Important metabolic and endocrine changes accompany healthy aging in men, including prominent decreases in growth hormone (GH) production and bioavailable testosterone. Reduced anabolic drive by GH and/or testosterone in aging may contribute to diminished well being, energy, strength, libido, muscle mass, and bone mass, and increased visceral fat accumulation. The resultant physical frailty, loss of independent activity status, a decline in exercise capacity, increased falls and fractures, and institutionalization can seriously impair quality of life. Recent limited studies of either GH or testosterone supplementation alone indicate that important anabolic actions can be elicited in healthy older men. However, androgen administration may cause polycythemia, diminished HDL concentrations, worsening of sleep apnea, and prostate growth, etc., whereas GH treatment can result in edema, a rise in blood pressure, arthralgias, carpal tunnel syndrome, gynecomastia, and glucose intolerance. Most notably, virtually no human dose-response data exist in older individuals for either GH or testosterone action alone. Based on the physiological anabolism of puberty, we propose that lower doses of testosterone and GH combined can elicit synergistic anabolic responses in clinically relevant target tissues such as bone, muscle, and the CNS, with fewer side effects due to down-scaled doses. We will test this thesis via a short-term (1- month) pilot GH dose-response study randomized with versus without a 2- dose targeted testosterone replacement strategy in healthy older men selected for relative androgen and GH deficiency. We predict that a low- intermediate dose of testosterone replacement combined with submaximal amounts,of GH (approaching the prepubertal daily GH production rate) will increase plasma IGF-I, BP-3, and bioavailable testosterone concentrations, stimulate skeletal remodeling, augment muscle IGF-I peptide and receptor mRNA expression while reducing muscle IGF-binding protein levels, improve strength, enhance libido and general well being, and elicit little adverse impact on serum HDL, hematocrit, and fasting insulin/glucose ratios or HbA(1c). Testing the foregoing GH-testosterone interactive hypothesis will help define the relevance of a 2 or 3 year trial combining lower-dose androgen and GH replacement in relatively GH- and/or androgen-deficient elderly individuals with or without frailty, fractures, reduced quality of life, and limited activity status.
| Brill, Kimberly T; Weltman, Arthur L; Gentili, Angela et al. (2002) Single and combined effects of growth hormone and testosterone administration on measures of body composition, physical performance, mood, sexual function, bone turnover, and muscle gene expression in healthy older men. J Clin Endocrinol Metab 87:5649-57 |
| Mulligan, T; Jaen-Vinuales, A; Godschalk, M et al. (1999) Synthetic somatostatin analog (octreotide) suppresses daytime growth hormone secretion equivalently in young and older men: preserved pituitary responsiveness to somatostatin's inhibition in aging. J Am Geriatr Soc 47:1422-4 |
| Wang, C; Iranmanesh, A; Berman, N et al. (1998) Comparative pharmacokinetics of three doses of percutaneous dihydrotestosterone gel in healthy elderly men--a clinical research center study. J Clin Endocrinol Metab 83:2749-57 |
| Giustina, A; Veldhuis, J D (1998) Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev 19:717-97 |
