Prominent age-dependent changes occur in the neuroendocrine control of GH secretion in the human and experimental animals. In some studies, the age-associated decline in pulsatile GH release is correlated best with serum total or free estradiol levels. Thus, there is a major fall-off in GH secretion in the postmenopausal estrogen-deficient state. However, the exact neuroendocrine regulatory mechanisms that drive such clarion estrogen-dependence are not known, but can now be investigated with persuasive clinical neuroendocrine tools. Given the preeminent importance of estrogen withdrawal in postmenopausal hyposomatotropism, our proposed studies will focus on the mechanisms by which postmenopausal estrogen replacement augments pulsatile GH release. In particular, we postulate that one or more of three plausible and testable neuroendocrine mechanisms underlie the strong estrogen-dependent regulation of the human GH axis as exemplified in aging postmenopausal women with or without estrogen-replacement therapy: 1. Estrogen replacement therapy influences GH metabolic clearance, distribution volume, and/or half-life in postmenopausal women. 2. Specific neuroendocrine mechanisms mediated via GH-releasing hormone (GHRH) and/or somatostatin direct pulsatile GH secretion differentially in estrogen-replete versus estrogen-impoverished postmenopausal women: (a) Estrogen sensitizes the GHRH dose-GH secretory response of the pituitary gland. (b)Somatostatin's potency or efficacy in inhibiting GH secretion is attenuated by estrogen. (c) Estrogen enhances L-arginine and GHRH synergism. (d) Estrogen reduces somatostatin release. (e) Estrogen amplifies GHRH's facilitation of post-somatostatin-rebound release of GH. 3. Estrogen replacement in postmenopausal women curtails inhibitory auto- feedback of the hypothalamo-pituitary GH unit otherwise exerted by IGF-I and/or GH. Novel insights into the specific neuroendocrine mechanisms of estrogen action will help explicate the critical physiological coupling between the sex-steroid and GH axes in estrogen-replaced and estrogen-withdrawn postmenopausal women. Such knowledge has significant clinical implications to rational estrogen-replacement strategies in older women with estrogen-deficiency states and physical frailty accompanied by relative hyposomatotropism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014799-02
Application #
2667639
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1997-03-01
Project End
2001-02-28
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Weltman, Arthur; Weltman, Judy Y; Roy, Cathy Pritzlaff et al. (2006) Growth hormone response to graded exercise intensities is attenuated and the gender difference abolished in older adults. J Appl Physiol 100:1623-9
Veldhuis, Johannes D; Keenan, Daniel M; Iranmanesh, Ali et al. (2006) Estradiol potentiates ghrelin-stimulated pulsatile growth hormone secretion in postmenopausal women. J Clin Endocrinol Metab 91:3559-65
Veldhuis, Johannes D; Iranmanesh, Ali; Mielke, Kristi et al. (2006) Ghrelin potentiates growth hormone secretion driven by putative somatostatin withdrawal and resists inhibition by human corticotropin-releasing hormone. J Clin Endocrinol Metab 91:2441-6
Soares-Welch, Cacia; Mielke, Kristi L; Bowers, Cyril Y et al. (2005) Short-term testosterone supplementation does not activate GH and IGF-I production in postmenopausal women. Clin Endocrinol (Oxf) 63:32-8
Veldhuis, Johannes D; Patrie, James M; Frick, Kirsten et al. (2005) Administration of recombinant human GHRH-1,44-amide for 3 months reduces abdominal visceral fat mass and increases physical performance measures in postmenopausal women. Eur J Endocrinol 153:669-77
Farhy, Leon S; Veldhuis, Johannes D (2005) Deterministic construct of amplifying actions of ghrelin on pulsatile growth hormone secretion. Am J Physiol Regul Integr Comp Physiol 288:R1649-63
Veldhuis, Johannes D; Erickson, Dana; Iranmanesh, Ali et al. (2005) Sex-steroid control of the aging somatotropic axis. Endocrinol Metab Clin North Am 34:877-93, viii
Liu, Peter Y; Hoey, Kelley A; Mielke, Kristi L et al. (2005) A randomized placebo-controlled trial of short-term graded transdermal estradiol in healthy gonadotropin-releasing hormone agonist-suppressed pre- and postmenopausal women: effects on serum markers of bone turnover, insulin-like growth factor-I, and osteo J Clin Endocrinol Metab 90:1953-60
Veldhuis, Johannes D; Erickson, Dana; Mielke, Kristi et al. (2005) Distinctive inhibitory mechanisms of age and relative visceral adiposity on growth hormone secretion in pre- and postmenopausal women studied under a hypogonadal clamp. J Clin Endocrinol Metab 90:6006-13
Keenan, Daniel M; Chattopadhyay, Somesh; Veldhuis, Johannes D (2005) Composite model of time-varying appearance and disappearance of neurohormone pulse signals in blood. J Theor Biol 236:242-55

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