Alcoholism abolishes the growth hormone response to sumatriptan administration in man

To assess the possible influence of alcoholism on serotonergic control of growth hormone (GH) secretion, 6 mg of the 5-HT1D serotonergic receptor agonist, sumatriptan, was injected subcutaneously in a group of nine normal controls (aged 32 to 49 years) and in nine age-matched nondepressed male alcoholic subjects after 10 to 25 days of abstinence from alcohol. During the same period, subjects were also tested with GH-releasing hormone ([GHRH] 1 microgram/kg body weight in an intravenous [i.v.] bolus) and L-arginine, which releases GH from somatostatin inhibition (50 g in 50 mL normal saline over 30 minutes) to determine whether GH secretion in response to alternate secretagogues is preserved in alcoholics. A control test with administration of normal saline instead of drug treatments was also performed. Plasma GH levels were recorded over 2 hours in all tests. Administration of placebo did not change plasma GH levels in any subject. Similar GH responses were observed in normal controls and alcoholic subjects when GHRH or arginine were administered. A significant GH increase was observed in normal controls after sumatriptan injection; in contrast, GH secretion was not modified by sumatriptan administration in alcoholic patients. These data show that alcoholism is associated with an impairment in the serotonergic-stimulatory regulation of GH secretion, whereas GH responses to direct pituitary stimulation with GHRH or to release from somatostatinergic inhibition with arginine appear to be preserved in alcoholics.     

Dynamics of growth hormone secretion in patients with primary hypothyroidism, before and after treatment with thyroideal hormones

Growth hormone (GH) secretion was studied in a group of alut controls and a series of patients with primary hypothyroidism before and after treatment with thyroid hormones. Intravenous insulin-induced hypoglycemia was the stimulus used (0,1 UI/kg body weight). It is concluded that in primary hypothyroidism, GH secretion is almost absent due to relative inactivity of the somatotropic cells and/or lack of GH-RH. This decreased secretory response becomes rapidly normal after treatment with physiological doses of thyroid hormones.     

Effect of acute pharmacological reduction of plasma free fatty acids on growth hormone (GH) releasing hormone-induced GH secretion in obese adults with and without hypopituitarism

In obesity, there is a markedly decreased GH secretion. The diagnosis of GH deficiency (GHD) in adults is based on peak GH responses to stimulation tests. In the severely obese, peak GH levels after pharmacological stimulation are often in the range that is observed in hypopituitary patients. To distinguish obese subjects from GHD patients, it will be necessary to demonstrate that reduced GH responsiveness to a given test is reversible in the former, but not in the latter, group. Recent studies have shown that reduction of plasma free fatty acids (FFA) with acipimox in obese patients restores their somatotrope responsiveness. There are no data evaluating GH responsiveness to acipimox plus GHRH in obese adults with hypopituitarism. The aim of the present study was to evaluate the effect of acute pharmacological reduction of plasma FFA on GHRH-mediated GH secretion in obese normal subjects and obese adults with hypopituitarism. Eight obese patients with a body mass index of 34.2+/-1.2; eight obese adults with hypopituitarism, with a body mass index of 35.5+/-1.9; and six control subjects were studied. All the patients showed an impaired response to an insulin-tolerance test (0.15 U/kg, i.v.), with a peak GH secretion of less than 3 microg/L. Two tests were carried out. On one day, they were given GHRH (100 microg, i.v., 0 min), preceded by placebo; and blood samples were taken every 15 min for 60 min. On the second day, they were given GHRH (100 microg, i.v., 0 min), preceded by acipimox (250 mg, orally, at -270 min and -60 min); and blood samples were taken every 15 min for 60 min. The administration of acipimox induced a FFA reduction during the entire test. Normal control subjects had a mean peak (microg/L) of 23.8+/-4.8 after GHRH-induced GH secretion; previous acipimox administration increased GHRH-induced GH secretion, with a mean peak of 54.7+/-14.5. In obese patients, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 3.9+/-1; previous administration of acipimox markedly increased GHRH-mediated GH secretion, with a mean peak of 16.0+/-3.2 (P < 0.05). In obese adults with hypopituitarism, GHRH-induced GH secretion was markedly reduced, with a mean peak (microg/L) of 2+/-0.7; previous acipimox administration did not significantly modify GHRH-mediated GH secretion, with a mean peak of 3.3+/-1.1 (P < 0.05). The GH response of obese patients and obese adults with hypopituitarism was similar after GHRH alone. In contrast, the GH response after GHRH plus acipimox, was markedly decreased in obese adults with hypopituitarism (mean peak, 3.3+/-1.1), compared with obese patients (mean peak, 16.0+/-3.2) (P < 0.05) and control subjects (mean peak, 54.7+/-14.5) (P < 0.01). In conclusion, GH secretion, after GHRH-plus-acipimox administration, is reduced in obese adults with hypopituitarism patients, when compared with obese normal patients. Testing with GHRH plus acipimox is safe and is free from side effects and could be used for the diagnosis of GHD in adults.     

