) gonadal Te secretion, which then feeds back on (inhibits) GnRH-driven LH secretion. LH and Te concentrations were measured repetitively (every 10 min) over 18 h during graded pharmacological blockade of endogenous GnRH outflow in 24 healthy 20- to 72-yr-old men. Data were analyzed using a new age-dependent regression model of GnRH-LH-Te interactions to estimate pulsatile LH secretion and elimination, GnRH outflow, LH feedforward, and Te feedback. By incorporating regression on age within the dose-response model, we show that aging erodes all three primary forward and reverse pathways linking the brain, pituitary gland, and testes. Aging is associated with concomitant deficits in GnRH → LH feedforward, LH → Te feedforward, and Te → GnRH/LH feedback. The analytical formalism should be generalizable to other ensemble regulatory systems, such as those that control growth, reproduction, stress adaptations, and glucose metabolism.

Original languageEnglish (US)
Pages (from-to)R1215-R1227
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number5
StatePublished - Nov 2009


  • Gonadotropin
  • Human
  • Men
  • Model
  • Testis
  • Testosterone

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)


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