Basal Growth Hormone Research Articles

Serum growth hormone and insulin but not insulin-like growth factor-1 levels are elevated in patients with fibromyalgia syndrome

Standard radioimmunoassay (RIA) was employed to quantify basal serum growth hormone (GH), insulin-like growth factor-I (IGF-1), and insulin levels in 32 normoglycemic patients with clinically active fibromyalgia and in 29 normoglycemic control subjects. The GH concentration was significantly higher (P < 0.001) in female fibromyalgia patients than age-matched, normal female subjects. In contrast, basal serum IGF-1 concentrations did not differ between these groups. A scatter plot generated from two-stage, least-squares analysis showed that serum GH lacked correlation with the serum IGF-1 concentrations of normal female subjects (P = 0.73) and female fibromyalgia patients (P = 0.19). In addition to the results from serum GH and IGF-1 RIA, we also found significantly higher fasting serum insulin levels (P = 0.03) in male fibromyalgia patients and a trend toward elevated fasting serum insulin levels in the female fibromyalgia population ( P = 0.07), with the mean fasting level in the male fibromyalgia group (35.7 microU/ml(-1)) exceeding the upper limit of normal serum insulin levels (i.e., 27 microU/ml(-1)). Based on these results, basal serum GH and fasting serum insulin levels appear to be valuable surrogate markers in clinically active, normoglycemic fibromyalgia patients.

Twenty-four hour growth hormone secretion in patients with panic disorder

Patients with panic disorder have blunted growth hormone (GH) responses to clonidine, suggesting subsensitivity of post-synaptic alpha(2)-adrenoreceptors, presumably in response to excessive central noradrenergic outflow. However, basal levels of GH release over a full circadian cycle have not been examined in panic. Reduced basal GH release would suggest an overall hypo-active GH system rather than a specific alpha-adrenergic abnormality. To determine whether panic patients show reduced basal GH secretion, 20 patients and 12 healthy controls were studied. Blood samples were drawn every 15 min for 24 h and plasma was assayed for GH. Patients were restudied during successful treatment with alprazolam. Groups were compared on overnight and daytime GH secretion and circadian patterns of release. Patients showed normal levels on all measures of GH release. Treatment may have reduced nocturnal GH release slightly, but treated patients still did not differ from controls. The normal predominance of sleep over waking GH secretion was seen in both groups. Panic patients, in contrast to depressed patients, have normal somatotrophic axis activity when measured in a resting state over a full circadian cycle. GH dysregulation may only be evident in these patients in activation paradigms and has been most consistently demonstrated by challenges with the alpha(2)-noradrenergic agonist, clonidine.

Réponses de GH, IGF-1 et IGF-BP3 à un exercice submaximal : différences entre sujets entraînés et sédentaires

Aim. – We explored growth hormone (GH), insulin-like growth factor 1 (IGF-1) and IGF-BP3 (IGFs binding protein 3) responses during a submaximal exercise and its recovery in trained and sedentary young subjects. Subjects and methods. – The study investigates 18 year old sportsmen ( N = 20) and sedentary boys of the same age as control group ( N = 19). A 20 min exercise is performed on an ergocycle to reach by steps 90% of the theoretical maximal heart rate which is maintained during the last 7 min. Blood samples were drawn before the test, at the end of exercise and at 10th, 20th and 45th minutes in the recovery period. Results. – Basal GH levels are higher in sportsmen than in controls (4 ± 5 vs. 2 ± 1 mUI/ml; P < 0.05) and during recovery ( P < 0.005). Basal IGF-1 level is lower in sportsmen than in controls (705 ± 232 vs. 357 ± 83 ng/ml; P < 0.0001), at all times during exercise. Basal IGF-BP3 levels are 4.5 ± 1.1 μg/ml in sportsmen and 4.4 ± 1.2 in controls. IGF-PB3 is not modified by exercise and does not depend on the training level. The W170 (power capacity at 170 pulses/min), and the maximal oxygen uptake differ between the two groups ( P < 0.0001). Glycaemic variations during the test did not differ significantly between the two groups. Conclusion. – Response of GH to exercise is more significant in sportsmen than in sedentary men; IGF-1 and IGF-BP3 levels do not vary significantly during exercise.