Neural networks in the analysis of episodic growth hormone release

Pulsatile secretion of growth hormone (GH) has been observed in healthy controls as well as acromegalic patients. In healthy adults, highly regulated secretory pulses of GH occur 4-8 times within 24 h. This episodic pattern of secretion seems to be related to the optimal induction of physiological effects at the peripheral level. In contrast to normal subjects, acromegalic patients demonstrate an irregular pattern of excessive GH release. This pattern of secretion is responsible for many systemic effects, such as the stimulation of connective tissue growth, cardiovascular and cerebrovascular disease, diabetes mellitus and arthritis. Standard methods for the analysis of pulsatile patterns of hormone secretion did not consistently separate the temporal dynamics of GH release in healthy controls and acromegalic patients under various study conditions. Using the cutting edge technology of artificial neural networks for time series prediction, we were able to achieve significant separation of both groups under various conditions by means of the predictability of their GH secretory dynamics. Improving the predictive results by using a more refined system of multiple neural networks acting in parallel (adaptive mixtures of local experts), we found that this system performed a self-organized segmentation of hormone pulsatility. It separated phases of secretory bursts and quiescence without any prior knowledge of the form of a GH pulse or a model of secretion. Comparing the predictive results for the GH dynamics with those for computer-stimulated stochastic processes, we were able to define the irregular pattern of GH secretion in acromegaly as a random autonomous process. The introduction of neural networks to the analysis of dynamic endocrine systems might help to expand the existing analytical approaches beyond counting frequency and amplitude of hormone pulses.     

Elevated nocturnal profiles of serum leptin in patients with depression

Leptin, the protein product of the obese (ob) gene, has been suggested to play a role in the regulation of food intake. As depressive episodes are frequently characterized by loss of appetite, reduced food intake and weight loss, altered leptin secretion might also be expected in patients with depression. Therefore, we examined nocturnal (10.00 p.m. to 7.00 a.m.) secretion of leptin, cortisol, ACTH and growth hormone (GH) in a group of 15 patients with depression and age- and sex-matched controls (age range 23-71 years). In addition, the effects of pulsatile administration of growth hormone-releasing hormone (GHRH), thought to be an endogenous antagonist of corticotropin-releasing hormone (CRH), which in turn is believed to play a critical role for the pathophysiology of depression, on nocturnal hormone secretion were assessed. Patients with depression showed a trend towards elevated nocturnal cortisol secretion (F = 3.8, p < 0.05). Nocturnal serum leptin was significantly higher in patients, despite a reported weight loss (F = 8, p < 0.05), but showed the same sexual dimorphism as in controls (F = 20.9, p < 0.01). No significant differences were seen between patients and controls with regard to plasma GH and ACTH. GHRH treatment increased GH secretion in both patients and controls, while the other hormones were not affected. Furthermore, serum leptin was correlated with body mass index (BMI) in controls, but not in patients with depression, supporting an altered regulation of leptin secretion in depressive illness. Finally, we provide some evidence that in young female patients the normal nocturnal leptin surge is blunted. As glucocorticoids can prevent the fasting-induced decline in serum leptin, we propose that hypercortisolism in depression might counteract the reduction in leptin secretion caused by decreased food intake and weight loss. Elevated serum leptin in depression might in turn further promote CRH release, as shown in animals and, hence, contribute to HPA system hyperactivity seen in depression.     

