Citations

Abstract Background: How endogenous testosterone (Te), 5α-dihydrotestosterone (DHT), and estradiol (E2) regulate pulsatile GH secretion is not understood. Hypothesis: Conversion of Te to androgenic (Te→DHT) or estrogenic (Te→E2) products directs GH secretion. Subjects and Location: Healthy older men (N = 42, ages 50–79 yr) participated at an academic medical center. Methods: We inhibited 5α-reduction with dutasteride and aromatization with anastrozole during a pharmacological Te clamp and infused somatostatin (SS), GHRH, GH-releasing peptide-2 (GHRP-2), and l-arginine/GHRH/GHRP-2 (triple stimulus) to modulate GH secretion. Endpoints: Deconvolution-estimated basal and pulsatile GH secretion was assessed. Results: Administration of Te/placebo elevated Te by 2.8-fold, DHT by 2.6-fold, and E2 concentrations by 1.9-fold above placebo/placebo. Te/dutasteride and Te/anastrozole reduced stimulated DHT and E2 by 89 and 86%, respectively. Stepwise forward-selection regression analysis revealed that 1) Te positively determines mean (P = 0.017) and peak (P < 0.001) GH concentrations, basal GH secretion (P = 0.015), and pulsatile GH secretion stimulated by GHRP-2 (P < 0.001); 2) Te and E2 jointly predict GH responses to the triple stimulus (positively for Te, P = 0.006, and negatively for E2, P = 0.031); and 3) DHT correlates positively with pulsatile GH secretion during SS infusion (P = 0.011). These effects persisted when abdominal visceral fat was included in the regression. Conclusion: The present outcomes suggest a tetrapartite model of GH regulation in men, in which systemic concentrations of Te, DHT, and E2 along with abdominal visceral fat determine the selective actions of GH secretagogues and SS.

Context: Obesity attenuates spontaneous GH secretion and the GH response to exercise. Obese individuals often have low fitness levels, limiting their ability to complete a typical 30-min bout of continuous exercise. An alternative regimen in obese subjects may be shorter bouts of exercise interspersed throughout the day. Objective: The objective of the study was to examine whether intermittent and continuous exercise interventions evoke similar patterns of 24-h GH secretion and whether responses are attenuated in obese subjects or affected by gender. Design: This was a repeated-measures design in which each subject served as their own control. Setting: This study was conducted at the University of Virginia General Clinical Research Center. Subjects: Subjects were healthy nonobese (n = 15) and obese (n = 14) young adults. Interventions: Subjects were studied over 24 h at the General Clinical Research Center on three occasions: control, one 30-min bout of exercise, and three 10-min bouts of exercise. Main Outcome Measures: Twenty-four hour GH secretion was measured. Results: Compared with unstimulated 24-h GH secretion, both intermittent and continuous exercise, at constant exercise intensity, resulted in severalfold elevation of 24-h integrated serum GH concentrations in young adults. Basal and pulsatile modes of GH secretion were attenuated both at rest and during exercise in obese subjects. Conclusions: The present data suggest that continuous and intermittent exercise training should be comparably effective in increasing 24-h GH secretion.

Background: Why pulsatile GH secretion declines in estrogen-deficient postmenopausal individuals remains unknown. One possibility is that estrogen not only enhances stimulation by secretagogues but also attenuates negative feedback by systemic IGF-I. Site: The study took place at an academic medical center. Subjects: Subjects were healthy postmenopausal women (n = 25). Methods: The study included randomized assignment to estradiol (n = 13) or placebo (n = 12) administration for 16 d and randomly ordered administration of 0, 1.0, 1.5, and 2.0 mg/m2 recombinant human IGF-I sc on separate days fasting. Analysis: Deconvolution analysis of pulsatile and basal GH secretion and approximate entropy (pattern-regularity) analysis were done to quantify feedback effects of IGF-I. Outcomes: Recombinant human IGF-I injections increased mean and peak serum IGF-I concentrations dose dependently (P < 0.001) and suppressed mean GH concentrations (P < 0.001), pulsatile GH secretion (P = 0.001), and approximate entropy (P < 0.001). Decreased GH secretion was due to reduced secretory-burst mass (P = 0.005) and frequency (P < 0.001) but not basal GH release (P = 0.52). Estradiol supplementation lowered endogenous, but did not alter infused, IGF-I concentrations while elevating mean GH concentrations (P = 0.012) and stimulating pulsatile (P = 0.008) and basal (P < 0.001) GH secretion. Estrogen attenuated IGF-I’s inhibition of pulsatile GH secretion (P = 0.042) but was unable to restore physiological GH pulse frequency or normalize approximate entropy. Conclusion: Short-term estrogen replacement in postmenopausal women selectively mutes IGF-I-mediated feedback on pulsatile GH secretion. Disinhibition of negative feedback thus confers a novel mechanism by which estrogen may obviate hyposomatotropism.

