Aromatase and 5alpha-reductase inhibition during an exogenous testosterone clamp unveils selective sex steroid modulation of somatostatin and growth hormone secretagogue actions in healthy older men.
BACKGROUND
How endogenous testosterone (Te), 5alpha-dihydrotestosterone (DHT), and estradiol (E(2)) regulate pulsatile GH secretion is not understood.


OBJECTIVE
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 5alpha-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.


METHODS
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.


CONCLUSIONS
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.
Veldhuis
Johannes D
JD
Department of Internal Medicine and Pediatrics, Endocrine Research Unit, Clinical Translational Research Center, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester Minnesota 55901, USA. Veldhuis.Johannes@mayo.edu
Mielke
Kristi L
KL
Cosma
Mihaela
M
Soares-Welch
Cacia
C
Paulo
Remberto
R
Miles
John M
JM
Bowers
Cyril Y
CY
D000368:Aged; D047072:Aromatase Inhibitors / Q000494:pharmacology*; D042944:Cholestenone 5 alpha-Reductase / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D004958:Estradiol / Q000502:physiology*; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D013004:Somatostatin / Q000378:metabolism*; D013739:Testosterone / Q000502:physiology*
D047072:Aromatase Inhibitors; D019382:Human Growth Hormone; D013739:Testosterone; D004958:Estradiol; D013004:Somatostatin; D042944:Cholestenone 5 alpha-Reductase