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.
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