Growth Hormone Secretory Bursts Research Articles

Effect of long-acting growth hormone treatment on endogenous growth hormone secretion in prepubertal patients with idiopathic short stature: A preliminary study

Long-acting growth hormone (LAGH) is emerging to be a new preparation for treatment of short stature. We aimed to determine whether 12-month treatment with LAGH in patients with idiopathic short stature has an effect on the nocturnal endogenous growth hormone (GH) secretion and metabolic consequences and efficacy. Participants included 10 GH-naïve prepubertal children with idiopathic short stature (ISS). One patient was withdrawn due to own decline during study. Participants were randomized on a 1:1 ratio to receive either a daily GH (0.37 mg/kg/week) or once-weekly LAGH (0.7 mg/kg/week) over a 12-month period. Nocturnal endogenous GH secretory profiles obtained from 12-h blood samplings at 30-min interval were assessed at baseline and 2 weeks after the completion of GH treatment. Post-treatment changes in height velocity, height standard deviation score (SDS), metabolic parameters, and adverse events were measured. A total of 4 patients received LAGH, and 5 patients received daily GH. Nocturnal endogenous GH secretory profiles, such as mean serum GH concentrations, frequency, amplitude, interpulse interval of spontaneous GH secretory bursts, and mass of GH released per secretory burst were similar at baseline and after 12-month treatment in both groups. The efficacy and safety after LAGH treatment for 12 months were similar to those of daily GH. In conclusions, these findings indicated that LAGH does not suppress endogenous GH secretion, and can be used for treatment of non-GH deficient short stature with similar efficacy and safety compared to daily GH. These may contribute to define and develop treatment and follow-up protocols for LAGH use in ISS patients.

Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E(2) (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E(2)/T administration potentiated both pulsatile (P = 0.006) and entropic (P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode (P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass (P = 0.005). The composite of gender, body mass index, E(2), IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

Growth hormone (GH) secretion, GH-dependent gene expression, and sexually dimorphic body growth in young rats with chronic renal failure

Chronic renal disease results in growth failure in children. This study sought to determine the influences of early renal failure on body growth, growth hormone (GH) secretion, and GH-dependent hepatic gene expression. Neonatal animals were subjected to five-sixth nephrectomy (Nephr) and monitored during growth. Sham-operated male (Sham) and female (Fem) rats served as controls. Whereas Nephr of adult animals causes renal insufficiency, neonatal nephrectomy leads to frank renal failure. In male Nephr compared with Sham animals, GH half-life and GH pulse frequency increased by 1.55- and 1.33-fold, respectively, and GH secretory-burst size decreased by 80%. Approximate entropy analysis quantified more disorderly patterns of GH secretion in Nephr animals, which differed from Sham males, but not from Fem rats. Expression of liver P450 CYP2C11 mRNA, which is dependent upon the male GH pattern, became undetectable, whereas expression of liver P450 CYP2C12 mRNA, which is dependent upon the female GH pattern, increased multifold. Renal failure in young rats abrogates the male pattern of GH pulsatility, abolishes the sexual dimorphism of body weight gain, and induces a female pattern of hepatic gene expression. These data raise the possibility that disruption of pulsatile GH secretion contributes to the growth failure of renal disease.

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

Estradiol (E(2)) drives growth hormone (GH) secretion via estrogen receptors (ER) located in the hypothalamus and pituitary gland. ERalpha is expressed in GH releasing hormone (GHRH) neurons and GH-secreting cells (somatotropes). Moreover, estrogen regulates receptors for somatostatin, GHR peptide (GHRP, ghrelin), and GH itself, while potentiating signaling by IGF-I. Given this complex network, one cannot a priori predict the selective roles of hypothalamic compared with pituitary ER pathways. To make such a distinction, we introduce an investigative model comprising 1) specific ERalpha blockade with a pure antiestrogen, fulvestrant, that does not penetrate the blood-brain barrier; 2) graded transdermal E(2) administration, which doubles GH concentrations in postmenopausal women; 3) stimulation of fasting GH secretion by pairs of GHRH, GHRP-2 (a ghrelin analog), and l-arginine (to putatively limit somatostatin outflow); and 4) implementation of a flexible waveform deconvolution model to estimate the shape of secretory bursts independently of their size. The combined strategy unveiled that 1) E(2) prolongs GH secretory bursts via fulvestrant-antagonizable mechanisms; 2) fulvestrant extends GHRH/GHRP-2-stimulated secretory bursts; 3) l-arginine/GHRP-2 stimulation lengthens GH secretory bursts whether or not E(2) is present; 4) E(2) limits the capability of l-arginine/GHRP-2 to expand GH secretory bursts, and fulvestrant does not inhibit this effect; and 5) E(2) and/or fulvestrant do not alter the time evolution of l-arginine/GHRH-induced GH secretory bursts. The collective data indicate that peripheral ERalpha-dependent mechanisms determine the shape (waveform) of in vivo GH secretory bursts and that such mechanisms operate with secretagogue selectivity.

