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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG029362-08
Application #
8721808
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Dutta, Chhanda
Project Start
2006-12-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$437,192
Indirect Cost
$148,929
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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