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Unequal Impact of Short-Term Testosterone Repletion on the Somatotropic Axis of Young and Older Men

Department of Internal Medicine (J.C.), General Clinical Research Center, Virginia Commonwealth University, Medical College of Virginia, Geriatrics and Extended Care Service Line, Richmond, Virginia 23298; Geriatrics and Extended Care Service (A.G., T.M., M.G.), McGuire Veterans Affairs Medical Center, Richmond, Virginia 23249; Division of Endocrinology (J.P., J.D.V.), Department of Internal Medicine, General Clinical Research Center, Center for Biomathematical Technology, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202; and Endocrine Section (A.I.), Medical Service, Salem Veterans Affairs Medical Center, Salem, Virginia 24153

Address all correspondence and requests for reprints to: J. D. Veldhuis, M.D., Division of Endocrinology, Department of Internal Medicine, P.O. Box 800202, University of Virginia School of Medicine, Charlottesville, Virginia 22908-0202. E-mail: jdv{at}virginia.edu

Abstract

The present clinical study compares the impact of low- and high-dose parenteral testosterone (T) supplementation on daily GH secretory patterns and serum IGF-I, IGFBP-1, and IGFBP-3 concentrations in healthy older (60–82 yr) and young (20–40 yr) men. To this end, we administered three consecutive weekly injections of randomly ordered saline and either a low (100 mg) or a high (200 mg) dose of testosterone enanthate im; namely, saline (n = 17, young and n = 16, older), a low dose (n = 8 young, n = 8 older) and a high dose (n = 9 young, and n = 8 older) of androgen. To monitor somatotropic-axis responses, blood was sampled every 10 min for 24 h for later chemiluminescence-based assay of serum GH, RIA of serum IGF-I, and immunoradiometric assay of serum IGFBP-1 and IGFBP-3 concentrations. Data were analyzed via a nested analysis of covariance statistical design. At baseline (saline injection), older, compared with young, men maintained: 1) similar serum total T, IGFBP-1, and IGFBP-3 but reduced IGF-I concentrations, namely, mean (±SEM) IGF-I 160 plus or minus 15 vs. 280 plus or minus 18 µg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 ± 0.09 vs. 1.2 ± 0.20 µg/liter, P = 0.031); 3) more disorderly GH release patterns (approximate entropy 0.501 ± 0.058 vs. 0.288 ± 0.021, P < 0.001); and 4) blunted 24-h rhythmic GH output (nyctohemeral amplitude 0.25 ± 0.05 vs. 0.47 ± 0.08 µg/liter, P = 0.025). Serum T concentrations (ng/dl) did not differ in the two age groups supplemented with either a low dose [550 ± 50 (young) and 544 ± 128 (older)] and high [1320 ± 92 (young) and 1570 ± 140 (older)] dose of T. The 100-mg dose of androgen exerted no detectable effect on GH secretion in either age cohort but increased the serum IGF-I concentration in young men by 20% (P = 0.00098). The 200-mg dose of T failed to alter daily GH production in young volunteers but in older men stimulated: 1) a 2.03-fold rise in the mean (24-h) serum GH concentration (P = 0.0053, compared with the response to saline); 2) a 1.20-fold increase in basal (nonpulsatile) GH production (P = 0.039); 3) a 2.15-fold amplification of GH secretory burst mass (P = 0.0020); 4) a 2.17-fold elevation of the Mesor of nyctohemeral GH output (P = 0.025); 5) a 1.79-fold enhancement in GH approximate entropy (P = 0.0003); and 6) a 40% increase in the fasting serum IGF-I concentration (P = 0.000005). Multivariate statistical analysis indicated that following high-dose T administration, the E2 increment significantly predicted the IGF-I increment in both age groups combined (P = 0.003); T dose positively forecast the serum total IGF-I concentration (P = 0.0031); and age and T dose jointly determined serum LH concentrations (P = 0.031). In summary, neither a physiological nor a pharmacological dose of T administered parenterally for 3 wk augments daily GH secretion in eugonadal young men. In contrast, a high dose of aromatizable androgen significantly amplifies 24-h basal, pulsatile, entropic, and nyctohemerally rhythmic GH production and elevates the serum IGF-I concentration in older men. The mechanistic basis for the foregoing age-related distinction in GH/IGF-I axis responsivity to T is not known.

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