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Tripartite Control of Growth Hormone Secretion in Women during Controlled Estradiol Repletion

Endocrine Research Unit 9 (J.D.V., M.C., D.E., R.P., K.M.), General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905; Division of Endocrinology and Metabolism (L.S.F.), Department of Internal Medicine, School of Medicine, University of Virginia, Charlottesville, Virginia 22908; and Endocrine Division, Department of Medicine (C.Y.B.), Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Endocrine Research Unit 9, General Clinical Research Center, Mayo Medical and Graduate Schools of Medicine, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Context: Studies of how aging attenuates GH secretion are confounded by differences in sex-steroid milieus, abdominal visceral fat mass (AVF), and IGF-I concentrations and limited in interpretability by the use of pharmacological doses of secretagogues.

Hypothesis: In a controlled estrogenic milieu, near-physiological secretagogue drive will unmask distinct influences of age, AVF, and IGF-I on GH secretion.

Location: The study was conducted at an academic medical center.

Subjects: Subjects included 10 healthy pre- (PRE) and 10 postmenopausal (POST) women.

Procedure: In a defined estradiol (E₂) milieu, we compared GH secretion after submaximal stimulation with GH-releasing peptide (GHRP)-2 (ghrelin analog), GHRH, and L-arginine (an inhibitor of somatostatin outflow).

Analysis: We related GH responses to age stratum (dichotomous variable) and AVF and IGF-I concentrations (continuous variables).

Results: In the face of comparable concentrations of E₂, testosterone, and SHBG: 1) age (P < 0.001) and secretagogue type (P < 0.001) independently determined GH secretion; 2) GH responses in POST subjects were only 26–33% of those in PRE (P 0.002) across all secretagogues; 3) POST women lost the PRE order of secretagogue potency (GHRP-2 > GHRH = L-arginine); and 4) in the combined cohorts, higher AVF predicted reduced L-arginine-stimulated GH secretion (R² = 0.46, P = 0.0013), whereas higher IGF-I concentrations forecast increased GHRP-2 and GHRH drive (R² 0.52, P 0.013).

Conclusion: A paradigm of near-physiological secretagogue drive in an E₂-clamped milieu unmasks tripartite deficits in peptide-signaling pathways in healthy POST, compared with PRE, women. Post hoc analyses indicate that both greater visceral adiposity and lower IGF-I concentrations mark this triple regulatory defect.

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