This competitive renewal of R01 AG029362 in postmenopausal women parallels the focus of ongoing R37 AG019695 (Actions of Testosterone on the Aging Male GH Axis). In postmenopausal women, sentinel questions are the roles of residual endogenous ovarian and adrenal-derived estrogen in GH regulation, and the hypothalamo-pituitary mechanisms by which estradiol (E2) regulates GH production. The roles of endogenous E2 in GH regulation will be investigated using a unique sex-steroid clamp paradigm designed to inhibit E2 synthesis from androgen precursors, and block tissue actions of E2 via ER. The mechanisms of E2 action will be studied using novel peptide-selective clamp paradigms created to unmask interacting peptide-mediated pathways that jointly (in ensemble) regulate pulsatile GH secretion. Pulsatile GH secretion accounts for >85% of total daily GH production. Prominent species differences in E2 action make clinical investigations essential for mechanistic understanding. The increased difficulty level of clinical studies in turn requires the application of more powerful analytical technology. Accordingly, the present renewal combines all three of (1) innovative sex-steroid clamps;(2) informative peptide-specific GH-pathway clamps;and (3) compelling new analytical methods to dissect ensemble-level (multipathway) mechanisms forcing the decline of pulsatile GH secretion in postmenopausal individuals. The significance of impoverished GH secretion in aging women and men is the increased risk of intra-abdominal obesity, insulin resistance, dyslipidemia, cardiovascular mortality, sarcopenia, osteopenia and physical frailty associated with the low-GH state: Prevention or remediation of these risks is central to maintaining the health of older U.S. citizens. The goal thereby is to promote the development of new non-steroidal and non-peptidyl means to forestall age-related decrements in GH and IGF-I drive to anabolism.
Although postmenopausal age diminishes and estrogen stimulates GH secretion, the mechanisms by which age and estrogen exert their effects remain unknown. The present studies introduce new clinical paradigms and newer technologies to resolve both issues. The expectation is to foster novel ways to limit age-related frailty in women without using estrogen per se.
|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; 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|
|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; 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|
|Adams, Jessica M; Otero-Corchon, Veronica; Hammond, Geoffrey L et al. (2015) Somatostatin is essential for the sexual dimorphism of GH secretion, corticosteroid-binding globulin production, and corticosterone levels in mice. Endocrinology 156:1052-65|
|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|
|Xie, T Y; Ngo, S T; Veldhuis, J D et al. (2015) Effect of Deletion of Ghrelin-O-Acyltransferase on the Pulsatile Release of Growth Hormone in Mice. J Neuroendocrinol 27:872-86|
|Norman, Catalina; Rollene, Nanette; Weist, Suanne M et al. (2014) Short-term estradiol supplementation potentiates low-dose ghrelin action in the presence of GHRH or somatostatin in older women. J Clin Endocrinol Metab 99:E73-80|
|Veldhuis, Johannes D; Dyer, Roy B; Trushin, Sergey A et al. (2014) Immunologic and mass-spectrometric estimates of SHBG concentrations in healthy women. Metabolism 63:783-92|
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