Determinants of GH-releasing hormone and GH-releasing peptide synergy in men

Abstract

Veldhuis JD, Bowers CY. Determinants of GH-releasing hormone and GH-releasing peptide synergy in men. Am J Physiol Endocrinol Metab 296: E1085-E1092, 2009. First published February 24, 2009 doi:10.1152/ajpendo.91001.2008.-Age, sex steroids, and abdominalvisceral 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 ϭ 7-1,950 ng/dl, estradiol (E 2) ϭ 5-79 pg/ml, insulin-like growth factor (IGF)-I ϭ 115-817 g/l, AVF ϭ 11-349 cm 2 ] were studied. GHRH-GHRP synergy correlated negatively with age and AVF (both P Ͻ 0.001) and positively with IGF-I (P Ͻ 0.001) and IGF-binding protein (IGFBP)-3 (P ϭ 0.031). Unstimulated basal (nonpulsatile) GH secretion correlated positively with T (P ϭ 0.015) and E 2 (P ϭ 0.004) concentrations. Fasting pulsatile GH secretion varied negatively with age (P ϭ 0.017) and positively with IGF-I (P ϭ 0.002) and IGFBP-3 (P ϭ 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 Ͻ 0.001), E 2 accounted for 17% of the variability in basal GH secretion (P ϭ 0.007), and IGF-I explained 20% of the variability in fasting pulsatile GH secretion (P ϭ 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.androgen; fat; human; male; insulin-like growth factor I; pulsatility; secretion; age PULSATILE SECRETION accounts for Ͼ85% of total daily growth hormone (GH) production (20). Burst-like GH release conveys significant physiological information to target tissues, including insulin-like growth factor I (IGF-I) production (22,40,41). Conversely, attenuation of GH pulse-dependent STAT5b signaling lowers IGF-I concentrations and causes growth failure (11,20,40). From a mechanistic perspective, a triad of pivotal peptides controls the size of GH secretory bursts: two amplifying signals, GH-releasing hormone (GHRH) and GH-releasing peptide (GHRP), and an inhibitory signal, somatostatin (SS) (4,6,16,29,34). Factors such as sex steroids, age, body composition, IGF-I, and GH feedback, thyroxine, glucocorticoids, free fatty acids, cytokines, neurotransmitters, exercise, and glycemia can modulate pulsatile GH secretion putatively by altering the release and/or actions of GHRH, ghrelin/GHRP, and SS (20,31,40). How such factors influence GHRH-GHRP synerg...

Preservation of GHRH and GH-releasing peptide-2 efficacy in young men with experimentally induced hypogonadism

“…Twenty-four healthy young men [age 24 ± 0.72 (SEM) yr, BMI 25 ± 0.91 kg/m 2 ] received 2 consecutive im injections of depot leuprolide acetate (3.75 mg im 3 wk apart) to deplete systemic T and E 2 concentrations. The synergy between GHRH and GHRP-2 in these subjects was presented earlier (16). Beginning on the day of the second leuprolide injection, volunteers were given either saline (N = 13) or a pharmacological dose of 200 mg T enanthate (N = 11) im weekly for 3 doses (designated as days 0, 7, and 14) double-blind.…”

“…As described earlier and in a Supplemental (Appendix) Table, baseline subject characteristics did not differ in volunteers assigned to the leuprolide/placebo (Pl) and leuprolide/T treatment groups (16). In contrast, post-leuprolide vs post-placebo hormone concentrations differed significantly with respect to: (a) IGFBP-1 (higher in the T addback group, P = 0.027); (b) prolactin (higher in the T group, P = 0.001); (c) FSH (lower in the T group, P < 0.001); and (d) E 2 , total T, bioavailable T and free T (each higher by P < 0.001 in the T group): Figure 1 .…”

Insulin-like growth factor-I (IGF-I) serum concentrations in healthy children and adolescents: Relationship to level of contamination by DDT-derivative pesticides

“…This pattern is attributed to the age-related decline in growth hormone secretion [33]. The complex interaction between sex steroids and GH-IGF axis is little known [39]. Nevertheless, physiologically, there is a positive association between androgens and IGF-I, and the contrary for estrogens [18].…”

“…Nevertheless, other unknown hepatic or non-hepatic mechanisms may be involved (such as genetic polymorphisms related to xenobiotic-metabolizing enzymes). In any case, the gender-and age-related differences observed may be linked to differences in interaction between sex steroid hormones and the GH/IGF system during infancy, pubertal transition, and adolescence [39].…”

Is there an undiscovered neurocircuit for regulating GH secretion? -Pitfalls of GHRP-2 and ITT as GH provocative tests-

“…In a result, his BMI was further increased. Therefore, he might have a visceral obesity, which may influence GH response to GHRP-2 [23]. The CT determination showed that he had no dominant of fat area in the abdomen compared with the subcutaneous tissue.…”