Estimation of the size and shape of GH secretory bursts in healthy women using a physiological estradiol clamp and variable-waveform deconvolution model

Because estrogen production and age are strong covariates, distinguishing their individual impact on hypothalamo-pituitary regulation of growth hormone (GH) output is difficult. In addition, at fixed elimination kinetics, systemic GH concentration patterns are controlled by three major signal types [GH-releasing hormone (GHRH), GH-releasing peptide (GHRP, ghrelin), and somatostatin (SS)] and by four dynamic mechanisms [the number, mass (size), and shape (waveform) of secretory bursts and basal (time invariant) GH secretion]. The present study introduces an investigative strategy comprising 1) imposition of an experimental estradiol clamp in pre- (PRE) and postmenopausal (POST) women; 2) stimulation of fasting GH secretion by each of GHRH, GHRP-2 (a ghrelin analog), and l-arginine (to putatively limit SSergic restraint); and 3) implementation of a flexible-waveform deconvolution model to estimate basal GH secretion simultaneously with the size and shape of secretory bursts, conditional on pulse number. The combined approach unveiled the following salient percent POST/PRE contrasts: 1) only 27% as much GH secreted in bursts during fasting (P < 0.001); 2) markedly attenuated burstlike GH secretion in response to bolus GHRP-2 (29%), bolus GHRH (30%), l-arginine (37%), constant GHRP-2 (38%), and constant GHRH (42%) (age contrasts, 0.0016 </= P </= 0.027); and 3) a 160% prolongation and 32% abbreviation of the time required to achieve maximal GH secretion after injection of l-arginine and bolus GHRP-2, respectively (both, P < 0.001). Accordingly, age selectively determines both the size (amount) and shape (waveform) of GH secretory bursts in healthy women independently of the short-term estrogen milieu.

Oral arginine attenuates the growth hormone response to resistance exercise

This study investigated the combined effect of resistance exercise and arginine ingestion on spontaneous growth hormone (GH) release. Eight healthy male subjects were studied randomly on four separate occasions [placebo, arginine (Arg), placebo + exercise (Ex), arginine + exercise (Arg+Ex)]. Subjects had blood sampled every 10 min for 3.5 h. After baseline sampling (30 min), subjects ingested a 7-g dose of arginine or placebo (blinded, randomly assigned). On the exercise days, the subject performed 3 sets of 9 exercises, 10 repetitions at 80% one repetition maximum. Resting GH concentrations were similar on each study day. Integrated GH area under the curve was significantly higher on the Ex day (508.7 +/- 169.6 min.ng/ml; P < 0.05) than on any of the other study days. Arg+Ex (260.5 +/- 76.8 min.ng/ml) resulted in a greater response than the placebo day but not significantly greater than the Arg day. The GH half-life and half duration were not influenced by the stimulus administered. The GH secretory burst mass was larger, but not significantly, on the Arg, Ex, and Arg+Ex day than the placebo day. Endogenous GH production rate (Ex > Arg+Ex > Arg > placebo) was greater on the Ex and Arg+Ex day than on the placebo day (P < 0.05) but there were no differences between the Ex and Arg+Ex day. Oral arginine alone (7 g) stimulated GH release, but a greater GH response was seen with exercise alone. The combined effect of arginine before exercise attenuates the GH response. Autonegative feedback possibly causes a refractory period such that when the two stimuli are presented there will be suppression of the somatotrope.

Sex-steroid modulation of growth hormone (GH) secretory control: three-peptide ensemble regulation under dual feedback restraint by GH and IGF-I.

