Aging depletes the primary trophic hormones, growth hormone (GH), insulin-like growth factor type I (IGF-I) and testosterone (Te). Inferred sequelae include diminished anabolic drive to muscle, bone, brain and sexual organs, and accentuated visceral adiposity, insulin resistance, dyslipidemia and cardiovascular risk. A major unmet need is to understand the fundamental mechanisms that enforce GH/IGF-I deprivation in older individuals with aging-related relative Te deficiency. Compelling data obtained during the initial tenure of the MERIT award frame the thesis that aging and Te-derived estradiol (E2) availability governs an ensemble of interlinked peptides that direct GH secretion. The minimal ensemble comprises GH-releasing hormone (GHRH), somatostatin (SS), GH-releasing peptide (ghrelin, GHRP), and GH and IGF-I. From this vantage, we pose the following mechanistic hypotheses: Hypothesis I. In older men, repletion of E2 will stimulate pulsatile GH secretion by 3 mechanisms: (i)/(ii) enhancing feedforward drive of GH secretion by endogenous GHRH and endogenous ghrelin, and (iii) attenuating inhibition of GH secretion by endogenous somatostatin (SS). Hypothesis II. In older men, supplemental E2 will potentiate the putative capabilities of ghrelin to: (i) amplify GH secretion driven by pulsatile GHRH stimulation;and (ii) augment rebound-like GH secretion evoked by intermittent SS inhibition. Because no single peptide signal controls GH output, unique analytical tools and experimental strategies will be applied to aid interpretation. The expectation is to clarify how E2 deficiency in older individuals, including those receiving androgen-withdrawal therapies for urological neoplasms, exacerbates aging-associated GH and IGF-I depletion. The outcomes should provide a fundamental rational basis for constructing novel interventions to forestall frailty-related disability, morbidity and mortality in older men.

Public Health Relevance

Estrogen in men, as in women, determines bone strength. We test here the new idea that estrogen also is the major regulator of growth hormone secretion in aging men.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG019695-11
Application #
8183294
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Sherman, Sherry
Project Start
2001-09-15
Project End
2017-01-31
Budget Start
2012-04-01
Budget End
2013-01-31
Support Year
11
Fiscal Year
2012
Total Cost
$391,035
Indirect Cost
$138,514
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
Roelfsema, Ferdinand; Pereira, Alberto M; Biermasz, Nienke R et al. (2014) Hormone secretion by pituitary adenomas is characterized by increased disorderliness and spikiness but more regular pulsing. J Clin Endocrinol Metab 99:3836-44
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; 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
Veldhuis, Johannes D; Erickson, Dana; Miles, John M et al. (2011) Complex regulation of GH autofeedback under dual-peptide drive: studies under a pharmacological GH and sex steroid clamp. Am J Physiol Endocrinol Metab 300:E1158-65
Veldhuis, Johannes D; Keenan, Daniel M; Pincus, Steven M (2010) Regulation of complex pulsatile and rhythmic neuroendocrine systems: the male gonadal axis as a prototype. Prog Brain Res 181:79-110
Keenan, Daniel M; Roelfsema, Ferdinand; Veldhuis, Johannes D (2010) Dose-response downregulation within the span of single interpulse intervals. Am J Physiol Regul Integr Comp Physiol 299:R11-8

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