Familial Acromegaly: A Familial Report and Review of the Literature

Familial acromegaly without features of multiple endocrine neoplasie type 1 (MEN 1) is an exceptional clinical entity. We report in this article three cases of acromegaly due to pituitary macroadenomas without any other endocrinopathy in a family. A 31‐year‐old woman (subject A) and her 34‐year‐old sister (subject B) with elevated basal rolactin (PRL) levels, elevated growth hormone (GH) levels during the oral glucose tolerance test (OGTT) and a pituitary adenoma in Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) were diagnosed as acromegaly. Subject A was treated only with radiotherapy and Lysuride. Subject B underwent transsphenoidal microsurgical extirpation 15 years ago. 11 years later her 24‐year‐old son (subject C) also presented with typical signs of acromegaly, elevated basal PRL level and elevated GH levels during OGTT. A pituitary macroadenoma was identified by MRI and he also underwent transsphenoidal adenomectomy. Pathology reports confirmed the diagnosis of GH‐secreting pituitary adenoma in subject B and C. Immunocytochemistry revealed that tumours of subject B (> 20% of tumour cells) and C (> 50% of tumour cells) were positive for GH. Tumours of subject B (> 10% of tumour cells) and C (> 50% of tumour cells) also exhibited immunoreactivity for PRL. On investigation of histocompatibility antigens, it was observed that the subject A, B, and C shared the same haplotypes [HLA A24(9), HLA B13(6), HLA B35, HLA DQ7(3), HLA DR13(6)] and so it is very possible that investigation of HLA antigens in patients with pituitary tumour, contributes to better identification of its familial nature and frequency. Here we describe an acromegaly family and the distributions of HLA antigens.

Constitutionally Tall Stature with Morphological Abnormality of the Pituitary Gland

We describe two male pubertal cases of constitutionally tall stature (CTS) with an enlarged pituitary gland or pituitary microadenoma. Both patients' basal serum growth hormone (GH) levels were normal. Neither had oversecretion of any other pituitary hormones. However, their serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). A later GH response to an intravenous administration of luteinizing hormone-releasing hormone (LHRH) was also found in one patient. In addition, oral glucose loading (OGL) caused a late increase in serum GH at 180 min in both patients. Our present findings suggest that endocrinological and morphological abnormalities of the pituitary gland are found in some subjects with CTS during puberty. It is speculated that these paradoxical GH responses are associated with dysregulation of GH secretion. Finally, it is important to investigate whether tall children with morphological abnormalities of the pituitary gland such as our patients are preacromegalic, in which case, given that overproduction of GH secretion may occur in the future, further observation is necessary.

Rapid suppressing action of insulin-like growth factor-I (IGF-I) on GH release from anterior pituitary cells of goats

Goat anterior pituitary cells were cultured to investigate the effects of insulin-like growth factor-I (IGF-I), insulin, and growth hormone (GH) on basal and GH-releasing hormone (GHRH)-induced GH release. Changes in cellular Ca 2+ concentrations were also assessed to enable discussion of the cellular mechanisms of IGF-I. The cells were cultured for 48 h, and then stimulated with GHRH (10 nmol/l) for 30 min, with or without each test substance. In the control cells, IGF-I (10 and 100 ng/ml) significantly raised the basal, but did not change GHRH-induced GH release, resulting in the abolishment of GH release induced by GHRH in the presence of 100 ng/ml IGF-I. However, there was no significant effect of insulin (10, 100, and 1000 μU/ml) on basal and GHRH-induced GH release. In the cells cultured for 48 h with each test substance but stimulated for 30 min without the test substance, no significant change in the basal and GHRH-stimulated GH release was observed. Regardless of treatment, there was no significant effect on intra-cellular GH content. Analysis with a confocal laser microscope revealed that IGF-I (100 ng/ml) significantly increased the basal, but significantly reduced GHRH (10 nmol/l)-induced increase in cellular Ca 2+ concentrations. From these findings we conclude that IGF-I exerts an acute suppressing action on the GHRH-induced GH release, which partly involves changes in cellular Ca 2+ metabolism in goat somatotrophs.

Contribution of elevated free fatty acid levels to the lack of glucose effectiveness in type 2 diabetes.