Longtime administration of growth hormone-releasing hormone (GHRH) does not restore the reduced efficiency of GHRH on sleep endocrine activity in 2 old-aged subjects--a preliminary study

Aging results in a more shallow sleep accompanied by a blunted growth hormone (GH) secretion. In young male normal controls repetitive administration of GH-releasing hormone (GHRH) at the beginning of the night results in an increased secretion of GH, a blunting of cortisol and a stimulation of slow-wave sleep (SWS). In healthy elderly men and women, however, GHRH exerts only weak effects on sleep-endocrine activity. In a previous report continuous treatment of healthy elderly males by repetitive administration of GHRH (during 12 days administration with 100 micrograms GHRH i.v. at 9.00 h every second day, "priming") enhanced GHRH stimulated GH secretion at daytime markedly. We tested if priming with GHRH results in a more distinct modulation of the nocturnal hormone secretion and of the sleep EEG than acute administration of the peptide. Two elderly male controls spent first three consecutive nights in the sleep laboratory, the first of which served for adaptation to laboratory conditions. During the two other nights (at days 1 and 2) sleep EEG was recorded and blood was sampled for determining the secretion of GH, cortisol and ACTH. In one of the nights the subjects received 50 micrograms GHRH hourly between 22.00 h and 1.00 h (4 x 50 micrograms) or placebo. The next examination followed after the priming period at day 14 and the last was performed two weeks after treatment at day 28. After the baseline administration of 4 x 50 micrograms GHRH before priming no clear changes of sleep EEG towards improved sleep were detectable, whereas GH secretion was increased. After priming sleep period time and SWS time were lower compared to the baseline night with GHRH administration, whereas REM time duration increased. GHRH induced GH secretion was not enhanced after priming. ACTH secretion was markedly enhanced compared to baseline stimulation. We conclude that priming with GHRH has no sleep improving effect and does not change hormone secretion in elderly normal subjects. Hence in the elderly priming with GHRH is not capable to induce a rejuvenation of sleep endocrine activity.     

Urinary growth hormone (GH), insulin-like growth factor I (IGF-I), and IGF-binding protein-3 measurements in the diagnosis of adult GH deficiency

The diagnosis of GH deficiency (GHD) in the elderly is based at present on the peak GH concentration during a stimulation test. We have now evaluated the performance of urinary GH (uGH), urinary insulin-like growth factor I (uIGF-I), and urinary IGF-binding protein-3 (uIGFBP-3) in the diagnosis of GHD in this group. Twenty GHD elderly patients with a history of pituitary disease and a peak GH response to arginine stimulation of less than 3 ng/mL (15 men and 5 women; age, 61.1-83.4 yr) and 19 controls (12 men and 7 women; age, 60.8-87.5 yr) were studied. GH secretion was assessed by 24-h profile and expressed as the area under the curve (AUCGH). Serum (s) IGF-I and sIGFBP-3 were measured in a single morning, fasted sample. Urinary GH, uIGF-I, and uIGFBP-3 were measured in a 24-h urine sample collected over the same interval as the GH profile, and results were expressed as total amount excreted in 24 h (tuGH24, nanograms; tuIGF-I24, nanograms; tuIGFBP-3(24), micrograms). Data are presented as the mean +/- SD, except for AUCGH, tuGH24, and tuIGFBP-3(24), which are presented as the geometric mean (-1, +1 tolerance factor). AUCGH, sIGF-I, and sIGFBP-3 were significantly lower in GHD subjects than in controls. Total uGH24 was lower in GHD subjects, but tuIGF-I24 and tuIGFBP-3(24) excretion were not different in the two groups. AUCGH provided the best separation between GHD and control subjects, whereas there was substantial overlap for sIGF-I, sIGFBP-3, and tuGH24. In both groups sIGF-I was correlated to sIGFBP-3 (GHD, r = 0.75; controls, r = 0.65; both P < 0.01), whereas tuIGF-I24 was not correlated to tuIGFBP-3(24) in either group. Moreover, tuIGF-I24 and tuIGFBP-3(24) were not related to their respective serum concentrations in either group. Total uGH24 was correlated with AUCGH only in controls (r = 0.54; P < 0.05). These data demonstrate that urinary GH and urinary and serum IGF-I and IGFBP-3 are not suitable diagnostic markers for GHD in elderly subjects.     

