Determinants of GH-releasing hormone and GH-releasing peptide synergy in men.
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-GHRP synergy. Nonetheless, how key modulators of GH secretion, such as age, sex steroids, and body mass index, modify GHRH-GHRP synergy is not known. The present strategy was to 1) infuse GHRH and GHRP-2 simultaneously to evoke synergy and 2) downregulate the gonadal axis with leuprolide and then restore placebo (Pl) or testosterone (T) to clamp the sex steroid milieu. Forty-seven men [18-74 yr of age, T = 7-1,950 ng/dl, estradiol (E(2)) = 5-79 pg/ml, insulin-like growth factor (IGF)-I = 115-817 microg/l, AVF = 11-349 cm(2)] were studied. GHRH-GHRP synergy correlated negatively with age and AVF (both P < 0.001) and positively with IGF-I (P < 0.001) and IGF-binding protein (IGFBP)-3 (P = 0.031). Unstimulated basal (nonpulsatile) GH secretion correlated positively with T (P = 0.015) and E(2) (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), E(2) 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 reveals highly selective control of basal, pulsatile, and synergistic peptide-driven GH secretion by AVF, E(2), and IGF-I in healthy men.
Veldhuis
Johannes D
JD
Mayo School of Graduate Medical Education, Mayo Clinic, Rochester, MN 55905, USA. veldhuis.johannes@mayo.edu
Bowers
Cyril Y
CY
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D015331:Cohort Studies; D004311:Double-Blind Method; D004958:Estradiol / Q000097:blood; D013007:Growth Hormone-Releasing Hormone / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016729:Leuprolide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009842:Oligopeptides / Q000008:administration & dosage* / Q000378:metabolism / Q000502:physiology*; D011446:Prospective Studies; D012044:Regression Analysis; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000008:administration & dosage / Q000097:blood; D055815:Young Adult
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D009842:Oligopeptides; D012738:Sex Hormone-Binding Globulin; C420120:gamma-aminobutyryl-2-methyltryptophyl-2-methyltryptophyl-2-methyltryptophyl-lysinamide; D013739:Testosterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D013007:Growth Hormone-Releasing Hormone; C091874:growth hormone-releasing peptide-2; D016729:Leuprolide