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Aromatase and 5-Reductase Inhibition during an Exogenous Testosterone Clamp Unveils Selective Sex Steroid Modulation of Somatostatin and Growth Hormone Secretagogue Actions in Healthy Older Men

Departments of Internal Medicine and Pediatrics (J.D.V., K.L.M., M.C., C.S.-W., R.P., J.M.M.) (RP), Endocrine Research Unit, Clinical Translational Research Center, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester Minnesota 55901; and Division of Endocrinology (C.Y.B.), Department of Internal Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana 70112

Address all correspondence and requests for reprints to: Johannes D. Veldhuis, Departments of Internal Medicine and Pediatrics (RP), Endocrine Research Unit, Clinical Translational Research Center, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester Minnesota 55901. E-mail: Veldhuis.Johannes{at}mayo.edu.

Background: How endogenous testosterone (Te), 5-dihydrotestosterone (DHT), and estradiol (E₂) regulate pulsatile GH secretion is not understood.

Hypothesis: Conversion of Te to androgenic (TeDHT) or estrogenic (TeE₂) products directs GH secretion.

Subjects and Location: Healthy older men (N = 42, ages 50–79 yr) participated at an academic medical center.

Methods: We inhibited 5-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and L-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion.

Endpoints: Deconvolution-estimated basal and pulsatile GH secretion was assessed.

Results: Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E₂ concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E₂ by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P < 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P < 0.001); 2) Te and E₂ jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E₂, P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression.

Conclusion: The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E₂ along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

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