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This version published online on October 19, 2004
Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-1313
A more recent version of this article appeared on January 1, 2005
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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*DEXAMETHASONE
*ESTRADIOL
*TESTOSTERONE

Submitted on July 7, 2004
Accepted on October 11, 2004

AGE AND TESTOSTERONE FEEDBACK JOINTLY CONTROL THE DOSE-DEPENDENT ACTIONS OF GONADOTROPIN-RELEASING HORMONE IN HEALTHY MEN

J. D. Veldhuis*, A. Iranmanesh, and T. Mulligan

Endocrinology Section, Medical Service, Research and Development Office, Veterans Affairs Medical Center, Salem, Virginia 24153; Geriatrics and Extended Care Service Line, Hunter Holmes McGuire VA Medical Center, Richmond, Virginia 23249

* To whom correspondence should be addressed.
J. D. Veldhuis, E-mail: Veldhuis.Johannes{at}mayo.edu

Healthy older men manifest combined declines in testosterone concentrations, LH secretory-burst mass (amount of LH released per pulse), and feedback-sensitive regularity of unknown cause. To test a unifying hypothesis of simultaneous reductions in GnRH outflow, gonadotrope responsiveness to GnRH and androgenic negative feedback, we monitored LH secretion: (a) after bolus iv injection of a 1000-fold range of randomly ordered individual doses of GnRH on separate mornings; (b) during unmodified (eugonadal) or testosterone-withdrawn (hypoandrogenemic) negative feedback; and (c) in 16 young (ages 18-35 y) and 15 older (ages 60-85 y) healthy men. LH secretory-burst mass and pattern regularity were quantitated by intensive blood sampling, high-specificity LH {beta} subunit-directed immunoradiometric assay, deconvolution analysis, and approximate entropy. GnRH dose-responsiveness was assessed by 4-parameter nonlinear regression analysis. Thereby, we demonstrate that older men exhibit: (a) delayed attainment of GnRH-evoked maximal LH secretion; (b) enhanced potency of GnRH stimulation in both the feedback-intact and feedback-withdrawn states; (c) elevated gonadotrope sensitivity to GnRH, unmasked by experimental testosterone depletion; (d) comparable young adult-like GnRH efficacy, independently of testosterone-feedback milieu; and (e) diminished regularity of GnRH-induced LH release evident only during unmodified androgenic feedback. We conclude that: (i) a 3-fold interaction among GnRH dose, testosterone concentration and age governs GnRH action; and (ii) age determines both testosterone-modulated and testosterone-independent actions GnRH.
Key words: androgen • lutropin • aging • male • GnRH • inhibition




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