Haemodynamic effects of intravenous growth hormone in congestive heart failure.
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Cardiac Output↗
Biomedical subjects
A Giustina
Publications and source records attributed to A Giustina.
Growth hormone treatment in aging: state of the art and perspectives.
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Aging↗
Effects of tamoxifen on GH and IGF-I levels in acromegaly.
Tamoxifen (TAM), a non steroid partially competitive antagonist to the estrogen receptors, has been reported to decrease plasma GH and IGF-I levels both in vitro and in vivo. These data prompted us to evaluate GH and IGF-I changes in acromegaly after acute and chronic TAM administration. Nineteen acromegalic patients (6 M, 13 F, aged 30-70 years) were studied in a prospective open study. Acute TAM test (20 mg po) did not induce any significant change in GH and IGF-I levels. Chronic TAM treatment (20 mg/day for a month and 40 mg/day for another month) induced a transient increase in GH levels (from 9 [3-139] micrograms/l [median, range] to 12 [3-188] micrograms/l, p = 0.0025) and a persistent decrease in IGF-I levels (from 785 [500-1200] micrograms/l to 553 [209-1420] micrograms/l, p = 0.0034). Individual IGF-I values decreased in 13 patients and reached the normal range in 4 of them. At TAM withdrawal hormonal levels increased up to pretreatment values. There was no correlation between GH and IGF-I changes and results were not influenced by age, sex or gonadal status. In this setting it is likely that the observed decrease in plasma IGF-I levels is dependent on TAM activity at the hepatic level.
Acromegaly↗
Glutamate decarboxylase autoimmunity and growth hormone secretion in type I diabetes mellitus.
Insulin-dependent (type I) diabetic patients are known to have an exaggerated growth hormone (GH) response to GH-releasing hormone (GHRH), which is hypothesized to be due to a decrease in somatostatin tone. The aim of the study was to ascertain the influence of the presence and activity of the autoimmune process involving a key enzyme (glutamic acid decarboxylase [GAD]) in the synthetic pathway of a neurotransmitter regulating somatostatin secretion, ie, gamma-aminobutyric acid (GABA), on the GH response to GHRH alone or combined with an acetylcholinesterase inhibitor, pyridostigmine (PD), in patients with type I diabetes mellitus. Twenty non-obese type I diabetic patients and 17 normal subjects underwent an intravenous (IV) injection of 100 micrograms GHRH(1-29)NH2. Twelve of 20 diabetic subjects and all of the control subjects also underwent a second experimental procedure, administration of 120 mg oral PD 60 minutes before IV injection of 100 micrograms GHRH. Diabetic subjects with serum GAD antibody (GADA) levels more than 3 U (n = 10) showed significantly higher serum GH levels after GHRH injection as compared both with diabetic patients with GADA less than 3 U (n = 10) and with normal controls, whether expressed as absolute or peak values. GH peaks after GHRH were significantly (rs = .46, P < .05) correlated with the level of GADA in the whole population of type I diabetic subjects studied. PD significantly enhanced the GH response to GHRH, in terms of both absolute and peak values, in patients without GADA (n = 6) and in normal subjects. On the contrary, PD failed to enhance the GH response to GHRH in diabetic patients with GADA (n = 6). Our findings suggest that autoimmunity may play a key role in determining the exaggerated GH response to GHRH in type I diabetes mellitus. The mechanism underlying this effect is hypothesized to be the production of antibodies to GAD, a key enzyme in the synthesis of GABA, and in turn a reduced GABAergic stimulatory tone on somatostatin production at the hypothalamic level.
Adult↗
Inhibitory effects of galanin on growth hormone (GH) release in cultured GH-secreting adenoma cells: comparative study with octreotide, GH-releasing hormone, and thyrotropin-releasing hormone.
