Unequal impact of short-term testosterone repletion on the somatotropic axis of young and older men.
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 microg/liter, (P < 0.001); 2) reduced GH secretory burst mass (0.68 +/- 0.09 vs. 1.2 +/- 0.20 microg/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 microg/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.
Gentili
A
A
Department of Internal Medicine, General Clinical Research Center, Virginia Commonwealth University, Medical College of Virginia, Geriatrics and Extended Care Service Line, Richmond, Virginia 23298, USA.
Mulligan
T
T
Godschalk
M
M
Clore
J
J
Patrie
J
J
Iranmanesh
A
A
Veldhuis
J D
JD
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D012739:Gonadal Steroid Hormones / Q000008:administration & dosage / Q000494:pharmacology*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013739:Testosterone / Q000008:administration & dosage / Q000494:pharmacology*; D013997:Time Factors
D012739:Gonadal Steroid Hormones; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D019382:Human Growth Hormone; D013739:Testosterone; D007334:Insulin-Like Growth Factor I