Technical, genetic, and clinical developments have unveiled a burgeoning array of novel effectors of GH secretion. The present appraisal of central neuroregulatory components of the somatotropic axis highlights a simplifying concept of ensemble control by the final common peptides, GH-releasing hormone (GHRH), GH-releasing peptide(s) (GHRP, ghrelin), and somatostatin. These potent signals act individually, antagonistically, and synergistically to direct pulsatile GH secretion. GHRH, GHRP/ghrelin, and somatostatin further adapt to autonegative feedback by GH and IGF-I. Estradiol modulates the impact of each of the primary peptidyl inputs; viz.: (i) enhances submaximally effective feedforward by discrete pulses of (injected) recombinant human GHRH-1,44-amide (as defined by increased agonistic potency and pituitary sensitivity); (ii) potentiates the submaximally stimulatory effects of GHRP-2, a hexapeptidyl mimetic of ghrelin; (iii) blunts dose-dependent inhibition of fasting GH secretion by somatostatin- 14; and (iv) relieves rhGH-enforced negative feedback on GHRP-2 (but not on basal, exercise, or GHRH)-stimulated GH secretion. The foregoing estrogenic activities collectively augment GH secretory burst mass by amplifying feedforward (via both GHRH and GHRP) and attenuating feedback (imposed by somatostatin and GH). Whether testosterone fully mimics the foregoing mechanistic actions of estradiol is not known. In conclusion, the present conceptual platform of tri-peptide-directed feedforward and GH/IGF-I-mediated feedback should aid in unraveling some of the complex regulatory dynamics targeted by sex-steroid hormones.

Effects of GH on protein metabolism during dietary restriction in man.

The metabolic response to dietary restriction involves a series of hormonal and metabolic adaptations leading to protein conservation. An increase in the serum level of growth hormone (GH) during fasting has been well substantiated. GH has potent protein anabolic actions, as evidenced by a significant decrease in lean body mass and muscle mass in chronic GH deficiency, and vice versa in patients with acromegaly. The present review outlines current knowledge about the role of GH in the metabolic response to fasting, with particular reference to the effects on protein metabolism. Physiological bursts of GH secretion seem to be of seminal importance for the regulation of protein conservation during fasting. Apart from the possible direct effects of GH on protein dynamics, a number of additional anabolic agents, such as insulin, insulin-like growth factor-I, and free fatty acids (FFAs), are activated. Taken together the effects of GH on protein metabolism seem to include both stimulation of protein synthesis and inhibition of breakdown, depending on the nature of GH administration, which tissues are being studied, and on the physiological conditions of the subjects.

Increased Orderliness of Growth Hormone (GH) Secretion in GH-Deficient Adults with Low Serum Insulin-Like Growth Factor I

Available studies suggest that a proportion of GH-deficient (GHD) adults maintain serum IGF-I concentrations within the age- and sex-matched normal range. The basis for this distinction is not known. In this study 24-h GH profiles (sampling every 30 min) were appraised in five GHD adults with low serum IGF-I concentrations (<2 SD of the age- and sex-matched normal range), five GHD adults with normal serum IGF-I levels (within +/-2 SD), and five healthy subjects. Serial GH concentrations, measured using a chemiluminescence assay, were analyzed by deconvolution and approximate entropy (ApEn; regularity) analyses. The apparent half-duration of GH secretory bursts was longer in both GHD groups than in the healthy controls, as determined by deconvolution analysis (P < 0.05 each). The GH burst frequency was higher, the interburst interval was shorter, and the GH burst amplitude was lower in GHD adults with normal serum IGF-I than in healthy controls (P < 0.05, P < 0.05, and P < 0.01, respectively). The percentage of total daily GH secretion that was pulsatile was also reduced in the GHD adults with normal serum IGF-I compared with the other two groups (P < 0.05 and P < 0.05, respectively). In contrast, ApEn ratios were lower in the GHD adults with low serum IGF-I than in the GHD adults with normal IGF-I and controls (P < 0.01 and P < 0.05, respectively). Serum IGF-I concentrations correlated positively with ApEn ratios in the total study population (n = 15) and in the GHD adults (n = 10). In conclusion, 24-h patterns of GH release differed in GHD adults with low vs. normal serum IGF-I concentrations. GHD adults with low IGF-I levels maintain low ApEn ratios (denoting greater relative orderliness of GH secretion), whereas GHD patients with normal IGF-I values generate a high frequency, low amplitude GH output. The foregoing contrasts point to distinct neuroendocrine features of the GH-deficient state of adults, which can be related to concurrent IGF-I production.

Impact of two or three daily subcutaneous injections of hexarelin, a synthetic growth hormone (GH) secretagogue, on 24-h GH, prolactin, adrenocorticotropin and cortisol secretion in humans