Increased circulating free fatty acids (FFAs) inhibit both hepatic and peripheral insulin action. Because the loss of effectiveness of glucose to suppress endogenous glucose production and stimulate glucose uptake contributes importantly to fasting hyperglycemia in type 2 diabetes, we examined whether the approximate twofold elevations in FFA characteristic of poorly controlled type 2 diabetes contribute to this defect. Glucose levels were raised from 5 to 10 mmol/l while maintaining fixed hormonal conditions by infusing somatostatin with basal insulin, glucagon, and growth hormone. Each individual was studied at two FFA levels: with (NA+) and without (NA-) infusion of nicotinic acid in nine individuals with poorly controlled type 2 diabetes (HbA(1c) = 10.1 +/- 0.7%) and with (LIP+) and without (LIP-) infusion of lipid emulsion in nine nondiabetic individuals. Elevating FFA to approximately 500 micro mol/l blunted the ability of glucose to suppress endogenous glucose production (LIP- = -48% vs. LIP+ = -28%; P < 0.01) and increased glucose uptake (LIP- = 97% vs. LIP+ = 51%; P < 0.01) in nondiabetic individuals. Raising FFA also blunted the endogenous glucose production response in 10 individuals with type 2 diabetes in good control (HbA(1c) = 6.3 +/- 0.3%). Conversely, normalizing FFA nearly restored the endogenous glucose production (NA- = -7% vs. NA+ = -41%; P < 0.001) and glucose uptake (NA- = 26% vs. NA+ = 64%; P < 0.001) responses to hyperglycemia in individuals with poorly controlled type 2 diabetes. Thus, increased FFA levels contribute substantially to the loss of glucose effectiveness in poorly controlled type 2 diabetes.

Canrenoate causes a set-point shift in the feed back regulation of the HPA axis

Objective: The purpose of our study was to investigate the role of central mineral corticoid receptors (MR) in the regulation of the activated HPA axis in healthy humans. Experimental design: In a double blinded design two age-matched groups of 12 male volunteers were pre-treated with either placebo or the MR antagonist canrenoate 16 and 8h prior to the experiment. After an initial resting period of 60min. subjects were asked to perform sub maximal treadmill exercise (160 watts) for 90min. after which they had to rest for another 90min. During the whole experiment blood samples were drawn in 10 minutes intervals and analysed for adrenocorticotropin (ACTH), cortisol and growth hormone (GH). Results: There were no significant differences between both groups for basal and stimulated GH and ACTH secretion. Basal GH (±SEM) (ng/ml) was 0.71 (0.7) for placebo vs. 0.57 (0.33) for canrenoate. Maximal response under physical stress was 14.96 (2.90) vs. 14.59 (2.56) and GH levels in the post exercise period gradually decreased to basal levels. ACTH (±SEM) (pg/ml) was 21.18 (2.86) vs. 21.68 (3.85) for the basal period, maximal 45.90 (12.93) vs. 50.07 (12.22) during exercise and decreased to 18.28 (2.20) vs. 20.45 (2.58) in the post exercise period. There was, however, a significant difference in the secretory cortisol response. Basal cortisol levels were 9.92 (1.12) vs. 11.10 (1.10) being significantly higher in the canrenoate group (p<0.05). Canrenoate pre-treatment also caused a more pronounced increase and ended in higher levels during the post exercise period 7.18 (1.07) vs. 10.13 (1.28) (p<0.05). Discussion: Previous experiments have already shown a modifying role for canrenoate on the HPA axis during sleep and after stimulation with corticotropin releasing hormone. Our findings add up to these results. Since cortisol levels are higher in the canrenoate group in the presence of similar ACTH levels, we speculate whether canrenoate facilitates ACTH mediated cortisol release from the adrenal gland. Alternatively, cortisol metabolism might have been inhibited by canrenoate. In addition canrenoate must have shifted the feedback inhibition of the HPA axis to a higher set point since higher pre- and postexercise cortisol levels in the canrenoate group, did not suppress ACTH secretion as compared to the placebo group. This set point-shift is probably mediated by supra-pituitary regions since MR are predominantly located in the hippocampus.