The aim of the present study was to characterize in a large series (N = 12) of cultured somatotrope adenomas the in vitro effects of the neuropeptide galanin on growth hormone (GH) secretion. This was contrasted with two peptides known to be GH secretagogues (GH-releasing hormone [GHRH] and thyrotropin-releasing hormone [TRH]) and a peptide with a known GH-inhibitory effect (the somatostatin analog octreotide). Groups of three wells were incubated for 4 hours with growth medium alone (control incubation), galanin, GHRH(1-29)NH2, TRH, or octreotide. Galanin and octreotide were applied at concentrations of 0.1, 1, and 10 mumol/L, and GHRH and TRH at concentrations of 0.01, 0.1, and 1 mumol/L. Galanin was able to inhibit GH release in nine of 12 cultured somatotrope adenoma cells. This inhibitory effect was clearly dose-dependent in five adenomas. Overall, the mean GH nadir after galanin was -36.1% in nine responder adenoma cultures versus control wells. Octreotide inhibited GH release in five of eight cultured somatotrope adenoma cells. The mean GH nadir after octreotide was -32.7% in five responder adenoma cultures compared with control wells. GHRH and TRH were able to stimulate GH release, respectively, in seven of 11 and in six of seven cultured somatotrope adenoma cells. The mean GH peaks after either GHRH or TRH in responder adenoma cultures were, respectively, +71.5% and +143.7% compared with levels in the control wells. In conclusion, the consistency and potency of the in vitro GH-inhibitory effect of galanin in a large series of somatotrope adenomas are at least similar to those of the most effective available GH-lowering agent, the somatostatin analog octreotide.
Adenoma↗
Physiological role of the opioid-cholinergic interaction in growth hormone neuroregulation: effect of sex and food intake.
Studies performed in animals and humans have suggested a functional interaction between opioid and cholinergic systems in the control of growth hormone (GH) secretion. Moreover, the sex-dependent modulation of GH secretion in humans is well established. To investigate the role of sex and food intake in the regulation of the reciprocal influences of opioids and acetylcholine in the modulation of GH secretion, we studied the GH response to pyridostigmine (PYR) alone and during a naloxone (NAL) infusion in a group of normal men and women before a meal (at 1:00 PM) and postprandially. In women, the response of GH to PYR alone before the meal was significantly lower than in the men (area under the curve [AUC], mean +/- SEM, 320.18 +/- 87.16 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Before the meal, NAL completely abolished the response of GH to PYR in men (AUC, 1,031.06 +/- 333.21 v 16.50 +/- 7.50 micrograms/L/90 min, P < .01), whereas infusion of NAL did not significantly modify the GH response to PYR in women. Consumption of the meal significantly decreased PYR-induced GH release in both women (AUC, 21.75 +/- 12.75 v 320.18 +/- 87.16 micrograms/L/90 min, P < .05) and men (AUC, 45.75 +/- 18.75 v 1,031.06 +/- 333.21 micrograms/L/90 min, P < .01). Conversely, food intake did not change the effects of NAL infusion on the GH response to PYR either in women or in men. We conclude that the sex-dependent opioid modulation of PYR-induced GH secretion is observed before a meal but not in the postprandial state. Food intake may be hypothesized to influence the cholinergic regulation of GH secretion and the sex-dependent opioid modulation of central cholinergic tone.
Adult↗
Effects of food deprivation on the GH axis: immunocytochemical and molecular analysis.
Neuroendocrine mechanisms governing growth hormone (GH) secretion are sensitive to nutritional status since the normal pulsatile pattern of GH release is disrupted during conditions of food deprivation or malnutrition. A reasonable hypothesis for this occurrence is the alteration of somatostatin and GH-releasing hormone (GHRH) synthesis, storage and secretion. In this study, we investigated the effects of food deprivation on GH, GHRH, hypothalamic and pituitary galanin (GAL), and somatostatin through immunocytochemical and mRNA analysis. Adult male rats were subjected to 72 h of food deprivation, during which an average of 18% total body weight was lost. ICC studies were performed on brain sections from the rostral, middle and caudal regions of the median eminence of the hypothalamus using the avidin-biotin-peroxidase method. Immunocytochemical results were generated for the percent area and optical density (intensity) of immunostaining in the median eminence. Messenger RNA analyses were performed using sense and antisense riboprobes produced from cDNA clones for GH, GHRH, somatostatin and GAL. Food deprivation decreased somatostatin immunostaining in middle and caudal regions of the median eminence; similarly, food deprivation resulted in decreased GHRH immunostaining in rostral and middle sections of the median eminence of the hypothalamus. mRNA levels for somatostatin, GHRH and GH and GAL were also reduced by food deprivation. Our data suggest that suppressed GH secretion in food-deprived rats may reflect a general downregulation of the neuroendocrine and pituitary GH axis.