To extend the insights on the action of GH secretagogues (GHS) on pituitary function, we studied the impact of intermittent daily s.c. administration of a peptidyl GHS, hexarelin (HEX), on 24-h GH, PRL, ACTH and cortisol release in healthy volunteers. We investigated the impact of two or three times daily s.c. administration of a short-acting peptidyl GHS, the hexapeptide HEX (1.5 microg/kg) on 24-h GH, PRL, ACTH and cortisol secretion (sampling every 20 min) in six normal young men. To monitor possible down-regulation, the effect of 1 microg/kg i.v. HEX at the end of each 24-h sampling period was studied. Multi-parameter deconvolution analysis was used to quantitate pulsatile GH, PRL, ACTH and cortisol secretion and estimate the corresponding hormone half-lives. Complementary to deconvolution analysis, approximate entropy was used as a scale- and model-independent statistic to quantify the serial orderliness or pattern regularity of hormone measurements. Mean and integrated (24-h) serum GH concentrations were increased from baseline values to the same extent by two and three HEX injections. Both HEX schedules equally increased GH secretory burst mass (but not burst frequency), mean daily GH production rate, GH half-life and irregularity of GH release patterns. No change occurred in the secretion of IGF-I, PRL, ACTH and cortisol. Intravenous HEX at the end of each spontaneous 24-h profile induced a significant rise in GH, PRL, ACTH and cortisol. Prior HEX administration blunted the GH response, abolished that of ACTH and cortisol and did not modify the PRL increase. The study showed that two or three daily s.c. injections of HEX augmented 24-h GH secretion equally, amplifying selectively GH secretory pulse mass without altering lactotroph and corticotroph secretion. IGF-I levels were not modified by these 1-day HEX treatment schedules.

Lowering Total Plasma Insulin-Like Growth Factor I Concentrations by Way of a Novel, Potent, and Selective Growth Hormone (GH) Receptor Antagonist, Pegvisomant (B2036-Peg), Augments the Amplitude of GH Secretory Bursts and Elevates Basal/Nonpulsatile GH Release in Healthy Women and Men

Lowering Total Plasma Insulin-Like Growth Factor I Concentrations by Way of a Novel, Potent, and Selective Growth Hormone (GH) Receptor Antagonist, Pegvisomant (B2036-Peg), Augments the Amplitude of GH Secretory Bursts and Elevates Basal/Nonpulsatile GH Release in Healthy Women and Men

Short-term estradiol supplementation augments growth hormone (GH) secretory responsiveness to dose-varying GH-releasing peptide infusions in healthy postmenopausal women.

Estrogen is a prominent stimulus to GH secretion throughout the human life span, albeit via neuroendocrine mechanisms that are incompletely defined. Here, we test the hypothesis that estradiol replacement in postmenopausal women enhances the responsiveness of the hypothalamo-pituitary unit to the GH-releasing effect of GH-releasing peptide-2 (GHRP-2). GHRP-2 is a potent and selective synthetic hexapeptide capable of activating an endogenous GHRP receptor/effector pathway, for which a (3)Ser-octanoylated 28-amino acid ligand was cloned recently. To examine this postulate, we studied 10 healthy estrogen-withdrawn postmenopausal women, who were given oral placebo or estrogen supplementation [1 mg micronized 17 beta-estradiol (E(2)) twice daily for 7-15 days] in a patient-blinded, prospective, randomized, and within-subject cross-over design. The GH-releasing actions of five semilogarithmically increasing doses of GHRP-2 (absolute range, 0.03-3 microg/kg by bolus iv infusion) vs. saline were evaluated by frequent blood sampling on separate days in the morning while fasting. Serum GH concentrations were determined in blood sampled every 10 min using an ultrasensitive chemiluminescence assay and analyzed by multiparameter deconvolution to calculate the summed mass of GH secreted during the 2-h interval after bolus GHRP-2 infusion. Logarithmically transformed secretory responses were compared across the different dosages of infused GHRP-2 by two-way repeated measures ANOVA. Estradiol replacement increased the global mean (+/-SEM) serum E(2) concentration from 15 +/- 0.8 to 470 +/- 17 pg/mL (55 +/- 2.9 to 1725 +/- 62 pmol/L; P = 0.004) and lowered insulin-like growth factor I levels by approximately 27% (P = 0.087). Administration of E(2) elevated the geometric mean basal (saline-infused) GH secretory burst mass by 2.1-fold (95% confidence interval, 1.4- to 3.1-fold) compared with placebo ingestion (geometric mean ratios; P < 0.001). E(2) exposure enhanced the efficacy of the highest GHRP-2 dose tested (3 microg/kg) by 2.1-fold (1.3- to 3.3-fold; P = 0.010). Compared with the effect of placebo and saline, E(2) combined with the highest dose of GHRP-2 stimulated GH secretory burst mass by a total of 31-fold (24- to 41-fold; P < 0.001). Random coefficient regression analysis of the relationship between the logarithm of GHRP-2 dose and GH secretory burst mass revealed that E(2) significantly augmented the amount of GH secreted per unit GHRP-2 dose (E(2), 16.6 +/- 1.8 slope units; placebo, 10.1 +/- 1.4 slope units; P = 0.03). Although the global mean endogenous GH half-life did not differ between the E(2) and placebo sessions (E(2), 18 +/- 0.6 min; placebo, 17 +/- 0.5 min), GH half-life varied directly with dose of GHRP-2 (and, hence, the mean serum GH concentration) in both the E(2) and placebo sessions (test of zero slope hypothesis, P = 0.0018). The deconvolved GH secretory burst peaked within 8-13 min of the bolus iv injection of GHRP-2, and this latency was not altered by E(2). Based on a mixed effects analysis of covariance model, GHRP-2 dose and E(2), but not the plasma insulin-like growth factor I concentration, determined the magnitude of the GH secretory response (P < 0.001). We conclude that short-term oral E(2) repletion in postmenopausal women selectively augments GH secretory pulse mass, enhances the steepness of the GHRP-2 dose-GH secretory response relationship (greater sensitivity), and heightens the maximal GH secretory response to the highest dose of GHRP-2 tested (greater efficacy). These data point to a facilitative interaction between E(2) and the GHRP receptor/effector pathway in driving the mass of GH secreted per burst.