Binding of the Thyroid Hormone Receptor to a Negative Element in the Basal Growth Hormone Promoter Is Associated with Histone Acetylation

Nuclear thyroid hormone receptors (TRs) act as ligand-dependent activators, but paradoxically unliganded TRs can increase transcription of promoters containing negative response elements (nTRE), and hormone binding represses this activation. The rat growth hormone (GH) promoter contains a positive TRE and a nTRE. Ligand-dependent negative regulation mediated by the nTRE could play an important physiological role in restricting GH gene expression in non-pituitary cells that express TRs. With chromatin immunoprecipitation assays, we show here that the nTRE is responsible for binding of TR to the promoter in non-pituitary HeLa cells and that this element also governs transactivation by the unoccupied receptor and repression by triiodothyronine. Occupancy of the promoter by TR is concomitant with appearance of acetylated histone H3, and triiodothyronine causes release of the receptor as well as disappearance of the acetylated histone from the promoter. Although the nTRE overlaps the TATA box, the receptor does not exclude binding of TATA-binding protein, but could rather facilitate formation of the preinitiation complex. Furthermore, the proximal GH promoter is synergistically stimulated by unliganded TR and TATA-binding protein, whereas the ligand represses this cooperation. Constitutive receptor activity and synergism with TATA-binding protein require binding of corepressors. Furthermore, inhibitors of histone deacetylases enhance promoter activation by the unliganded receptor and reduce triiodothyronine-dependent repression, whereas expression of HDAC1 reverses promoter stimulation. This suggests that partitioning of histone acetylases and deacetylases between the receptors and basal transcription factors could be involved in regulation of the basal GH promoter by TRs.

Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child-Pugh classification in male patients with alcoholic and virus-related cirrhosis.

To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child-Pugh score in male patients with alcoholic and virus-related liver cirrhosis. Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child-Pugh class A (CPA), 16 Child-Pugh class B (CPB) and 10 Child-Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age-matched controls. A normal cortisol response to corticotropin-releasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin-like growth factor 1 (IGF-1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid-stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle-stimulating hormone (FSH) levels were comparable in all groups. Child-Pugh score was correlated positively to prolactin and was correlated negatively to IGF-1, stimulated luteinizing hormone and free testosterone. In cirrhotics, the hypothalamic-pituitary-adrenal and -gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormone-releasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF-1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamic-pituitary-glandular axes.

Dysfunction of the hypothalamic-pituitary-glandular axes and relation to Child???Pugh classification in male patients with alcoholic and virus-related cirrhosis

Objective To investigate anterior pituitary function (adrenal, somatotropic, thyroid and gonadal axes, and prolactin) in relation to the Child-Pugh score in male patients with alcoholic and virus-related liver cirrhosis. Method Anterior pituitary function was evaluated in 52 male cirrhotics (26 Child-Pugh class A (CPA), 16 Child-Pugh class B (CPB) and 10 Child-Pugh class C (CPC)) by a combined pituitary stimulation test, and was compared with 50 age-matched controls. Results A normal cortisol response to corticotropinreleasing hormone (CRH) stimulation was demonstrated in 57.6% of CPA patients, 31.1% of CPB patients and 20% of CPC patients, while basal levels of adrenocorticotropic hormone (ACTH) and cortisol in cirrhotics were comparable to those in controls. Levels of basal growth hormone (P < 0.001) and stimulated growth hormone (P < 0.01) were significantly higher in cirrhotics compared with controls, while levels of insulin-like growth factor 1 (IGF-1) were significantly lower (P < 0.001). Basal prolactin levels were elevated significantly in CPC patients (P < 0.01), while stimulated prolactin as well as basal and stimulated thyroid-stimulating hormone (TSH) levels were comparable. Basal luteinizing hormone levels were significantly higher in CPA (P < 0.001) and CPB (P < 0.001) patients, and stimulated luteinizing hormone levels were significantly lower in CPC patients than in controls (P < 0.005). Basal and stimulated follicle-stimulating hormone (FSH) levels were comparable in all groups. Child-Pugh score was correlated positively to prolactin and was correlated negatively to IGF-1, stimulated luteinizing hormone and free testosterone. Conclusions In cirrhotics, the hypothalamic-pituitaryadrenal and -gonadal axes and prolactin secretion are impaired. Growth hormone response to growth hormonereleasing hormone (GHRH) is accelerated in cirrhotics. Thus, elevated basal and stimulated levels of growth hormone probably reflect compensation for low levels of IGF-1, which are associated with deteriorating liver function. The aetiology of cirrhosis was found to have no influence on the degree of alteration of the hypothalamicpituitary-glandular axes.

