Age and testosterone feedback jointly control the dose-dependent actions of gonadotropin-releasing hormone in healthy men.
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 1) after bolus iv injection of a 1000-fold range of randomly ordered individual doses of GnRH on separate mornings, 2) during unmodified (eugonadal) or testosterone-withdrawn (hypoandrogenemic) negative feedback, and 3) in 16 young (age, 18-35 yr) and 15 older (age, 60-85 yr) healthy men.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 four-parameter nonlinear regression analysis. We demonstrated that older men exhibit 1) delayed attainment of GnRH-evoked maximal LH secretion; 2) enhanced potency of GnRH stimulation in both the feedback-intact and feedback-withdrawn states; 3) elevated gonadotrope sensitivity to GnRH, unmasked by experimental testosterone depletion; 4) comparable young adult-like GnRH efficacy, independent of testosterone feedback milieu; and 5) diminished regularity of GnRH-induced LH release evident only during unmodified androgenic feedback. We conclude that a 3-fold interaction among GnRH dose, testosterone concentration, and age governs GnRH action, and age determines both testosterone-modulated and testosterone-independent actions of GnRH.
Veldhuis
Johannes D
JD
Division of Endocrinology and Metabolism, Mayo School of Graduate Medical Education, General Clinical Research Center, Mayo Clinic, Rochester, Minnesota 55905, USA. veldhuis.johannes@mayo.edu
Iranmanesh
Ali
A
Mulligan
Thomas
T
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000097:blood; D005246:Feedback; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D013739:Testosterone / Q000097:blood*
D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D003907:Dexamethasone; D007986:Luteinizing Hormone; D007654:Ketoconazole