Body composition in growth hormone deficient adults over the age of 60 years

OBJECTIVE: Elderly patients with hypothalamic-pituitary disease exhibit a reduction in GH secretion distinct from the decline in GH secretion related to age. GH deficiency in young adults causes a change in body composition, with increased fat mass (FM) and reduced fat free mass (FFM), similar to that seen as a result of the normal ageing process. The aim of this study was to determine whether organic GH deficiency in elderly patients may cause changes in body composition beyond those due to ageing. SUBJECTS: Twenty-one patients (15 male) with documented pituitary disease and 24 controls (17 male) matched for age, height, weight and BMI, all over the age of 60, in whom GH status had been defined by a 24-hour GH profile and an arginine stimulation test. MEASUREMENTS: Serum was taken for fasting IGF-l and IGFBP-1 estimations. Total and regional FM and FFM were determined using dual-energy X-ray absorptiometry. RESULTS: FM (median (range)) was increased in the patients, 27.76 (19.25-50.24) vs 21.23 (8.81-49.15) kg in the controls (P < 0.005). FM was significantly increased in the arms, legs and trunk in the patients compared with the controls. The proportion of fat deposited centrally did not differ significantly between the two groups (57.0% (47.6-65.1) in the patients vs 55.3% (44.1-63.8) in the controls, P = 0.25). There was an inverse relation between total FM and serum IGFBP-1 present in the patients, p = -0.632, P < 0.005, and in the controls p = -0.467, P < 0.05, but the relation between total FM and area under the GH profile was significant only in the controls (p = -0.651, P < 0.001) and not in the patients. FFM (51.19 (26.96-69.18) kg in the patients vs 51.55 (32.35-60.53) kg in the controls, P = 0.99) and serum IGFBP-1 levels did not differ significantly between the two groups. CONCLUSION: Organic growth hormone deficiency causes changes in body composition beyond the changes associated with the ageing process. These changes differ from those seen in younger GH deficient adults in that they are limited to an increase in FM with no change in FFM. These findings indicate that even in the elderly, in whom GH secretion is normally very low, the additional imposition of GH deficiency due to organic disease has significant biological impact.     

Differential effect of insulin-like growth factor-1 and growth hormone on hypothalamic regulation of growth hormone secretion in the rat

Pharmacological administration of either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) were reported to inhibit endogenous GH release in humans and in the laboratory animal. We have evaluated the short-term differential mechanisms whereby the two hormones affect hypothalamic regulation of GH secretion. Wistar male rats (90 days old) were injected i.p. with either GH (recombinant GH NIAMDD, Baltimore, MD, USA), rIGF-1 (Fujisawa Pharmaceutical Co. Ltd., Osaka, Japan) or saline. Animals were sacrificed at 15, 30, 60 and 120 minutes following injection. Hypothalami were dissected and extracted immediately and the levels of growth hormone-releasing hormone (GHRH) and somatostatin were determined using specific antisera. Trunk blood was collected for GH and IGF-1 determination by RIA. Administration of IGF-1 or GH markedly decreased hypothalamic somatostatin stores by 77% and 54% respectively, within 15 minutes. Concomitantly, the wide range of GH levels found in the control group was reduced in the IGF-1 treated group suggesting that the pulsatile pattern of GH secretion was suppressed. Growth hormone administration induced an increase in hypothalamic GHRH stores (60% at 120 minutes). During this period serum IGF-1 levels were not altered. It is suggested that short term modulation of hypothalamic neurohormones by GH and IGF-1 is mediated by rapid stimulation of somatostatin release by both hormones, and inhibition of GHRH release is induced only by GH.     

Interrelations between sleep and the somatotropic axis

In the human as in other mammals, growth hormone (GH) is secreted as a series of pulses. In normal young adults, a major secretory episode occurs shortly after sleep onset, in temporal association with the first period of slow-wave (SW) sleep. In men, approximately 70% of the daily GH output occurs during early sleep throughout adulthood. In women, the contribution of sleep-dependent GH release to the daily output is lower and more variable. Studies involving shifts of the sleep-wake cycle have consistently shown that sleep-wake homeostasis is the primary determinant of the temporal organization of human GH release. Effects of circadian rhythmicity may occasionally be detected. During nocturnal sleep, the sleep-onset GH pulse is caused by a surge of hypothalamic GHRH release which coincides with a circadian-dependent period of relative somatostatin disinhibition. Extensive evidence indicates the existence of a consistent relationship between SW sleep and increased GH secretion and, conversely, between awakenings and decreased GH release. There is a linear relationship between amounts of SW sleep--whether measured by visual scoring or by delta activity--and amounts of concomitant GH secretion, although dissociations may occur, most likely because of variable levels of somatostatin inhibition. Pharmacological stimulation of SW sleep results in increased GH release, and compounds which increase SW sleep may therefore represent a novel class of GH secretagogues. During aging, SW sleep and GH secretion decrease with the same chronology, raising the possibility that the peripheral effects of the hyposomatotropism of the elderly may partially reflect age-related alterations in sleep-wake homeostasis. While the association between sleep and GH release has been well documented, there is also evidence indicating that components of the somatotropic axis are involved in regulating sleep. The studies are most consistent in indicating a role for GHRH in promoting NREM and/or SW sleep via central, rather than peripheral, mechanisms. A role for GH in sleep regulation is less well-documented but seems to involve REM, rather than NREM, sleep. It has been proposed that the stimulation of GH release and the promotion of NREM sleep by GHRH are two separate processes which involve GHRH neurons located in two distinct areas of the hypothalamus. Somatostatinergic control of GH release appears to be weaker during sleep than during wake, suggesting that somatostatinergic tone is lower in the hypothalamic area(s) involved in sleep regulation and sleep-related GH release than in the area controlling daytime GH secretion. While the concept of a dual control of daytime and sleep-related GH secretion remains to be directly demonstrated, it allows for the reconciliation of a number of experimental observations.     

Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting

It is unknown whether hypogonadism contributes to decreased insulin-like growth factor I (IGF-I) production and/or how testosterone administration may effect the GH-IGF-I axis in human immunodeficiency virus (HIV)-infected men with the acquired immunodeficiency syndrome (AIDS) wasting syndrome (AWS). In this study, we investigate the GH-IGF-I axis in men with the AWS and determine the effects of testosterone on GH secretory dynamics, pulse characteristics determined from overnight frequent sampling, arginine stimulation, and total and free IGF-I levels. Baseline GH-IGF-I parameters in hypogonadal men with AWS (n=51) were compared before testosterone administration (300 mg, im, every 3 weeks vs. placebo for 6 months) with cross-sectional data obtained in two age-matched control groups: eugonadal men with AIDS wasting (n=10) and healthy age-matched normal men (n=15). The changes in GH-IGF-I parameters were then compared prospectively in testosterone- and placebo-treated patients. Mean overnight GH levels [1.8+/-0.3 and 2.4+/-0.3 vs. 0.90+/-0.1 microg/L (P=0.04 and P=0.003 vs. healthy controls)] and pulse frequency [0.35+/-0.06 and 0.37+/-0.02 vs. 0.22+/-0.03 pulses/h (P=0.06 and P=0.002 vs. healthy controls)] were comparably elevated in the eugonadal and hypogonadal HIV-positive groups, respectively, compared to those in the healthy control group. No significant differences in pulse amplitude, interpulse interval, or maximal GH stimulation to arginine administration (0.5 g/kg, i.v.) were seen between either the eugonadal and hypogonadal HIV-positive or healthy control patients. In contrast, IGF-I levels were comparably decreased in both HIV-positive groups compared to the healthy control group [143+/-16 and 165+/-14 vs. 216+/-14 microg/L (P=0.004 and P=0.02 vs. healthy controls)]. At baseline, before treatment with testosterone, overnight GH levels were inversely correlated with IGF-I (r=-0.42; P=0.003), percent ideal body weight (r=-0.36; P=0.012), albumin (r=-0.37; P=0.012), and fat mass (r=-0.52; P=0.0002), whereas IGF-I levels correlated with free testosterone (r=0.35; P=0.011) and caloric intake (r=0.32; P= 0.023) in the hypogonadal HIV-positive men. In a stepwise regression model, albumin (P=0.003) and testosterone (P=0.011) were the only significant predictors of GH [mean GH (microg/L)=-1.82 x albumin (g/dL) + 0.003 x total testosterone (microg/L) + 6.5], accounting for 49% of the variation in GH. Mean overnight GH levels decreased significantly in the testosterone-treated patients compared to those in the placebo-treated hypogonadal patients (0.9+/-0.3 vs. 0.2+/-0.4 microg/L; P=0.020). In contrast, no differences in IGF-I or free IGF-I were observed in response to testosterone administration. The decrement in mean overnight GH in response to testosterone treatment was inversely associated with increased fat-free mass (r=-0.49; P= 0.024), which was the only significant variable in a stepwise regression model for change in GH [change in mean GH (microg/L)=-0.197 x kg fat-free mass - 0.53] and accounted for 27% of the variation in the change in GH. In this study, we demonstrate increased basal GH secretion and pulse frequency in association with reduced IGF-I concentrations, consistent with GH resistance, among both hypogonadal and eugonadal men with AIDS wasting. Testosterone administration decreases GH in hypogonadal men with AIDS wasting. The change in GH is best predicted by and is inversely related to the magnitude of the change in lean body mass in response to testosterone administration. These data demonstrate that among hypogonadal men with the AWS, testosterone administration has a significant effect on the GH axis.     