Animals↗
Modulation by galanin of growth hormone and gonadotropin secretion from perifused pituitary and median eminence of prepubertal male calves.
Galanin is widely distributed in the peripheral and central nervous system and has been indicated as a putative hypothalamic-hypophysiotropic hormone. This study was performed to investigate the effects of galanin on both growth (GH) and luteinizing hormones (LH) from pituitaries of young male calves. Pituitary slices (P, 500 microm in thickness) were perfused alone or coincubated with median eminence terminals (ME) in DMEM-F12 plus BSA 0.1% and antibiotics. The perifusion chambers were kept in equilibrium for 150 min, and medium samples were collected every 10 min for 240 min and stored at -20 degrees C until the measurement of LH and GH levels. Basal GH release increased up to 60% after galanin infusion (p < 0.01 vs. baseline levels) for 60 min in P alone; in P + ME coincubation, galanin-stimulated GH secretion was further increased by up to 200%. Basal LH release in chambers with P was significantly increased (up to 25%; p < 0.05) for 70 min after galanin infusion; P + ME coincubation showed a galanin-mediated increase in LH release of up to 50%. GH and LH responsiveness to exogenous GH-releasing hormone and gonadotropin-releasing hormone was not significantly modulated by galanin in our experimental model. In conclusion, galanin is demonstrated to have a significant stimulatory role in the secretion of GH and LH, with a combined action at both the hypothalamic and pituitary levels. ......................
Animals↗
Maturation of the regulation of growth hormone secretion in young males with hypogonadotropic hypogonadism pharmacologically exposed to progressive increments in serum testosterone.
To study the onset of the action of gonadal sex steroids on the GH axis in spontaneous puberty, which is prolonged and sparingly predictable, we present a clinical investigative paradigm in which six previously untreated boys with isolated hypogonadotropic hypogonadism were exposed to progressively higher testosterone levels designed to mimic the androgen environment recognized during the early stages of puberty. We administered three incremental doses of testosterone (25-, 50-, and 100-mg im injections), each over a period of 4 weeks. Studies of overnight pulsatile GH secretion and GH responses to GHRH alone or combined with L-arginine (a functional somatostatin antagonist) were performed before testosterone administration and after each dose of testosterone. Serum testosterone, but not estrogen, levels increased progressively in all subjects during therapy. Deconvolution analysis of GH release profiles disclosed that GH secretory burst mass was stimulated significantly even by 25 mg testosterone. This parameter was not altered further by higher doses of testosterone. Spontaneous GH secretory burst number and amplitude increased significantly only after the 50- and 100-mg testosterone treatments, after which the serum GH response to GHRH and arginine also rose significantly. In contrast, the GH response to GHRH alone was not significantly affected by any dose of testosterone. Serum testosterone levels correlated significantly with the primary parameters of nocturnal GH secretion. In summary, our experimental model suggests that in males even very small increases in circulating testosterone occurring during the earliest stages of puberty are able to amplify pulsatile GH secretion. Our concomitant secretagogue data further suggest that testosterone exerts its action at different sites in the hypothalamo-somatotropic axis, i.e. directly at the pituitary level, and also at hypothalamic loci, possibly increasing both GHRH and somatostatin release.
Adolescent↗
Effect of galanin on growth hormone (GH) response to thyrotropin releasing hormone of rat pituitary GH-secreting adenomatous cells (GH1) in culture.
The growth hormone (GH) releasing effect of thyrotropin-releasing hormone (TRH) and galanin, a 29-amino acid peptide widely distributed in mammalian CNS, alone or in combination was investigated in cultured rat pituitary tumor cells (GH1). TRH stimulated GH secretion in GH1 cells (maximal stimulation at the dose of 0.1 microM). Galanin alone had a significant GH inhibitory effect in GH1 cells at all the doses used. When the two peptides were administered in combination, no significant changes as compared to baseline levels were observed. The results of this study indicate that galanin has potent direct inhibitory effects on baseline and TRH-stimulated GH release from rat tumor cells.
