A major unresolved question in clinical endocrinology is how aging impairs the production of anabolic hormones, such as GH and IGF-I. A scientific impasse arises because existing studies are confounded by the strong interdependence between age and gonadal sex steroids, which also maintain GH production. Distinguishing the roles of these two factors is central to framing rational nonsteroidal vis-a-vis steroidal interventions to obviate age-associated loss of trophic-hormone drive. The theme is important, given that diminished GH output is associated with osteopenia, sarcopenia, impaired well being, visceral adiposity, insulin resistance, and increased cardiovascular morbidity and mortality. As a novel approach to this fundamental problem, we recently validated an investigative model of a short-term systemic estradiol (E2) clamp in healthy premenopausal and postmenopausal women that vividly separates the impact of age stratum and estrogen availability on GH secretion and attendant IGF-I production, and discriminates a 23% contribution of abdominal visceral fat mass (AVF). This framework will allow us to parse for the first time the fundamental mechanisms that mediate separate and combined effects of post- and premenopausal age and estrogenic status on GH availability. The thesis advanced is that aging and estrogen deprivation reduce GH secretion by modifying a finite ensemble of interlinked peptides: (i) GH-releasing hormone (GHRH);(ii) GH-releasing . peptide (GHRP/ghrelin);and (iii) somatostatin. The fact that all 3 signals are physiologically interlinked means that no single peptide acts alone or may be validly interpreted in isolation. Ensemble connectivity will be dissected experimentally by delivering peptidyl signals in pairs and then assessing how age and E2 availability (at comparable AVF) determine actions of the third (endogenous) effector peptide. This new stratagem will permit noninvasive quantification of distinct effects of age and E2 under the following hypotheses: Hypothesis I: Age reduces whereas E2 enhances feedforward drive of GH secretion by endogenous GHRH and endogenous ghrelin;and conversely age elevates and E2 attenuates inhibition of GH secretion by endogenous SS. Hypothesis II: Age attenuates and E2 potentiates 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. Hypothesis III: Age and E2 availability jointly modulate concentration-dependent negative feedback by free (protein-unbound) IGF-I, thus controlling mean daily GH secretion. Methodologies will include a low and physiological E2 clamp in both post- and premenopausal women;adjustments for confounding by AVF;and application of a versatile analytical formalism to reconstruct ensemble control of GH secretion. The expectation thereby is to establish the mechanistic contributions of age stratum vis-a-vis estrogen deprivation to hyposomatotropism in the postmenopausal setting. Understanding the fundamental mechanisms by which postmenopausal age, independently of E2 depletion, impairs central regulation of GH production should foster innovative approaches to forestall the decline in GH/IGF-I availability in aging women without necessarily requiring estrogen repletion. Public Precis Estrogen administration in postmenopausal women carries a finite risk and is contraindicated in some patient groups. Therefore, this proposal seeks to unravel fundamental mechanisms that control the production of the major trophic hormones GH and IGF-I, which maintain bone and muscle mass, reduce abdominal fat and enhance quality of life.

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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Sherman, Sherry
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Mayo Clinic, Rochester
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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
Veldhuis, Johannes D; Dyer, Roy B; Trushin, Sergey A et al. (2016) Interleukins 6 and 8 and abdominal fat depots are distinct correlates of lipid moieties in healthy pre- and postmenopausal women. Endocrine 54:671-680
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; Erickson, Dana; Yang, Rebecca et al. (2016) Endogenous Estrogen Regulates Somatostatin-Induced Rebound GH Secretion in Postmenopausal Women. J Clin Endocrinol Metab 101:4298-4304
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

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