Body Composition Modulates the Effects of Hormone Replacement Therapy on Growth Hormone and Insulin-Like Growth Factor-I Levels in Postmenopausal Women

Objective: To examine the relationships of body composition with basal serum estrone, estradiol, androstenedione, cortisol, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in 73 postmenopausal women. Design: Cross-sectional study of hormone levels and body composition determined by dual-energy X-ray absorptiometry and anthropometry in women who were not taking oral hormone replacement therapy (HRT) and women taking HRT. Because high adiposity may modify hormone levels, subjects were grouped by fatness into obese (BMI >25 kg/m² and waist circumference >80 cm) and lean groups, as well as by HRT use. Results: Total levels of estrone, estradiol, GH and cortisol were significantly higher and IGF-1 was lower in HRT users. In HRT users, estradiol levels were higher and GH levels were lower in obese than lean women. IGF-1 levels were lower in obese HRT users than lean nonusers. Total cortisol levels were significantly higher in lean HRT users than lean nonusers and obese users. GH and IGF-1 were significantly inversely correlated with trunk fat and percent body fat. Multiple regression revealed that only trunk fat was a significant (negative) determinant of GH and IGF-1 levels, whereas HRT use positively and negatively predicted GH and IGF-1, respectively. Percent body fat significantly predicted estradiol levels. Body composition did not differ by HRT use. Conclusions: Our results suggest that trunk fat attenuates the HRT-induced increase on GH levels. In addition, trunk fat is a significant determinant of low IGF-1 levels in postmenopausal women, and IGF-1 levels decline more with HRT use.

Somatostatin treatment affects testicular function in stallions

This study investigated the regulation of growth hormone (GH) release in stallions and tested the hypothesis that the somatotrophic axis influences testicular function. Basal plasma GH concentrations, effects of an experimental decrease of GH release on testicular function and an opioidergic regulation of GH release were investigated in Shetland stallions ( n=6). No seasonal variations in plasma GH concentrations were found over a 12-month period. Treatment with the somatostatin analogue octreotid (100 mg twice daily over 10 days) caused a decrease in semen motility from 38.7±8.4% progressively motile spermatozoa before treatment to 18.3±5.4% on day 3 after end of treatment ( P<0.05). Values returned to 35.0±8.5% on day 5 after treatment. On the last day of octreotid treatment, a hCG stimulation test was performed (3000 IU hCG i.v.). The hCG-induced testosterone release was significantly higher in saline treated than in octreotid pretreated animals ( P<0.05). Neither plasma GH concentrations nor volume and density of ejaculates, total sperm count, or semen morphology were different between saline and octreotid treatments. Injection of the opioid antagonist naloxone (0.5 mg/kg) significantly increased GH release in June (from 1.1±0.3 ng/ml before to 3.7±2.2), while a minor and not significant increase occurred in January. In conclusion, our results indicate a non-seasonal basal GH release with a fine-modulation by season-dependent opioidergic mechanisms in the male horse. A transient decrease in semen motility and hCG-induced testosterone release following ocreotid treatment indicate a role of GH in the regulation of testicular function in stallions.

Somatotropic axis in hypocretin-deficient narcoleptic humans: altered circadian distribution of GH-secretory events.

Narcolepsy is a sleep disorder caused by impaired hypocretin (orexin) neurotransmission. Growth hormone (GH) secretion may be altered in narcolepsy for various reasons. Slow-wave sleep episodes, which are closely associated with GH-secretory events, are more randomly dispersed over 24 h in narcoleptics. Furthermore, hypocretins may inhibit pituitary GH release. We assessed the function of the somatotropic axis in narcolepsy by deconvolving 24-h (10-min sampling interval) plasma GH concentration profiles in seven hypocretin-deficient narcoleptic patients and in seven healthy controls matched for age, sex, and body weight. Both basal and pulsatile GH secretion rate and secretagogue-induced GH release were similar in patients and controls. However, narcoleptics secreted approximately 50% of their total production during the daytime, whereas controls secreted only 25% during the day. Also, the GH output pattern of narcoleptics was significantly less regular. We propose that hypocretin deficiency disrupts the circadian distribution of hypothalamic GH-releasing hormone release in narcoleptic patients to simultaneously cause daytime GH release and promote their propensity to fall asleep during the day.

Effect of training on the GH/IGF-I axis during exercise in middle-aged men: relationship to glucose homeostasis.