Adenoma↗
Impaired spontaneous growth hormone secretion in severe dialated cardiomyopathy.
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Cardiomyopathy, Dilated↗
Hypothalamic control of growth hormone (GH) secretion in type I diabetic men: effect of the combined administration of GH-releasing hormone and hexarelin, a novel GHRP-6 analog.
Insulin dependent (type I) diabetic patients show abnormal growth hormone (GH) secretion. Hexarelin is an analog of GHRP-6 which releases GH in part via somatostatin inhibition. The aim of our study was to evaluate the effects of hexarelin and GHRH, administered either alone or in combination, on GH secretion in 10 type I diabetic and 7 normal men. All the subjects were administered: 1) human GHRH (1-29) NH2 100 micrograms i.v. bolus at 0 min; 2) hexarelin 100 micrograms i.v. bolus at 0 min; 3) hexarelin 100 micrograms + hGHRH 100 micrograms i.v. bolus at 0 min. In type I diabetic patients significantly greater GH responses to GHRH and hexarelin have been observed with normal subjects. Hexarelin caused a significantly (p < 0.05) greater GH response as compared to GHRH in both diabetic and control subjects. After the administration of hexarelin+GHRH, a significant increase in both GH absolute and peak levels as compared to hexarelin or GHRH alone was found in all the subjects. However, the GH responses to the combined stimuli were not significantly different in diabetics as compared to normals; moreover, the interaction of GHRH and hexarelin was synergistic in controls and additive in diabetics. We hypothesize that a reduction in the hypothalamic somatostatin inhibitory tone combined with increased pituitary GH production may be responsible for the pattern of the GH responses to hexarelin and GHRH observed in our type I diabetic patients.
Adult↗
Immunocytochemical and molecular analysis of the effects of glucocorticoid treatment on the hypothalamic-somatotropic axis in the rat.
Glucocorticoids are potent inhibitors of linear growth and growth hormone (GH) secretion when secreted or administered in pharmacological amounts in vivo. The mechanisms involved require further clarification although enhanced somatostatin tone has been suggested to play a role. In this study, we investigated the effects of excess glucocorticoids on pituitary GH, hypothalamic GHRH and hypothalamic somatostatin through immunocytochemical (ICC) and mRNA analysis. Twelve adult male rats were injected daily with dexamethasone (40 micrograms/day, i.p.) or saline for 4 days. ICC studies were performed on brain sections from the rostral, middle and caudal regions of the median eminence of the hypothalamus using the avidin-biotin-peroxidase method. Messenger RNA analyses were performed using sense and antisense riboprobes produced from GH, GHRH and somatostatin cDNAs. Immunocytochemical results were generated for the percent area and intensity (optical density) of immunostaining in the median eminence. Glucocorticoids increased somatostatin immunostaining of the rostral, middle and caudal regions of the median eminence while GHRH staining was only reduced in the rostral region of the median eminence and unchanged in the other hypothalamic regions. GH and somatostatin mRNA levels dramatically increased following glucocorticoid treatment concomitantly with a decrease in GHRH mRNA levels. Our data suggest that increased somatostatin synthesis and storage and a decrease in GHRH mRNA synthesis play a major role in the GH inhibitory effects of glucocorticoids.
Animals↗
Cardiopulmonary performance during exercise in acromegaly, and the effects of acute suppression of growth hormone hypersecretion with octreotide.
