Aromatase and 5α-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men

Johannes D Veldhuis, Kristi L. Mielke, Mihaela Cosma, Cacia Soares-Welch, Remberto Paulo, John M. Miles, Cyril Y. Bowers

Research output: Contribution to journalArticle

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Abstract

Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E 2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E 2) 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 5α-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 E 2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E 2 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 E 2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E 2 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 E 2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

Original languageEnglish (US)
Pages (from-to)973-981
Number of pages9
JournalJournal of Clinical Endocrinology and Metabolism
Volume94
Issue number3
DOIs
StatePublished - Mar 2009

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Aromatase
Clamping devices
Somatostatin
Growth Hormone
Testosterone
Oxidoreductases
Steroids
Modulation
Dihydrotestosterone
Intra-Abdominal Fat
Placebos
Peptides
Fats
Aromatization
Deconvolution
Regression analysis
Arginine
Estradiol
Healthy Volunteers
Regression Analysis

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Medicine(all)
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Aromatase and 5α-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men. / Veldhuis, Johannes D; Mielke, Kristi L.; Cosma, Mihaela; Soares-Welch, Cacia; Paulo, Remberto; Miles, John M.; Bowers, Cyril Y.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 3, 03.2009, p. 973-981.

Research output: Contribution to journalArticle

Veldhuis, Johannes D ; Mielke, Kristi L. ; Cosma, Mihaela ; Soares-Welch, Cacia ; Paulo, Remberto ; Miles, John M. ; Bowers, Cyril Y. / Aromatase and 5α-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men. In: Journal of Clinical Endocrinology and Metabolism. 2009 ; Vol. 94, No. 3. pp. 973-981.
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abstract = "Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E 2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E 2) 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 5α-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 E 2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E 2 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 E 2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E 2 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 E 2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.",
author = "Veldhuis, {Johannes D} and Mielke, {Kristi L.} and Mihaela Cosma and Cacia Soares-Welch and Remberto Paulo and Miles, {John M.} and Bowers, {Cyril Y.}",
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T1 - Aromatase and 5α-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men

AU - Veldhuis, Johannes D

AU - Mielke, Kristi L.

AU - Cosma, Mihaela

AU - Soares-Welch, Cacia

AU - Paulo, Remberto

AU - Miles, John M.

AU - Bowers, Cyril Y.

PY - 2009/3

Y1 - 2009/3

N2 - Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E 2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E 2) 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 5α-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 E 2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E 2 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 E 2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E 2 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 E 2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

AB - Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E 2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E 2) 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 5α-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 E 2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E 2 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 E 2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E 2 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 E 2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

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