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Factors Other than Sex Steroids Modulate GHRH and GHRP-2 Efficacies in Men: Evaluation Using a GnRH Agonist/Testosterone Clamp

Department of Medicine (J.D.V.), Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905; 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, Department of Medicine, Endocrine Research Unit, Mayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota 55905. E-mail: veldhuis.johannes{at}mayo.edu.

Background: Sex steroids are prominent regulators of pulsatile GH secretion.

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

Subjects: Eleven young (age, 24 ± 0.99 yr) and 11 older (64 ± 2.4 yr) men participated in the study.

Location: 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.

Outcomes: The experimental leuprolide/T clamp yielded statistically age-comparable total, bioavailable, and free T and estradiol (E₂) 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; R² = 0.39) and GHRP-2 (R² = 0.29) efficacy, whereas IGF-I positively predicted the same endpoints (R² = 0.25 to 0.30). In multivariate analysis, AVF emerged as a dominant negative determinant of GHRH efficacy (P = 0.002; R² = 0.41) and IGF-I as a primary positive determinant of GHRP-2 efficacy (P = 0.007; R² = 0.31).

Conclusion: During fixed T/E₂ 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/E₂-independent modulators of GHRH and GHRP efficacy in men.