The aim of this study was to compare circulating levels of growth hormone (GH), IGF-I, and IGF-binding protein (IGFBP)-1 and IGFBP-3 in response to a long-duration endurance exercise in trained vs. sedentary middle-aged males and to determine whether a relationship with glucose homeostasis exists. Seven trained men (Tr) were compared with seven age-matched sedentary men (Sed) during two trials of 60 min of cycling exercise performed below (-VT) and above (+VT) the ventilatory threshold. Insulin sensitivity (S(I)) was higher in Tr than in Sed (P < 0.001). Basal GH, IGF-I, and IGFBP-1 and -3 were higher in Tr (P < 0.05). During +VT, Tr had a threefold higher GH response, whereas their blood glucose level was better maintained (P < 0.05). Basal IGFBP-1 was correlated with S(I) (P < 0.01). These data indicate that endurance training in middle-aged men increased the activity of the GH/IGF-I system and improved glucoregulation both at rest and during high-intensity endurance exercise.

Cloning and characterization of the 5′-flanking region of the canine growth hormone gene

The growth hormone (GH) gene is expressed in a variety of tissues outside the pituitary, including the mammary gland. GH expression in the mammary gland is stimulated by progestins. The local synthesis of mammary GH may provide a highly proliferative environment within the mammary gland that may contribute to the development or progression of mammary tumours. To elucidate the mechanism regulating mammary GH expression, we cloned the 5′-flanking region of the canine GH gene using inverse polymerase chain reaction. Gel-shift experiments showed that several sequences in the 5′-flanking region of the GH gene bind mammary nuclear proteins and may be involved in basal and progesterone-induced mammary GH expression. Sequence analysis and comparison with the GH promoters of human, rat, and mouse genes revealed a number of shared binding sites for transcription factors such as Pit-1, which is involved in pituitary GH expression, and for factors involved in the differentiation of lymphoid cells. Moreover, a putative binding site for the progesterone receptor (PR) was identified in all promoters, indicating that the progestin-induced expression of GH in mammary tissue is most probably a direct effect of activated PRs on the GH gene promoter and that this may occur in various species.

Pulsatile secretion pattern of growth hormone in dogs with pituitary-dependent hyperadrenocorticism

The amplitude and frequency of growth hormone (GH) secretory pulses are influenced by a variety of hormonal signals, among which glucocorticoids play an important role. The aim of this study was to investigate the pulsatile secretion pattern of GH in dogs in which the endogenous secretion of glucocorticoids is persistently elevated, i.e. in dogs with pituitary-dependent hyperadrenocorticism (PDH). Blood samples for the determination of the pulsatile secretion pattern of GH were collected at 10-min interval between 08:00 and 14:00 h in 16 dogs with PDH and in 6 healthy control dogs of comparable age. The pulsatile secretion patterns of GH were analyzed using the Pulsar program. GH was secreted in a pulsatile fashion in both dogs with PDH and control dogs. There was no statistical difference between the mean (±S.E.M.) basal GH level in dogs with PDH (0.7±0.1 μg/l) and the control dogs (0.6±0.1 μg/l). The mean area under the curve (AUC) for GH above the zero-level in dogs with PDH (4.6±0.6 μg/l per 6 h) was significantly lower than that in the control dogs (7.3±1.0 μg/l per 6 h). Likewise, the mean AUC for GH above the base-level in dogs with PDH (0.6±0.1 μg/l per 6 h) was significantly lower than that in the control dogs (3.7±1.0 μg/l per 6 h). The median GH pulse frequency in the dogs with PDH (2 pulses/6 h, range 0–7 pulses/6 h) was significantly lower ( P=0.04) than that (5 pulses/6 h, range 3–9 pulses/6 h) in the control group. The results of this study demonstrate that PDH in dogs is associated with less GH secreted in pulses than in control dogs, whereas the basal plasma GH concentrations were similarly low in both groups. It is discussed that the impaired pulsatile GH secretion in dogs with PDH is the result of alterations in function of pituitary somatotrophs and changes in supra-pituitary regulation.

Growth hormone releasing factor decreases long form leptin receptor expression in porcine anterior pituitary cells

Pituitary cells from six pigs, 180–200 days of age, were studied in primary culture to determine if growth hormone releasing factor (GRF) affects long form leptin receptor (Ob-Rl) expression. On Day 4 of culture, 10 5 live cells per well were challenged with either 0, 10 −6, 10 −7 or 10 −8 M [Ala15]-hGRF-(1–29)NH 2 (3 wells per treatment per pig). Secretion of growth hormone (GH) into the media and pituitary Ob-Rl mRNA expression were determined at 4 h after treatment. Media were analyzed for GH by radioimmunoassay, and total RNA was isolated from cells for determination of Ob-Rl expression by semi quantitative reverse transcription PCR. Basal GH concentration was 32±2 ng per 10 5 cells per well ( n=18 wells) for 4 h. Relative to control at 4 h, 10 −6,10 −7 and 10 −8 M GRF increased ( P<0.01) GH secretion by 151, 129 and 120%, but decreased ( P<0.05) Ob-Rl expression by 32, 50 and 38%, respectively. These results indicate that GRF directly modulates Ob-Rl expression at the level of the pituitary, and thereby playing a role in regulating pituitary sensitivity to leptin.

