Circulating Growth Hormone Levels Research Articles

The intersection between ghrelin, metabolism and circadian rhythms.

Despite the growing popular interest in sleep and diet, many gaps exist in our scientific understanding of the interaction between circadian rhythms and metabolism. In this Review, we explore a promising, bidirectional role for ghrelin in mediating this interaction. Ghrelin both influences and is influenced by central and peripheral circadian systems. Specifically, we focus on how ghrelin impacts outputs of circadian rhythm, including neuronal activity, circulating growth hormone levels, locomotor activity and eating behaviour. We also consider the effects of circadian rhythms on ghrelin expression and the consequences of disrupted circadian patterns, such as shift work and jet lag, on ghrelin secretion. Our Review is aimed at both the casual reader interested in gaining more insight into the scientific context surrounding the trending topics of sleep and metabolism, as well as experienced scientists in the fields of ghrelin and circadian biology seeking inspiration and a comprehensive overview of how these fields are related.

Aerobic Exercise Increases Release of Growth Hormone in the Blood Circulation in Obese Women

Physical exercise is one of the modulators in increasing the release of growth hormone (GH) levels in blood circulation, but the effective exercise model for obese subjects is still being debated. Therefore, this study aims to prove the effect of aerobic exercise on increasing the release of GH levels in the blood circulation in obese women. A total of 20 obese adult women, aged 21.00 ± 1.08 years were selected to be subjects in the study and were given one aerobic exercise intervention by running on a treadmill at moderate-intensity (60-70% HRmax) for 40 minutes. The ELISA method was used to measure the release of GH levels in all samples (pre- and post-exercise). Statistical analysis in this study used an independent sample t-test with a significant level of 5%. The results showed that the release of GH levels in the blood circulation was found to be higher in post-exercise compared to pre-exercise after one session of aerobic exercise (484.92±128.29 vs 892.63±273.54 pg/mL; p=0.001) and has a large effect size with a Cohen's d value of 1.909. GH levels in the post-exercise blood circulation in the aerobic exercise group (Exr) were also found to be higher than the GH levels in the control group (Ctr) (892.63±273.54 vs 542.97±140.01 pg/mL; p=0.003) and has a large effect size with a Cohen's d value of 1.609. This study proves that one session of aerobic exercise with moderate intensity increases the release of circulating GH levels in obese women. Therefore, aerobic exercise with moderate intensity can be used as an alternative therapy option to increase the release of circulating GH levels in individuals with obesity. Keywords: aerobic exercise, growth hormone, metabolism, obesity.

Diffuse traumatic brain injury substantially alters plasma growth hormone in the juvenile rat.

Traumatic brain injury (TBI) can damage the hypothalamus and cause improper activation of the growth hormone (GH) axis, leading to growth hormone deficiency (GHD). GHD is one of the most prevalent endocrinopathies following TBI in adults; however, the extent to which GHD affects juveniles remains understudied. We used postnatal day 17 rats (n = 83), which model the late infantile/toddler period, and assessed body weights, GH levels, and number of hypothalamic somatostatin neurons at acute (1, 7 days post injury (DPI)) and chronic (18, 25, 43 DPI) time points. We hypothesized that diffuse TBI would alter circulating GH levels because of damage to the hypothalamus, specifically somatostatin neurons. Data were analyzed with generalized linear and mixed effects models with fixed effects interactions between the injury and time. Despite similar growth rates over time with age, TBI rats weighed less than shams at 18 DPI (postnatal day 35; P = 0.03, standardized effect size [d] = 1.24), which is around the onset of puberty. Compared to shams, GH levels were lower in the TBI group during the acute period (P = 0.196; d = 12.3) but higher in the TBI group during the chronic period (P = 0.10; d = 52.1). Although not statistically significant, TBI-induced differences in GH had large standardized effect sizes, indicating biological significance. The mean number of hypothalamic somatostatin neurons (an inhibitor of GH) positively predicted GH levels in the hypothalamus but did not predict GH levels in the somatosensory cortex. Understanding TBI-induced alterations in the GH axis may identify therapeutic targets to improve the quality of life of pediatric survivors of TBI.