Growth hormone secretion and circulating insulin-like growth factor-I (IGF-I) and IGF binding protein-3 concentrations in children with sickle cell disease

Impaired growth involving both height and weight accompanying sickle cell disease (SCD) poses diagnostic and therapeutic problems. We undertook this study to test the hypothesis that this impaired growth is associated with abnormalities of the growth hormone (GH)/insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3) axis in 21 children with SCD and that SCD is associated with GH resistance. Nine of 21 children with SCD had a defective GH response to both clonidine and glucagon provocation (peak < 10 micrograms/L); these children differed from the 12 others in having slower linear growth velocity (GV and GVSDS), lower circulating concentrations of IGF-I and IGFBP-3, and either partial or complete empty sellae in computed tomographic scans of the hypothalamic-pituitary area. In this group of patients with SCD, it appears that defective GH secretion and consequent low IGF-I production are the major etiological factors causing the slow growth. The two groups with SCD did not differ significantly in dietary intake, body mass index (BMI), midarm circumferences, skinfold thickness, serum albumin concentration, or intestinal absorption of D-xylose. A single injection of GH produced a smaller increase in circulating IGF-I in children with SCD with or without defective GH secretion versus 10 age-matched children with idiopathic short stature (ISS) and 11 children with isolated GH deficiency (GHD), suggesting partial GH resistance in the SCD group. The presence of defective GH secretion, decreased IGF-I synthesis, and partial resistance to GH in short children with SCD suggests that treatment with IGF-I may be superior to GH therapy for improving growth.     

Association between Ala54Thr substitution of the fatty acid-binding protein 2 gene with insulin resistance and intra-abdominal fat thickness in Japanese men

In insulin-dependent diabetes mellitus (IDDM), inappropriate growth hormone (GH) responses to several stimuli, including GH-releasing hormone (GHRH), have been described. A decreased hypothalamic somatostatinergic tone is one of the most likely explanations for these findings. His-DTrp-Ala-Trp-DPhe-Lys-NH2 [GH-releasing peptide-6 [GHRP-6]] is a synthetic hexapeptide that stimulates GH release in vitro and in vivo. The mechanism of action of GHRP-6 is unknown, but it probably does not inhibit hypothalamic somatostatin secretion. Also, GHRH and GHRP-6 apparently activate different intracellular pathways to release GH. The aim of this study was to evaluate whether there is a differential effect of IDDM on GHRP-6- and GHRH-induced GH secretion. Six patients with IDDM and seven control subjects were studied. Each subject received GHRP-6 (1 microgram/kg intravenously [IV]), GHRH (100 micrograms IV), and GHRP-6 + GHRH on 3 separate days. GH peak values (mean +/- SE in micrograms per liter) were similar in controls and diabetics after GHRH (22.5 +/- 7.8 v 24.0 +/- 9.7) and after GHRP-5 (20.5 +/- 5.3 v 24.4 +/- 6.3). The association of GHRP-6 and GHRH induced a significantly higher GH release than administration of the isolated peptides in both groups. The synergistic GH response to combined administration of GHRP-6 and GHRH was not different in controls (70.5 +/- 20.0) and diabetics (119.0 +/- 22.2). In summary, the effectiveness of GHRP-6 in IDDM could reinforce the evidence that this peptide probably does not release GH through a decrease in hypothalamic somatostatin secretion. Moreover, our data suggest that both GHRH and GHRP-6 releasing mechanisms are unaltered in IDDM.     

Dexamethasone inhibition of interferon-alpha 2-induced stimulation of cortisol and growth hormone secretion in chronic myeloproliferative syndrome

