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.
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.
|Roelfsema, Ferdinand; Veldhuis, Johannes D (2016) Growth Hormone Dynamics in Healthy Adults Are Related to Age and Sex and Strongly Dependent on Body Mass Index. Neuroendocrinology 103:335-44|
|Keenan, Daniel M; Veldhuis, Johannes D (2016) Pulsatility of Hypothalamo-Pituitary Hormones: A Challenge in Quantification. Physiology (Bethesda) 31:34-50|
|Veldhuis, Johannes; Yang, Rebecca; Roelfsema, Ferdinand et al. (2016) Proinflammatory Cytokine Infusion Attenuates LH's Feedforward on Testosterone Secretion: Modulation by Age. J Clin Endocrinol Metab 101:539-49|
|Veldhuis, Johannes D; Olson, Thomas P; Takahashi, Paul Y et al. (2015) Multipathway modulation of exercise and glucose stress effects upon GH secretion in healthy men. Metabolism 64:1022-30|
|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; 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|
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