We studied 10 adult patients with active acromegaly (4 men and 6 women, mean age 55 +/- 5 years and mean body mass index 27.9 +/- 1.1 kg/m2). Control values for the echocardiographic and exercise studies were obtained from 10 normal subjects matched for sex and age (5 men and 5 women, age 51.1 +/- 3.7 years and body mass index 25.3 +/- 1 kg/m2). Each patient underwent: (1) blood sampling for growth hormone (GH) assay every 3 hours; (2) a 2-dimensional, guided M-mode echocardiographic study; and (3) a cycloergometric exercise test at baseline and after treatment with a portable pump infusing octreotide, 500 micrograms/24 hours subcutaneously. All patients had left ventricular hypertrophy. Systolic function indexes did not significantly differ among normal subjects, whereas baseline Doppler studies showed abnormalities in left ventricular diastolic filling in acromegalic patients. At anaerobic threshold and at maximal exercise, acromegalic subjects sustained a significantly (p < 0.05) decreased workload (54 +/- 23 vs 94 +/- 11 and 87 +/- 37 vs 152 +/- 15 W) compared with control subjects. After octreotide, baseline heart rate (79 +/- 7 vs 87 +/- 8 beats/min, p < 0.05) and serum GH levels significantly decreased compared with levels before administration of octreotide. Systolic and diastolic functional indexes at rest significantly improved after octrotide in acromegalic patients. Both at anaerobic threshold and at maximal exercise, workload and oxygen consumption were significantly increased after octretide administration. Exercise capacity at anaerobic threshold was not significantly different in acromegalic subjects after octreotide when compared with normal subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Acromegaly↗
Relationship between pharmacokinetics and pharmacodynamics of eptastigmine in young healthy volunteers.
Eptastigmine is a long-lasting acetyl-cholinesterase inhibitor, currently being developed for the symptomatic treatment of Alzheimer's disease. In the present study, we investigated the relationship between pharmacokinetics and pharmacodynamics of eptastigmine in young healthy volunteers. Eight male subjects received single oral doses of 10, 20, and 30 mg of eptastigmine and placebo according to a double-blind, randomized, crossover design. Blood was collected before and 0.5, 1, 1.5, 2, 3, 4, 6, and 24 hours after drug administration. Cholinesterase activity was measured using a potentiometric method in both plasma (butyryl-cholinesterase) and in red blood cells (acetyl-cholinesterase). Eptastigmine plasma levels were measured by a very sensitive high-performance liquid chromatography method (limit of quantitation 0.2 ng/mL). Eptastigmine plasma concentrations increased proportionally with the dose (mean +/- SEM AUC0-24 was 0.74 +/- 0.58, 3.61 +/- 1.15, and 6.25 +/- 1.51 ng.h/mL with 10, 20, and 30 mg, respectively) and were undetectable at 24 hours. The inhibition of acetyl-cholinesterase was dose-dependent (peak inhibition was 15 +/- 2%, 30 +/- 4%, and 36 +/- 6% with 10, 20, and 30 mg, respectively) and long-lasting, with a residual inhibition of 8 to 11% at 24 hours. Acetyl-cholinesterase inhibition and drug plasma levels were related over time with a counterclockwise hysteresis curve, suggesting the formation of active metabolites and/or a slow association to and dissociation from the enzyme in red blood cells. Butyryl-cholinesterase inhibition was weak and not dose-dependent (peak inhibition was 12 +/- 4%, 13 +/- 3%, and 12 +/- 2% with 10, 20, and 30 mg, respectively). The drug was well tolerated by all subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effect of two beta 2-agonist drugs, salbutamol and broxaterol, on the growth hormone response to exercise in adult patients with asthmatic bronchitis.
