Veldhuis, Johannes D.

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.

Abstract Poor growth in early life is associated with numerous adverse outcomes later in life. In 123 adolescents 16–18 yr of age, the previous findings of a positive relation between size in early life and later bone mass was confirmed. These associations were mediated by the current height and weight, but it was not confirmed that alterations of the GH–IGF axis cause this. Introduction: Numerous studies have found associations between low birth weight and disease later in life, including decreased bone mass. Materials and Methods: A longitudinal cohort of 16- to 19-year-old adolescents (n = 123) with data on third trimester fetal growth velocity (FGV) was assessed by serial ultrasound measurements, birth weight (BW), and weight at 1 yr. A follow-up study included DXA scan, anthropometric measurements, and measurements of the growth hormone (GH) –IGF-I axis in a representative subpopulation (n = 30). Results: BW and weight at 1 yr were positively associated with whole body BMC (p = 0.02 and p < 0.0001, respectively), lumbar spine BMC (p = 0.001 and p = 0.03, respectively), and lumbar spine BMD (p = 0.04). After correction for adolescent height and weight, no association remained significant. There was no relation between IGF-I and IGF binding protein 3 (IGFBP-3) levels in adolescence and size in early life or bone mass. In the subpopulation, GH secretion (median, 2.58 versus 4.05), GH pulse mass (median, 10.7 versus 19.4 mU/liter), and total GH (median, 74.9 versus 108.8 mU/liter/12 h) were decreased in the small for gestational age (SGA) group compared with the appropriate for gestational age (AGA) group; this did not reach statistical significance. Likewise, there were no differences in IGF-I, IGF-II, and IGFBP-1, −2, and −3 levels between the SGA and AGA groups. A statistically significant positive association between FGV and adolescent IGF-II was found (B = 199.9, p = 0.006). Significant negative associations between GH measurement and BMC, as well as BMD, were found (B = −0.008, p = 0.005 and B = −0.008, p = 0.006, respectively). Conclusions: This study confirms the previous findings of a positive relation between size in early life and later BMC, an association apparently independent of the distal part of the GH/IGF-I axis. However, this association may be mediated mainly by postnatal growth determining size of the skeletal envelope rather than an effect of fetal programming on bone mass per se.

Abstract Context: Whether testosterone (Te) depletion in aging men reflects deficits in the testis, hypothalamus, and/or pituitary gland is unknown. Objective: Our objective was to quantify the impact of age on gonadal Te secretion driven by amplitude-varying pulses of recombinant human LH (rhLH) in the absence of confounding by endogenous hypothalamo-pituitary signals. Design: This was a double-blind, placebo-controlled study. Setting: The setting was an academic medical center. Subjects: Fifteen healthy community-dwelling men ages 22–78 yr were included in the study. Intervention: Saline or four separate rhLH doses were each infused twice iv in randomized order as one pulse every 2 h over 20 h to stimulate Te secretion, after LH secretion was suppressed by a GnRH-receptor antagonist, ganirelix. Main Outcome: LH and Te concentrations were determined in blood samples collected every 5 min. Maximal and minimal (as well as mean) Te responses were regressed linearly on age to reflect LH peak and nadir (and average) effects, respectively. Results: The ganirelix/rhLH paradigm yielded serum LH concentrations of 4.6 ± 0.22 IU/liter (normal range 1–9). By regression analysis, age was associated with declines in rhLH pulse-stimulated peak and nadir (and mean) concentrations of total Te (P = 0.0068), bioavailable Te (P = 0.0096), and free Te (P = 0.013), as well as lower Te/LH concentration ratios (P < 0.005). Deconvolution analysis suggested that the half-life of infused LH increases by 12%/decade (P = 0.044; R2 = 0.28). Conclusions: Infusion of amplitude-varying pulses of rhLH during gonadal-axis suppression in healthy men unmasks prominent age-related deficits in stimulated total (39%), bioavailable (66%), and free (63%) Te concentrations, and a smaller age-associated increase in LH half-life. These data suggest that age-associated factors reduce the efficacy of LH pulses.