Food deprivation and feeding of broiler chickens is associated with rapid and interdependent changes in the somatotrophic and thyrotrophic axes

1. In several experiments, hormonal changes in the somatotrophic axis, growth hormone (GH) sensitivity to a GH-secretagogue, thyroid hormones and their metabolising enzymes and plasma glucose levels were measured in relation to food deprivation and reinitiation after a single daily meal in 4- to 5-week-old male broiler chickens. 2. Floor-reared male broiler chickens were fed ad libitum or were restricted to a daily food intake of 40 or 45 g per d from the age of 2 weeks onwards. The daily food allowance was consumed in 0.5 h. 3. Food deprivation increased plasma GH concentrations but decreased GH-dependent variables such as plasma insulin-like growth factor-I and 3,3',5-triiodothyronine (T 3 ) concentrations. Hepatic inner ring deiodinating type III activity was markedly elevated, presumably as a consequence of low hepatic GH receptor numbers, and is thought to be the causal mechanism for the low plasma T 3 concentrations. Food intake reversed these variables in a time-related manner. 4. GH pulsatility characteristics, as calculated by deconvolution analysis, revealed profound changes between food restricted and ad libitum fed animals. Chickens deprived of food for about 23.5 h were characterised by an enhanced pulsatile GH release as reflected in the higher GH secretory burst amplitude, GH mass per burst, GH production rate and GH pulse frequency . These variables returned very quickly to normal values after refeeding. 5. In summary, these experiments taken together demonstrate very clearly the interdependent and timerelated changes of the somatotrophic and thyroid axes upon a single meal in previously food-deprived broiler chickens.

Tripartite Neuroendocrine Activation of the Human Growth Hormone (GH) Axis in Women by Continuous 24-Hour GH-Releasing Peptide Infusion: Pulsatile, Entropic, and Nyctohemeral Mechanisms1

