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Testosterone Supplementation in Older Men Restrains Insulin-Like Growth Factor’s Dose-Dependent Feedback Inhibition of Pulsatile Growth Hormone Secretion

Departments of Medicine (J.D.V., J.N.B., A.A., J.M.M., M.C., C.S.W.) and Pediatrics (R.P.), Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905; and Department of Statistics (D.M.K.), University of Virginia, Charlottesville, Virginia 22904

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Background: Pulsatile GH secretion declines in older men. The causal mechanisms are unknown. Candidates include deficient feedforward (stimulation) by endogenous secretagogues and excessive feedback (inhibition) by GH or IGF-I due to age and/or relative hypoandrogenemia.

Hypothesis: Testosterone (T) supplementation in healthy older men will restrain negative feedback by systemic concentrations of IGF-I.

Subjects: Twenty-four healthy men (ages, 50 to 75 yr; body mass index, 24 to 30 kg/m²) participated in the study.

Methods: We performed a prospectively randomized, double-blind, placebo-controlled assessment of the impact of pharmacological T supplementation on GH responses to randomly ordered separate-day injections of recombinant human IGF-I doses of 0, 1.0, 1.5, and 2.0 mg/m².

Analysis: Deconvolution and approximate entropy analyses of pulsatile, basal, and entropic (pattern-sensitive) modes of GH secretion were conducted.

Results: Recombinant human IGF-I injections 1) elevated mean and peak serum IGF-I concentrations dose-dependently (both P < 0.001); 2) suppressed pulsatile GH secretion (P = 0.003), burst mass (P = 0.025), burst number (P = 0.005), interpulse variability (P = 0.032), and basal GH secretion (P = 0.009); and 3) increased secretory pattern regularity (P = 0.020). T administration did not alter experimentally controlled IGF-I concentrations, but it elevated mean GH concentrations (P = 0.015) and stimulated pulsatile GH secretion (frequency P = 0.037, mass per burst P = 0.038). Compared with placebo, T attenuated exogenous IGF-I’s inhibition of GH secretory-burst mass (P < 0.038) without restoring pulse number, basal secretion, or pattern regularity.

Conclusion: The capability of systemic T to mute IGF-I feedback on pulsatile GH secretion suggests a novel mechanism for augmenting GH production.

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