The aim of our study was to evaluate the effect of the iv administration of two different beta 2- receptors agonists, salbutamol and broxaterol, on the growth hormone (GH) response to maximal exercise in 11 patients (8 males and 3 females; age range 18-65 yr; mean +/- SE age 56 +/- 13 yr; BMI 26.2 +/- 1.4 kg/m2) with chronic asthmatic bronchitis. All the subjects underwent four cycloergometric exercise tests (incremental workload until maximal predicted heart rate). At baseline, at maximal exercise, at the end of the recovery period and 60 min after the end of each exercise, blood samples were drawn for the assay of GH, glucose, insulin, lactates, norepinephrine and epinephrine. Two exercises were performed without treatment while the remaining two were performed 60 min after the administration of 400 micrograms of either salbutamol or broxaterol (both diluted in 10 ml of saline) according to a randomized double blind cross-over design. Both exercise tests performed without treatment caused a significant (p < 0.05) and similar GH peak with respect to baseline values (from 0.3 +/- 0.1 micrograms/L to 2.8 +/- 1.3 micrograms/L, mean of the two exercise tests). Salbutamol pretreatment blunted the GH response to exercise which caused a no more significant serum GH peak over the baseline levels (from 0.6 +/- 0.2 micrograms/L to 1.4 +/- 0.6 micrograms/L,). Moreover, broxaterol completely abolished the GH response to exercise (baseline level 0.6 +/- 0.2 micrograms/L; peak levels 0.4 +/- 0.1 micrograms/L). The serum GH peak after exercise + broxaterol was significantly (p < 0.05) lower as compared to exercise + salbutamol. In conclusion, we have demonstrated for the first time that beta 2 stimulation blunts the physiological GH response to maximal exercise in adult human subjects. It can be suggested that changes in brain neurotransmitters, possibly an increase in the alpha-adrenergic tone, are likely to be involved in this endocrine effects of exercise.
Adolescent↗
Effect of GHRP-6 and GHRH on GH secretion in rats following chronic glucocorticoid treatment.
The aim of our study was to investigate the effects of His-DTrp-Ala-Trp-Phe-Lys-NH2 (GHRP-6) on baseline and growth hormone-releasing hormone (GHRH) stimulated growth hormone (GH) release in conscious, freely-moving rats receiving chronic glucocorticoid treatment. Animals were treated daily for seven days with either vehicle or dexamethasone (dex, 40 micrograms/day). On the day of experimentation, rats received an i.v. injection of saline or GHRP-6 followed 15 min later by an i.v. injection of saline or rat GHRH. Three doses of GHRP-6 were evaluated, 1 microgram, 4 micrograms and 25 micrograms/kg; one dose of GHRH was evaluated, 500 ng/kg. GHRP-6 increased plasma GH levels over baseline concentrations in a dose-dependent fashion both in vehicle- and dex-treated rats. The GH response to GHRP-6 and GHRH was significantly less in dex-treated rats as compared to vehicle-treated rats. The combined administration of GHRP-6 and GHRH did not result in any change in plasma GH levels which could not be predicted from the administration of either peptide alone. Our results show that GHRP-6 is able to stimulate GH secretion in glucocorticoid-treated rats but it is unable to counteract the glucocorticoid-induced inhibition of GH secretion.
Amino Acid Sequence↗
Role of galanin in the regulation of somatotrope and gonadotrope function in young ovulatory women.
The aim of the study was to elucidate the role of the neuropeptide galanin in the regulation of somatotropic and gonadotropic function in normal women. Thirteen normally ovulating (aged 28 to 40 years), non-obese (body mass index, 18.4 to 27.1 kg/m2) women with infertility due to a tubal or male factor were studied. Each woman underwent three tests: (1) bolus intravenous (IV) injection of growth hormone (GH)-releasing hormone (GHRH) (1-29)NH2 1 microgram/kg plus gonadotropin-releasing hormone (GnRH) 100 micrograms at time 0; (2) IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 minutes; and (3) bolus IV injection of GHRH(1-29)NH2 1 microgram/kg plus GnRH 100 micrograms at time 0 plus IV infusion of porcine galanin 500 micrograms in 100 mL saline from -10 to +30 minutes. All results are expressed as the mean +/- SEM. GH peak after GHRH was 14 +/- 5 micrograms/L; porcine galanin significantly increased serum GH (GH peak, 7.3 +/- 1.2) with respect to baseline levels. No significant differences were observed between either GH peak or GH absolute values after galanin as compared with GHRH alone. Porcine galanin significantly enhanced GH response to GHRH (peak, 31.4 +/- 4.4 micrograms/L) with respect to either GHRH or galanin alone. Luteinizing hormone (LH)/follicle-stimulating hormone (FSH) peaks after GnRH were 16.5 +/- 5.3 and 17.4 +/- 4 IU/L, respectively. Porcine galanin did not cause significant increases in serum LH and FSH levels with respect to baseline.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