Despite the discovery of potent GH-releasing peptides (GHRPs) more than 15 yr ago and the recent cloning of human, rat, and pig GHRP receptors in the hypothalamus and pituitary gland, the neuroregulatory mechanisms of action of GHRP agonists on the human hypothalamo-somatotroph unit are not well delineated. To gain such clinical insights, we evaluated the ultradian (pulsatile), entropic (pattern orderliness), and nyctohemeral GH secretory responses during continuous 24-h i.v. infusion of saline vs. the most potent clinically available hexapeptide, GHRP-2 (1 microg/kg x h) in estrogen-unreplaced (mean serum estradiol, 12 +/- 2.4 pg/mL) postmenopausal women (n = 7) in a paired, randomized design. Blood was sampled every 10 min for 24 h during infusions and was assayed by ultrasensitive GH chemiluminescence assay. Pulsatile GH secretion was quantitated by deconvolution analysis, orderliness of GH release patterns by the approximate entropy statistic, and 24-h GH rhythmicity by cosinor analysis. Statistical analysis revealed that GHRP-2 elicited a 7.7-fold increase in (24-h) mean serum (+/-SEM) GH concentrations, viz. from 0.32 +/- 0.042 (saline) to 2.4 +/- 0.34 microg/L (GHRP-2; P = 0.0006). This occurred via markedly stimulated pulsatile GH release, namely a 7.1-fold augmentation of GH secretory burst mass: 0.87 +/- 0.18 (control) vs. 6.3 +/- 1.3 microg/L (GHRP-2; P = 0.0038). Enhanced GH pulse mass reflected a commensurate 10-fold (P = 0.023) rise in GH secretory burst amplitude [maximal GH secretory rate (micrograms per L/min) attained within a secretory pulse] with no prolongation in event duration. GH burst frequency, interpulse interval, and calculated GH half-life were all invariant of GHRP-2 treatment. Concurrently, as detected in the ultrasensitive GH assay, GHRP-2 augmented deconvolution-estimated interpulse (basal) GH secretion by 4.5-fold (P = 0.025). The approximate entropy of 24-h serum GH concentration profiles rose significantly during GHRP-2 infusion; i.e. from 0.592 +/- 0.073 (saline) to 0.824 +/- 0.074 (GHRP-2; P = 0.0011), signifying more irregular or disorderly GH release patterns during secretagogue stimulation. Cosinor analysis of 24-h GH rhythms disclosed a significantly earlier (daytime) acrophase at 2138 h (+/- 140 min) during GHRP-2 stimulation vs. 0457 h (+/-42 min) during saline infusion (P = 0.013). Concomitantly, the cosinor amplitude rose 6-fold (P = 0.018), and the mesor (cosine mean) rose 5-fold (P = 0.003). Fasting (0800 h) plasma insulin-like growth factor (IGF-I) concentrations rose by -11 +/- 12 microg/L during saline infusion and by 102 +/- 18 microg/L during GHRP-2 infusion (P = 0.0036). GHRP-2 infusion did not modify (24-h pooled) serum LH, FSH, or TSH concentrations and minimally increased serum (pooled) daily PRL (6.8 +/- 0.83 vs. 12 +/- 1.2 microg/L; P < 0.05) and cortisol (5.3 +/- 0.59 to 7.0 +/- 0.74; P < 0.05) concentrations. In summary, 24-h constant iv GHRP-2 infusion in the gonadoprival female neurophysiologically activates the GH-IGF-I axis by potentiating GH secretory burst mass and amplitude by 7- to 10-fold and augmenting the basal (nonpulsatile) GH secretion by 4.5-fold. GHRP-2 action is highly selective, as it does not alter GH secretory burst frequency, interpulse interval, event duration, or GH half-life. GHRP-2 effectively elevates IGF-I concentrations, unleashes greater disorderliness of GH release patterns, and heightens the 24-h rhythmicity of GH secretion. These tripartite features of GHRP-2's action in estrogen-withdrawn (postmenopausal) women also characterize normal human puberty and/or sex steroid regulation of the GH-IGF-I axis. However, how or whether GHRP-2 interacts further with sex hormone modulation of GH neurosecretory control in older women and men is not yet known.

Increased disorderliness and decreased mass and daily rate of endogenous growth hormone secretion in adult turner syndrome: the impact of body composition, maximal oxygen uptake and treatment with sex hormones

The objectives of this study were to (1) quantify pulsatility and orderliness of 24-h growth hormone (GH) secretion in adult Turner syndrome; (2) study the impact of sex steroid replacement therapy in adult Turner syndrome on these measures of GH secretion, and in addition examine the differential effect of oral vs transdermal estrogen administration on GH secretion patterns. To these ends, we used deconvolution analysis and approximate entropy (ApEn) to quantify GH release over 24 h in 21 patients with Turner syndrome before and during sex hormone substitution, compared to an age-matched control group. Deconvolution analysis revealed that the mass of GH secreted per burst and production rate was significantly lower in Turner patients compared to controls, resulting in a significantly lower integrated 24-h GH concentration. However, multiple stepwise regression revealed that lean body mass (LBM) and maximal oxygen uptake were significant discriminative variable, explaining a large part of the variation in mass secreted per burst (r = 0.72, P < 0.0005) and production rate (r = 0.73, P < 0.0005), while group (Turner or control) did not explain any of the difference. There was a significant difference in ApEn between Turner patients and controls, denoting more disorderly GH release in Turner syndrome. During administration of sex hormones, a significant increase was seen in basal secretion and GH secretory burst half-duration, as well as in integrated 24-h GH concentration. No change in ApEn was evident. We conclude that GH secretion in adult Turner syndrome is irregular, reduced in mass and production rate. The reduction in mass and production rate could be explained by differences in body composition and maximal oxygen uptake compared to relevant controls, while the irregularity of GH secretion was unexplained by the measured variables. We hypothesize that the increased irregularity could be attributable to low levels of circulating androgens or an increased biological age in the Turner patients.

