Aging is marked by progressively reduced secretion of sex steroids (gonadopause) and GH-IGF-1 (somatopause). In the female, hyposomatotropism is especially evident in the postmenopausal estrogen-deficient state. Indeed, estrogen is a dominant positive determinant of GH secretion in both women and men at all ages. However, how estrogen drives output of the human GH axis remains largely unknown. Our clinical studies of hyposomatotropism in postmenopausal women now point to major interactions between estrogen and so-called GH-releasing peptides (GHRP's) in regulating GH production. GHRP's were identified first as potent in vitro GH-releasing (enkephalin-derived) peptides (1977-81), than as in-vivo GH secretagogues acting on structurally novel hypothalamo-pituitary receptors (1996), and most recently, by way of a native human and rat Ser-octanoylated peptidyl ligand of this endogenous effector pathway (1999). In ongoing clinical investigations, we now show that short-term estrogen replacement: (i) amplifies GHRP-2's acute secretagogue potency and efficacy; (ii) augments GHRP-2 driven 24-h entropic and rhythmic GH release; and (iii) modulates GHRP-2 stimulated IGF-1 production. In contrast, we find that estradiol supplementation does not influence the direct pituitary action of infused GHRH or somatostatin. The foregoing basic-science and clinical discoveries jointly motivate our overall thesis that estrogen and GHRP can interact as potent, multifaceted, and mechanistically complementary co-regulators of the GH-IGF-1 axis in postmenopausal women, such that: Hypothesis I: Estrogen supplementation can facilitate GHRP-receptor mediated GH secretion. Hypothesis II: Estradiol replacement can enhance GH secretion further by restricting the hypothalamic release of somatostatin. Hypothesis III: Estrogen add back can override GH's autonegative feedback restraint of GH secretion. Hypothesis IV: Estrogen repletion can amplify GH secretion independently of withdrawing IGF-1 negative feedback. Given the practicability and significance of addressing these clinical mechanistic hypotheses, we anticipate that the proposed studies will yield important new insights into the neuroendocrine pathophysiology of the aging and gonadoprival GH-IGF-1 axis. An enhanced knowledge base should aid ultimately in formulating more innovative preventive and interventional strategies to limit hyposomatotropism in older and/or estrogen-deficient humans.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG014799-08
Application #
6631518
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Sherman, Sherry
Project Start
1997-03-01
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
8
Fiscal Year
2004
Total Cost
$292,000
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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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