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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Aging Systems and Geriatrics Study Section (ASG)
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Dutta, Chhanda
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Mayo Clinic, Rochester
United States
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Roelfsema, Ferdinand; Yang, Rebecca J; Takahashi, Paul Y et al. (2018) Aromatized Estrogens Amplify Nocturnal Growth Hormone Secretion in Testosterone-Replaced Older Hypogonadal Men. J Clin Endocrinol Metab 103:4419-4427
Roelfsema, Ferdinand; Yang, Rebecca J; Veldhuis, Johannes D (2018) Differential Effects of Estradiol and Progesterone on Cardiovascular Risk Factors in Postmenopausal Women. J Endocr Soc 2:794-805
Roelfsema, Ferdinand; Yang, Rebecca J; Takahashi, Paul Y et al. (2018) Effects of Toremifene, a Selective Estrogen Receptor Modulator, on Spontaneous and Stimulated GH Secretion, IGF-I, and IGF-Binding Proteins in Healthy Elderly Subjects. J Endocr Soc 2:154-165
Roelfsema, Ferdinand; Yang, Rebecca J; Veldhuis, Johannes D (2018) Estradiol Does Not Influence Lipid Measures and Inflammatory Markers in Testosterone-Clamped Healthy Men. J Endocr Soc 2:882-892
Roelfsema, Ferdinand; van Heemst, Diana; Iranmanesh, Ali et al. (2017) Impact of age, sex and body mass index on cortisol secretion in 143 healthy adults. Endocr Connect 6:500-509
Roelfsema, Ferdinand; Yang, Rebecca J; Olson, Thomas P et al. (2017) Enhanced Coupling Within Gonadotropic and Adrenocorticotropic Axes by Moderate Exercise in Healthy Men. J Clin Endocrinol Metab 102:2482-2490
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
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 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

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