Pyridostigmine treatment selectively amplifies the mass of GH secreted per burst without altering GH burst frequency, half-life, basal GH secretion or the orderliness of GH release

Growth hormone (GH) release from the anterior pituitary gland is predominantly regulated by the two antagonistic hypothalamic peptides, growth hormone-releasing hormone (GHRH) and somatostatin. Appraising endogenous GHRH action is thus made difficult by the confounding effects of (variable) hypothalamic somatostatin inhibitory tone. Accordingly, to evaluate endogenous GHRH actions, we used a clinical model of presumptively acute endogenous somatostatin withdrawal with concomitant GHRH release. To this end, we administered in randomized order placebo or the indirect cholinergic agonist, pyridostigmine, for 48 h to 13 healthy men of varying ages (29-77 years) and body mass indices (21-47 kg/m2). We sampled blood at 10-min intervals for 48 h during both placebo and pyridostigmine (60 mg orally every 6 h) administration, and used an ultrasensitive GH chemiluminescence assay (sensitivity 0.0002-0.005 microgram/l) to capture GH pulse profiles. Multiparameter deconvolution analysis was applied to quantitate the number, amplitude, mass, and duration of significant underlying GH secretory bursts, and simultaneously estimate the GH half-life and concurrent basal GH secretion. Approximate entropy was utilized as a novel regularity statistic to quantify the relative orderliness of the hormone release process. All measures of GH secretion/half-life and orderliness were statistically invariant across the two consecutive 24-h placebo sessions. In contrast, pyridostigmine treatment significantly increased the mean serum GH concentration from 0.23 +/- 0.054 microgram/l during placebo to 0.45 +/- 0.072 microgram/l during the first day of treatment (P < 0.01). There was also a significant rise in the calculated 24-h pulsatile GH production rate from 8.9 +/- 1.7 micrograms/l/day on placebo to 27 +/- 5.6 micrograms/l/day during active drug treatment (P < 0.01). Pyridostigmine significantly and selectively amplified GH secretory burst mass to 1.5 +/- 0.35 micrograms/l compared with 0.74 +/- 0.19 microgram/l on placebo (P < 0.01). This was attributable to stimulation of GH secretory burst amplitude (maximal rate of GH secretion attained within the release episode) with no prolongation of estimated burst duration. Basal GH secretion and approximate entropy were not altered by pyridostigmine. However, age was strongly related to more disorderly GH release during both days of pyridostigmine treatment (r = +0.79, P = 0.0013). During the second 24-h of continued pyridostigmine treatment, most GH secretory parameters decreased by 15-50%, but in several instances remained significantly elevated above placebo. Body mass index, but not age, was a significantly negative correlate of the pyridostigmine-stimulated increase in GH secretion (r = -0.65, P = 0.017). In summary, assuming that somatostatin is withdrawn and (rebound) GHRH release is stimulated via pyridostigmine administration, we infer that relatively unopposed GHRH action principally controls GH secretory burst mass and amplitude, rather than apparent GH secretory pulse duration, the basal GH secretion rate, or the serial regularity/orderliness of the GH release process in the human. Moreover, we infer that increasing age is accompanied by greater disorderliness of somatostatin-withdrawn GHRH, and hence rebound GH, release. The strongly negative correlation between pyridostigmine-stimulated GH secretion and body mass index (but not age) further indicates that increased relative adiposity may result in decreased effective (somatostatin-withdrawn) endogenous GHRH stimulus strength.

Impaired secretion of growth hormone in experimental uremia: Relevance of caloric deficiency

To evaluate the impact of uremia and associated caloric restriction on physiologically pulsatile growth hormone (GH) release, we used deconvolution analysis of spontaneous plasma GH profiles in 5/6-nephrectomized male rats (NX, N = 9). Three different normal renal function sham-operated groups were used: rats fed a normal diet ad libitum (SAL, N = 9); NX pair-fed rats (SPF, N = 6); NX rats pair-fed for protein ingestion but calorically supplemented up to the energy intake of SAL (SPF+, N = 8). Severe renal failure was confirmed by much higher (P < 0.001) BUN in NX than sham groups. NX rats were growth retarded as shown by reduced (P < 0.01) weight and length gains as compared with sham animals. Deconvolution analysis (mean +/- SEM) of plasma samples obtained every 10 minutes over 6 hours, and 14 to 16 days after second stage nephrectomy showed that NX rats had a longer GH t(1/2) (17.0 +/- 1.8 vs. 11.6 +/- 0.8 min), less GH mass secreted per burst (48 +/- 15 vs. 95 +/- 16 ng/ml/pulse), lower secretory pulse amplitude (1.9 +/- 0.5 vs. 5.8 +/- 0.9 ng/ml/min), and a reduced total GH secretion (240 +/- 69 vs. 400 +/- 56 ng/ml/6 hr) than SAL rats. Corresponding data were not significantly different between NX and SPF, or between SAL and SPF+ groups. In summary, stunted rats with chronic renal failure exhibit a prolonged GH t(1/2) and suppression of GH secretory pattern burst mass. Control data from rats with normal renal function suggest that the amplitude-specific depression of GH secretion may be attributed, at least in part, to chronic renal failure-associated calorie deficiency.