This study investigated the acute effects of interferon-alpha 2 (IFN-alpha 2) on hormonal secretion in adult patients affected by a chronic myeloproliferative syndrome and tried to shed some light on the mechanism by which IFN-alpha 2 stimulates cortisol and GH secretion in humans. We compared the pattern of IFN-alpha 2-induced cortisol and GH release with that elicited after the same challenge given subsequent to pretreatment with dexamethasone (Dex). We studied eight patients affected by a chronic myeloproliferative syndrome (thrombocythemia) who had been selected for treatment with IFN-alpha 2. Four sets of experiments were performed: 1) 2 mL iv saline was given at 0800 h in eight cases; 2) 3 x 10(6) IU iv IFN-alpha 2 was given at 0800 h in eight cases; 3) 3 x 10(6) IU iv IFN-alpha 2 was given at 0800 h after pretreatment with 1.5 mg Dex (1 mg at midnight the previous night and 0.5 mg at 0700 h on the day of the test) in six cases; and 4) 2 mL iv saline was given at 0800 h after the same Dex pretreatment in four cases. Cortisol and GH were measured in plasma samples drawn at 30-min intervals between 0800 and 1300 h. Acute iv administration of IFN-alpha 2 stimulated the release of both cortisol and GH in each patient with a significant increment vs. control values, as assessed by areas under the curve. The administration of Dex significantly decreased basal plasma cortisol secretion and abolished cortisol response to IFN-alpha 2 administration. These data suggest that the stimulatory action of IFN-alpha 2 on cortisol release is mediated via a modulation of the activity of the hypothalamic-pituitary axis rather than through a direct effect at the level of the adrenal cortex. After Dex plus saline administration, no significant effect was observed on plasma GH levels, which remained low. Dex administration significantly decreased GH response to IFN-alpha 2. These data suggest that a hypothalamic or pituitary stimulation (or both) is involved in the mechanism of IFN-alpha 2-induced GH secretion. It remains to be established whether IFN-alpha 2 directly stimulates pituitary somatotropic cells or whether the cytokine exerts a stimulatory action on GH secretion by indirectly modulating the hypothalamic or pituitary activity. In conclusion, acute iv administration of IFN-alpha 2 represents a potent stimulus for cortisol and GH secretion in adult human subjects.(ABSTRACT TRUNCATED AT 400 WORDS)     

Overnight growth hormone secretion in achondroplasia: deconvolution analysis, correlation with sleep state, and changes after treatment of obstructive sleep apnea

The normal profile for overnight GH secretion in achondroplasia has not been previously studied. Factors that have been shown to influence GH secretion include age, obesity, sleep state, and the presence of obstructive sleep apnea (OSA). We assessed GH levels in a group of subjects with achondroplasia, during overnight polysomnography. Nineteen subjects with achondroplasia were studied at 11.3 y of age (median 6.7, range 1.8-30.9). Levels of GH were measured using time-resolved immunofluorometric assay (DELFIA, Pharmacia Biotech Inc.) and analyzed by a deconvolution method. Five subjects were restudied after treatment for OSA. Secretion rates of GH were greater in slow wave (SWS) and rapid eye movement (REM) sleep than in stage one and two (SI-II = light non-REM) sleep (p < 0.01). Total overnight GH secretion decreased with increasing age (r2 = 0.22 p < 0.04). Neither the frequency of arousals, frequency of sleep state transitions nor the severity of OSA correlated with measures of GH secretion. Levels of IGF-I correlated independently with age, body weight (percent ideal), and GH secretion rate (r2 = 0.76, p < 0.001). In a group of five subjects treated for OSA, improved respiratory distress index and reduced sleep state transitions were not associated with significant changes in GH secretion rate by sleep stage; SWS [from 0.62 +/- 0.28 mIU/L/min to 1.02 +/- 0.25 mIU/L/min (NS)] and SI-II sleep [from 0.26 +/- 0.07 mIU/L/min to 0.60 +/- 0.16 mIU/L/min (NS)]. However, in those five subjects, a GH secretion peak during the first 2 h of SWS was initially absent, appearing only after treatment of OSA (1.09 +/- 0.38 mIU/L/min) compared with (2.40 +/- 0.59 mIU/L/min (p = 0.01). A profile of overnight GH secretion is presented for subjects with achondroplasia.     

Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation

Indirect observations suggest that the dopaminergic system may be involved in the pathophysiology of obsessive-compulsive disorder (OCD). The dopaminergic function of 15 patients with OCD and 15 age/sex-matched controls was evaluated by measuring the growth hormone (GH) responses to stimulation with the dopaminergic agonist apomorphine (APO), which increases growth hormone-releasing hormone (GHRH), GH, and somatomedine C (SMD-C) secretions. Therefore, we measured basal plasma GH and SMD-C concentrations and GH responses to GHRH stimulation to exclude that a downstream pathology of the somatotropic axis could obscure the significance of the results of the APO test. The response of prolactin (PRL) to APO inhibition were also measured. Basal plasma levels of GH, SMD-C, and PRL, GH responses to GHRH stimulation, and PRL responses to APO inhibition did not differ in the two groups of subjects. GH responses to APO stimulation were blunted in obsessive-compulsive (OC) patients. The emetic response to the same stimulation was stronger in patients than in controls. These responses suggest that in our OC patients there is a dysregulation of the dopaminergic system, which is possibly expressed in different ways in the various areas of the central nervous system.     

