Factors other than sex steroids modulate GHRH and GHRP-2 efficacies in men: evaluation using a GnRH agonist/testosterone clamp.
BACKGROUND
Sex steroids are prominent regulators of pulsatile GH secretion.


OBJECTIVE
An experimentally controlled sex-steroid milieu will permit detection of nonsteroidal factors that determine GH secretion.


METHODS
Eleven young (age, 24 +/- 0.99 yr) and 11 older (64 +/- 2.4 yr) men participated in the study.


METHODS
The study was conducted at a tertiary medical center.


METHODS
The study consisted of GnRH-agonist down-regulation of the gonadal axis followed by fixed-dose testosterone (T) replacement (leuprolide/T clamp) and consecutive infusion of l-arginine and GHRH or GH-releasing peptide-2 (GHRP-2) to quantify peptide-secretagogue efficacies.


RESULTS
The experimental leuprolide/T clamp yielded statistically age-comparable total, bioavailable, and free T and estradiol (E(2)) concentrations. In this controlled milieu, sequential l-arginine/GHRH infusion stimulated 1.4-fold more (P = 0.021) and l-arginine/GHRP-2 1.3-fold more (P = 0.045) GH release in young than older men. Abdominal visceral fat (AVF) correlated negatively with both GHRH (P = 0.0006; R(2) = 0.39) and GHRP-2 (R(2) = 0.29) efficacy, whereas IGF-I positively predicted the same endpoints (R(2) = 0.25 to 0.30). In multivariate analysis, AVF emerged as a dominant negative determinant of GHRH efficacy (P = 0.002; R(2) = 0.41) and IGF-I as a primary positive determinant of GHRP-2 efficacy (P = 0.007; R(2) = 0.31).


CONCLUSIONS
During fixed T/E(2) availability, AVF contributes 41% of the GH-response variability to maximal GHRH drive, whereas IGF-I accounts for 31% of that for GHRP-2. Accordingly, a statistically equalized sex-steroid milieu permits dissection of age-independent and T/E(2)-independent modulators of GHRH and GHRP efficacy in men.
Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905, USA. veldhuis.johannes@mayo.edu
Johannes D
JD
Veldhuis
Cyril Y
CY
Bowers
D000328:Adult; D000368:Aged; D003940:Diagnostic Techniques, Endocrine; D012734:Disorders of Sex Development / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D012739:Gonadal Steroid Hormones / Q000502:physiology*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000819:agonists; D013007:Growth Hormone-Releasing Hormone / Q000627:therapeutic use*; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000627:therapeutic use*; D013739:Testosterone / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
D012739:Gonadal Steroid Hormones; D009842:Oligopeptides; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D013007:Growth Hormone-Releasing Hormone; C091874:growth hormone-releasing peptide-2; D016729:Leuprolide