Age disrupts androgen receptor-modulated negative feedback in the gonadal axis in healthy men

Johannes D. Veldhuis, Paul Y. Takahashi, Daniel M. Keenan, Peter Y. Liu, Kristi L. Mielke, Suanne M. Weist

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Testosterone (T) exerts negative feedback on the hypothalamo-pituitary (GnRH-LH) unit, but the relative roles of the CNS and pituitary are not established. We postulated that relatively greater LH responses to flutamide (brainpermeant antiandrogen) than bicalutamide (brain-impermeant antiandrogen) should reflect greater feedback via CNS than pituitary/ peripheral androgen receptor-dependent pathways. To this end, 24 healthy men ages 20-73 yr, BMI 21-32 kg/m2, participated in a prospective, placebo-controlled, randomized, double-blind crossover study of the effects of antiandrogen control of pulsatile, basal, and entropic (pattern regularity) measurements of LH secretion. Analysis of covariance revealed that flutamide but not bicalutamide 1) increased pulsatile LH secretion (P = 0.003), 2) potentiated the agerelated abbreviation of LH secretory bursts (P = 0.025), 3) suppressed incremental GnRH-induced LH release (P = 0.015), and 4) decreased the regularity of GnRH-stimulated LH release (P = 0.012). Furthermore, the effect of flutamide exceeded that of bicalutamide in 1) raising mean LH (P = 0.002) and T (P = 0.017) concentrations, 2) accelerating LH pulse frequency (P = 0.013), 3) amplifying total (basal plus pulsatile) LH (P = 0.002) and T (P < 0.001) secretion, 4) shortening LH secretory bursts (P = 0.032), and 5) reducing LH secretory regularity (P < 0.001). Both flutamide and bicalutamide elevated basal (nonpulsatile) LH secretion (P < 0.001). These data suggest the hypothesis that topographically selective androgen receptor pathways mediate brain-predominant and pituitary-dependent feedback mechanisms in healthy men.

Original languageEnglish (US)
Pages (from-to)E675-E682
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Issue number4
StatePublished - Oct 2010


  • Approximate entropy
  • Human
  • Leuteinizing hormone
  • Pulsatile
  • Secretion
  • Testosterone

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)


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