14C]leucine incorporation into proteins of pancreatic juice in rats fed soya-bean flour

1. The effect of a diet containing a trypsin inhibitor on the incorporation of radioactively labelled leucine into the pancreatic proteins secreted during stimulation with cholecystokinin-pancreozymin (CCK) was studied in rats. 2. The total output of protein was significantly greater in the rats given raw soya-bean flour (RSF) compared with those given heat-inactivated soya-bean flour (HSF) (controls) in response to the sub- and supramaximal stimulation with CCK, but similar responses were obtained to maximal stimulation with CCK. Total protein output decreased continuously with time after reaching peak values at 90--120 min after the start of stimulation with CCK. 3. The total output of radioactively labelled protein in RSF-fed rats was not different from that of the controls with sub- and supramaximal dose rats of CCK, but was significantly lower than that of the controls in response to the dose rate of CCK which produced maximal rates of pancreatic secretion. 4. The specific activity of radioactively labelled protein increased continuously, while the output attained a constant rate during stimulation with all doses of CCK. 5. We concluded that feeding the trypsin inhibitor-containing diet led to increased secretion of stored pancreatic protein, while secretion of newly synthesized protein was not altered. During the course of prolonged stimulation with CCK, irrespective of diet, there was increasing secretion of the newly synthesized protein compared with the pre-existing stored proteins of the pancreas, it was unable to compensate for the decreased secretion of pre-formed protein.     

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome

OBJECTIVE: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING: Reproductive endocrinology unit. PATIENT(S): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S): Growth hormone, glucose, and insulin responses to OGTT. RESULT(S): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.     

Increased pulsatile, but not basal, growth hormone secretion rates and plasma insulin-like growth factor I levels during the periovulatory interval in normal women

The secretion of GH changes during the menstrual cycle, exhibiting high levels during the periovulatory phase (PO). Previous studies have not investigated whether this difference in GH status is due to increased secretion or reduced clearance of pituitary GH and amplified pulsatile vs. basal GH secretion. It is also unclear whether the PO phase is accompanied by changes in circulating insulin-like growth factor I (IGF-I). In this study we investigated the 24-h GH release patterns in the early follicular (EF) vs. the periovulatory menstrual phase in the same individuals. Ten young (aged 24-34 yr) healthy women with regular menses were studied with deconvolution analysis of GH profiles obtained by blood sampling every 20 min for 24 h, followed by an arginine stimulation test. A high sensitivity immunofluorometric GH assay was used. All women were studied in both the EF and PO phases in random order. There were no differences in the basal GH secretion rate or GH half-life during the two phases. The number of GH secretory bursts identified during the 24-h sampling period was significantly increased during the PO (13.3 +/- 0.5) compared to the EF (10.3 +/- 0.6) phase (P = 0.002); conversely, the mean interburst interval was shorter in the PO (107 +/- 5 min) than in the EF (134 +/- 8 min) phase (P = 0.004). There was no difference in GH pulse mass (P = 0.13) or amplitude (P = 0.21) between the two phases. The pulsatile GH production rate (milligrams per L/24 h) was significantly elevated during the PO (61 +/- 6) compared to that during the EF (37 +/- 8; P = 0.004). Increased total GH pulse area was confirmed by Cluster analysis (P = 0.027). Furthermore, the 24-h mean serum GH concentration was significantly increased in the PO (1.4 +/- 0.1 mg/L) vs. that in the EF (0.9 +/- 0.1 mg/L; P = 0.002). There was a positive correlation between estradiol (E2) and GH secretory pulse amplitude, frequency, and mean 24-h serum GH concentration in the PO cycle phase, indicating E2 to be a major statistical determinant of GH secretion. Serum GH increased significantly after arginine infusion in both phases (P < 0.001), whereas there was no difference between the two cycle phases (P = 0.20). Serum IGF-I levels were increased during the PO phase (253 +/- 20 mg/L) compared to those during the EF phase (210 +/- 16 mg/L; P = 0.03), whereas serum IGF-binding protein-3, IGF-II, and GH-binding protein were similar during the two phases. This study unequivocally documents elevated GH levels during the PO phase of the menstrual cycle, mediated by increased GH production rate and burst frequency. The concomitant increase in serum IGF-I suggests a central stimulation of the GH-IGF-I axis, which may be mediated by endogenous E2 levels.