Sexual dimorphic expression of ADH in rat liver: importance of the hypothalamic-pituitary-liver axis.

Hepatic alcohol dehydrogenase (ADH) activity is higher in female than in male rats. Although sex steroids, thyroid, and growth hormone (GH) have been shown to regulate hepatic ADH, the mechanism(s) for sexual dimorphic expression is unclear. We tested the possibility that the GH secretory pattern determined differential expression of ADH. Gonadectomized and hypophysectomized male and female rats were examined. Hepatic ADH activity was 2.1-fold greater in females. Because protein and mRNA content were also 1.7- and 2.4-fold greater, results indicated that activity differences were due to pretranslational mechanisms. Estradiol increased ADH selectively in males, and testosterone selectively decreased activity and mRNA levels in females. Effect of sex steroids on ADH was lost after hypophysectomy; infusion of GH in males increased ADH to basal female levels, supporting a role of the pituitary-liver axis. However, GH and L-thyroxine (T4) replacements alone in hypophysectomized rats did not restore dimorphic differences for either ADH activity or mRNA levels. On the other hand, T4 in combination with intermittent administration of GH reduced ADH activity and mRNA to basal male values, whereas T4 plus GH infusion replicated female levels. These results indicate that the intermittent male pattern of GH secretion combined with T4 is the principal determinant of low ADH activity in male liver.

Glycemic control determines hepatic and peripheral glucose effectiveness in type 2 diabetic subjects.

Glucose effectiveness is impaired in type 2 diabetes. We hypothesize that chronic hyperglycemia and hyperlipidemia contribute importantly to this defect. To test this hypothesis, we compared the effect of acute hyperglycemia on glucose turnover in type 2 diabetic subjects in good control (GC) (n = 14, age 51.7 +/- 3.7 years, BMI 28.4 +/- 1.0 kg/ m(2), HbA(1c) 5.9 +/- 0.2%) and poor control (PC) (n = 10, age 50.0 +/- 2.5 years, BMI 27.9 +/- 1.5 kg/m(2), HbA(1c) 9.9 +/- 0.6%) with age- and weight-matched nondiabetic subjects (ND) (n = 11, age 47.0 +/- 4.4 years, BMI 28.5 +/- 1.0 kg/m(2), HbA(1c) 5.1 +/- 0.2%). Fixed hormonal conditions were attained by infusing somatostatin for 6 h with replacement of basal insulin, glucagon, and growth hormone. Glucose fluxes ([3-(3)H]glucose) were compared during euglycemic (5 mmol/l, t = 180-240 min) and hyperglycemic (Hy) (10 mmol/l, t = 300-360 min, variable glucose infusion) clamp intervals. Acute hyperglycemia suppressed hepatic glucose production (GP) by 43% and increased peripheral glucose uptake (GU) by 86% in the ND subjects. Conversely, GP failed to suppress (-7%) and GU was suboptimally increased (+34%) in response to Hy in the PC group. However, optimal glycemic control was associated with normal glucose effectiveness in GC subjects (GP -38%, GU +72%; P > 0.05 for GC vs. ND). To determine whether short-term correction of hyperglycemia and/or hyperlipidemia is sufficient to reverse the impairment in glucose effectiveness, five PC subjects were restudied after 72 h of normoglycemia ( approximately 100 mg/dl; variable insulin infusions). These subjects regained normal effectiveness of glucose to suppress GP and stimulate GU and in response to Hy (GP -47%, GU + 71%; P > 0.05 vs. baseline studies). Thus, chronic hyperglycemia and/or hyperlipidemia contribute to impaired effectiveness of glucose in regulating glucose fluxes in type 2 diabetes and hence to worsening of the overall metabolic condition. Short-term normalization of plasma glucose might break the vicious cycle of impaired glucose effectiveness in type 2 diabetes.