Submitted on December 16, 2008
Revised on January 28, 2009
Accepted on February 16, 2009
Determinants of GH-Releasing Hormone and GH-Releasing Peptide Synergy in Men
Johannes D. Veldhuis1* and Cyril Y. Bowers2
1 Mayo School of Graduate Medical Education, Center for Translational Science Activities
2 Tulane University Health Sciences Center
* To whom correspondence should be addressed. E-mail: veldhuis.johannes{at}mayo.edu.
Age, sex steroids and abdominal-visceral fat (AVF) jointly affect pulsatile growth hormone (GH) secretion. Pulsatile GH secretion in turn is controlled by GH-releasing hormone (GHRH), GH-releasing peptide (GHRP) and somatostatin. Marked stimulation of pulsatile GH secretion is achieved via GHRH and GHRP synergy. Nonetheless, how key modulators of GH secretion like age, sex steroids and BMI modify GHRH/GHRP synergy is not known. To address this question, the present strategy was to: (i) infuse GHRH and GHRP-2 simultaneously to evoke synergy; and (ii) downregulate the gonadal axis with leuprolide, and then add back placebo (Pl) or testosterone (T) to clamp the sex-steroid milieu. Forty-seven men (ages 18 to 74 yr, T range 7 - 1950 ng/dL, E2 range 5 - 79 pg/mL, IGF-I range 115 - 817 µg/L, AVF range 11 - 349 cm2) were studied. GHRH/GHRP synergy correlated negatively with age and AVF (both P < 0.001) and positively with IGF-I (P < 0.001) and IGFBP-3 (P = 0.031). Unstimulated basal (nonpulsatile) GH secretion correlated positively with T (P = 0.015) and estradiol (P = 0.004) concentrations. Fasting pulsatile GH secretion varied negatively with age (P = 0.017), and positively with IGF-I (P = 0.002) and IGFBP-3 (P = 0.001). By stepwise forward-selection multivariate analyses, AVF, IGF-I and IGFBP-3 together explained 60% of the variability in GHRH/GHRP synergy (P < 0.001); E2 accounted for 17% of the variability in basal GH secretion (P = 0.007); and IGF-I explained 20% of the variability in fasting pulsatile GH secretion (P = 0.002). In conclusion, a paradigm examining GHRH/GHRP synergy under a sex-steroid clamp unveils highly selective control of basal, pulsatile and synergistic peptide-driven GH secretion by AVF, E2, and IGF-I in healthy men.