Context: Sex-steroid hormones amplify pulsatile GH secretion by unknown mechanisms. Ghrelin is the most potent natural GH secretagogue discovered to date. A plausible unifying postulate is that estradiol (E2) enhances hypothalamo-pituitary sensitivity to ghrelin (a physiological effect). The hypothesis is relevant to understanding the basis of hyposomatotropism in aging and other relatively hypogonadal states. Objective: Our objective was to test the hypothesis that E2 supplementation potentiates ghrelin’s stimulation of pulsatile GH secretion. Setting: The study was conducted at an academic medical center. Subjects: Healthy postmenopausal women (n = 20) were included in the study. Interventions: Separate-day iv infusions of saline vs. five graded doses of ghrelin were performed in volunteers prospectively randomly assigned to receive (n = 8) or not receive (n = 12) transdermal E2 for 21 d were performed. Measures: GH secretion was estimated by deconvolution analysis and abdominal visceral fat mass determined by computerized axial tomography were calculated. Results: E2 supplementation augmented ghrelin’s stimulation of basal (nonpulsatile) GH secretion by 3.6-fold (P = 0.022), increased GH responses to low-dose ghrelin by 2.9-fold (P = 0.035), did not alter ghrelin efficacy, and elicited more regular patterns of acylated ghrelin concentrations during saline infusion (P = 0.033). Abdominal visceral fat negatively determined responses to ghrelin (R = −0.346; P < 0.005). Conclusions: Transdermal E2 supplementation potentiates GH secretion stimulated by physiological but not pharmacological concentrations of acylated ghrelin, and concomitantly regularizes patterns of bioactive ghrelin secretion in postmenopausal women. Accordingly, the estrogen milieu appears to control sensitivity of the hypothalamopituitary unit to acylated ghrelin.

Background: Ghrelin is a 28-amino acid acylated peptide that potentiates GHRH stimulation and opposes somatostatin inhibition acutely. Whether prolonged ghrelin administration can sustain physiological patterns of GH secretion remains unknown. Hypothesis: Continuous delivery of ghrelin will amplify physiological patterns of GH secretion over 24 h. Subjects: Men and women ages 29–69 yr, body mass indices 23–52 kg/m2, were included in the study. Location: The study was performed at an academic medical center. Methods: Twenty-four hour continuous sc infusion of saline vs. ghrelin (1 μg/kg·h) with frequent sampling was examined. Deconvolution and entropy analyses were performed. Outcomes: IGF-I concentrations were determined. Basal, pulsatile, nycthemeral, and entropic measures of GH secretion were calculated. Results: Ghrelin infusion compared with saline infusion for 24 h elevated (median) acylated ghrelin, GH, and IGF-I concentrations by 8.1-fold (P < 0.001),11-fold (P < 0.001), and 1.4-fold (P = 0.002). GH secretory-burst mass and frequency increased by 6.6-fold (P = 0.004) and 1.7-fold (P < 0.001), respectively, resulting in a 12-fold increase in pulsatile GH secretion (P < 0.001). Interpulse variability decreased significantly (P = 0.046), whereas GH secretory-burst shape and half-life did not change. The amplitude of the nycthemeral GH rhythm increased by 3.4-fold (P < 0.001), and GH patterns became more irregular (higher approximate entropy P < 0.001). Combining GHRH with ghrelin was not an additive in driving GH secretion. Conclusions: Continuous ghrelin infusion for 24 h elevates acylated ghrelin, GH and IGF-I concentrations, and stimulates pulsatile, nycthemeral, and entropic modes of GH secretion. The consistency of outcomes in a heterogeneous cohort of adults suggests potentially broad utility of this physiological secretagogue in hyposomatotropic states.