Compensatory growth of broiler chickens is associated with an enhanced pulsatile growth hormone (GH) secretion: Preferential amplification of GH secretory burst mass

1. The present study was conducted to establish the effect of compensatory growth of broiler chickens on pulsatile growth hormone (GH) secretion. 2. Exposing male broiler chickens to intermittent lighting (IL) at 10 d of age was associated with a transient reduction in body weight gain which was followed by compensatory growth from 4 weeks of age onwards. At 34 d of age, cannulated IL broiler chickens manifesting compensatory growth and control chickens reared under continuous illumination (CL) were serially sampled at 10 min intervals over 5 consecutive hours and plasma GH concentrations measured. The resultant GH time series were analysed by deconvolution analysis. 3. The overall mean GH concentration was higher for IL than for GL broilers. The burst frequency did not differ between lighting treatments, but during each GH surge, IL broilers released a higher GH mass which resulted in higher GH amplitude values. As a consequence, GH production rates of IL broilers during the entire sampling session were markedly elevated compared to those of dieir age‐matched CL broilers. There were no differences in the monoexponential GH half‐life. 4. Compensatory growth in broiler chickens is associated with an amplification of GH secretory burst mass. The underlying causal mechanisms remain to be elucidated.

The orderliness of the growth hormone (GH) release process and the mean mass of GH secreted per burst are highly conserved in individual men on successive days.

Endocrine glands signal their remote target tissues via physiologically pulsatile release of regulatory molecules. A cardinal assumption of most pathophysiological experiments is that discrete attributes of pulsatile hormone secretion are stable over successive untreated observation intervals; i.e. repeated measurements show serial within-subject reproducibility. To test this hypothesis in the GH axis, we sampled blood every 10 min for 48 h in 14 healthy men (age range, 29-77 yr; body mass index, 21-51 kg/m2). The 2 consecutive 24-h serum profiles were subjected to ultrasensitive GH chemiluminescence assay (sensitivity, 0.002 micrograms/L) with a new dose-dependent variance model to estimate within-assay precision. We then applied deconvolution analysis to estimate the number, mass, amplitude, and duration of underlying GH secretory bursts as well as simultaneously calculate the apparent GH half-life and any concurrent basal hormone secretion. Test-retest consistency was assessed by the Pearson correlation coefficient, and differences were determined by paired nonparametric (Wilcoxon) testing. Comparing successive 24-h profiles, no significant differences existed in any of the foregoing secretion or half-life measures or in a novel estimate of the relative disorderliness of hormone release, namely approximate entropy. Correlation was minimal for secretory burst amplitude and half-duration. In contrast, the calculated mean mass of GH secreted per burst was highly conserved across sessions within subjects, with an r value of 0.932 (P < 10(-6). This correlation equaled or exceeded that of mean and integrated serum GH concentrations on consecutive days (r = 0.920; P = 0.00003). The calculated daily GH production rate was also strongly reproduced (r = 0.784; P = 0.0009). Moreover, the within-subject GH half-life and GH secretory burst frequency estimates were well correlated on successive days (P = 0.034-0.004; r = 0.568-0.711). Approximate entropy values were consistent at r = 0.837 (P = 0.0019). In addition, basal GH secretion rates correlated at r = 0.622 (P = 0.0176). We conclude that homeostatic control mechanisms within the GH-insulin-like growth factor I axis strongly preserve the day to day mean mass of GH secreted per burst and the serial orderliness of the GH release process in individual healthy men across a wide span of ages and body compositions.

Somatostatin infusion suppresses GH secretory burst frequency and mass in normal men

In attempting to elucidate the neuroendocrine mechanisms that regulate pulsatile growth hormone (GH) secretion, we measured serum GH concentrations by an ultrasensitive immunofluorometric method in blood collected every 10 min for 8 h in 11 young healthy male volunteers (age range 21-31 yr) before and during somatostatin (SS) administration (an iv bolus dose of 350 micrograms followed by a continuous infusion at the rate of 6 micrograms.kg-1.h-1, which increases the circulating SS levels to approximately 570 pg/ml). Pulsatile GH secretion was analyzed using the computer-assisted pulse detection program cluster method and deconvolution analysis. The area and frequency of GH peaks were significantly reduced during SS infusion compared with basal values, but detectable pulsatile episodes were still present. These data suggest that, in adult males, SS controls pulsatile GH secretion and can decrease the mass and frequency of GH secretory bursts.