Recent patient-oriented investigations establish that progressive hyposomatotropism and hypogonadism consistently accompany healthy aging. The daily secretion of GH and the output of testosterone wane concomitantly in older men, such that by the sixth through eighth decades of life the bioavailability of these hormones is reduced by approximately 50%. The ensuant so-called somatopause and gonadopause encompass an ensemble of signs and symptoms associated with the overall frailty of aging;e.g.. limited physical performance and stamina, reduced muscle mass and strength, loss of bone mineral content, increased visceral adiposity, relative dyslipidemia, declining libido and potentia, and variably impaired cognition, sense of well being and quality of life. Based on new and compelling preliminary neuroendocrine data (see Bkgd), here we explore the specific regulatory thesis that the pathophysiological mechanisms that drive the concomitant somatopause and gonadopause are linked causally in the aging male. In particular, we postulate that: I. Short-term restoration of young-adult GH availability by pulsatile i.v. infusions of rh GH will mitigate the age-related decline in LH-driven Leydig-cell testosterone secretion;and, conversely, II. Short-term supplementation with testosterone in older men amplifies GH secretion by way of specific neuroregulatory actions, which explicate its unique twofold stimulation of simultaneous GH and IGF-I production (unlike estrogen action in postmenopausal women);viz..: (i) muting of GH's autonegative feedback restraint; (ii) enhancement of GHRH feedforward drive; (iii) relief of somatostatinergic inhibition of GH secretion;and/or (iv) facilitation of the endogenous GHRP (GH-releasing peptide)-ligand pathway. The foregoing pivotal clinical postulates will be tested via the combination of a novel interventional strategy (Aim I) and complementary neuroregulatory experiments (Aim II). The outcomes of these clinical mechanistic investigations should clarify further the nature of the pathophysiology subserving joint failure of the somatotropic and gonadal axes in aging men, and thereby begin to illuminate potential targets for preventive strategies designed to limit bihormonal failure and aging-associated frailty in the human.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG019695-10
Application #
8039950
Study Section
Special Emphasis Panel (NSS)
Program Officer
Sherman, Sherry
Project Start
2001-09-15
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
10
Fiscal Year
2011
Total Cost
$302,643
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Veldhuis, Johannes D; Bondar, Olga P; Dyer, Roy B et al. (2014) Immunological and mass spectrometric assays of SHBG: consistent and inconsistent metabolic associations in healthy men. J Clin Endocrinol Metab 99:184-93
Veldhuis, Johannes D (2013) Changes in pituitary function with ageing and implications for patient care. Nat Rev Endocrinol 9:205-15
Norman, Catalina; Miles, John; Bowers, Cyril Y et al. (2013) Differential pulsatile secretagogue control of GH secretion in healthy men. Am J Physiol Regul Integr Comp Physiol 304:R712-9
Veldhuis, Johannes D; Norman, Catalina; Miles, John M et al. (2012) Sex steroids, GHRH, somatostatin, IGF-I, and IGFBP-1 modulate ghrelin's dose-dependent drive of pulsatile GH secretion in healthy older men. J Clin Endocrinol Metab 97:4753-60
Iranmanesh, Ali; Lawson, Donna; Veldhuis, Johannes D (2012) Distinct metabolic surrogates predict basal and rebound GH secretion after glucose ingestion in men. J Clin Endocrinol Metab 97:2172-9
Keenan, Daniel M; Wang, Xin; Pincus, Steven M et al. (2012) Modeling the Nonlinear Time Dynamics of Multidimensional Hormonal Systems. J Time Ser Anal 33:779-796
Veldhuis, Johannes D; Keenan, Daniel M (2012) Model-based evaluation of growth hormone secretion. Methods Enzymol 514:231-48
Veldhuis, Johannes D; Erickson, Dana; Wigham, Jean et al. (2011) Gender, sex-steroid, and secretagogue-selective recovery from growth hormone-induced feedback in older women and men. J Clin Endocrinol Metab 96:2540-7
Veldhuis, Johannes D; Roelfsema, Ferdinand; Keenan, Daniel M et al. (2011) Gender, age, body mass index, and IGF-I individually and jointly determine distinct GH dynamics: analyses in one hundred healthy adults. J Clin Endocrinol Metab 96:115-21
Veldhuis, Johannes D; Bowers, Cyril Y (2011) Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation. Am J Physiol Regul Integr Comp Physiol 301:R1143-52

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