Circulating follicle stimulating hormone levels influence body growth in pre-menarcheal girls in a latitude-dependent manner

IntroductionAge at menarche is an essential determinant of reproductive life of a woman. Latitude is an important driver of age at menarche, however the contributions of circulating follicle stimulating hormone (FSH) and socio-economic status (SES) to age at menarche in a latitude-dependent manner is not known. MethodsThis population-based cross-sectional study is a component of our major cohort of 10,050 schoolgirls aged 8–16 years from 35 schools across 10 districts. The selected districts were categorised into high and low latitudes by applying a cut-off point at latitude 31.5⁰N. We evaluated the physical parameters, SES, circulating FSH, and growth hormone (GH) levels in pre-menarche girls (N = 252) at different latitudes. ResultsSelf-reported age at menarche of girls residing at different latitudes in Pakistan showed that higher latitude is associated with delayed age at menarche. Higher latitude was associated with reduced circulating FSH levels, as well as lower parameters of physical growth including body mass index (BMI), waist-hip ratio and, waist-height ratio (all p < 0.05) in the pre-menarcheal girls. However, circulating GH levels were not affected by latitude. On the other hand, lower SES was associated with reduced GH levels and lower BMI, which are considered as probably the primary determinants of physical growth. ConclusionsTaken together, we show that higher latitude may delay the sexual maturation, while poor SES may delay the physical growth in girls.

The multiple roles of GH in neural ageing and injury.

Advanced age is typically associated with a decrease in cognitive function including impairment in the formation and retention of new memories. The hippocampus is critical for learning and memory, especially spatial learning, and is particularly affected by ageing. With advanced age, multiple neural components can be detrimentally affected including a reduction in the number of neural stem and precursor cells, a decrease in the formation of adult born neurons (neurogenesis), and deficits in neural circuitry, all of which ultimately contribute to impaired cognitive function. Importantly, physical exercise has been shown to ameliorate many of these impairments and is able to improve learning and memory. Relevantly, growth hormone (GH) is an important protein hormone that decreases with ageing and increases following physical exercise. Originally described due to its role in longitudinal growth, GH has now been identified to play several additional key roles, especially in relation to the brain. Indeed, the regular decrease in GH levels following puberty is one of the most well documented components of neuroendocrine ageing. Growth hormone deficiency (GHD) has been described to have adverse effects on brain function, which can be ameliorated via GH replacement therapy. Physical exercise has been shown to increase circulating GH levels. Furthermore, we recently demonstrated the increase in exercise-mediated GH is critical for improved cognitive function in the aged mouse. Here we examine the multiple roles that GH plays, particularly in the aged brain and following trauma, irradiation and stroke, and how increasing GH levels can ameliorate deficits in cognition.

Understanding the role of growth hormone in situations of metabolic stress.

Growth hormone (GH) is secreted by the anterior pituitary gland and plays a key role in controlling tissue and body growth. While basal GH secretion is considerably reduced along adulthood and aging, several situations of metabolic stress can lead to robust increases in circulating GH levels. The objective of the present review is to summarize and discuss the importance of GH regulating different physiological functions in situations of metabolic stress, including prolonged food restriction, hypoglycemia, exercise, pregnancy, and obesity. The presented data indicate that GH increases hunger perception/food intake, fat mobilization, blood glucose levels and insulin resistance, as well as produces changes in energy expenditure and neuroendocrine responses during metabolic challenges. When all these effects are considered in the context of situations of metabolic stress, they contribute to restore homeostasis by 1) helping the organism to use appropriate energy substrates; 2) preventing hypoglycemia or increasing the availability of glucose; 3) stimulating feeding to provide nutrients in response to energy-demanding activities or to accelerate the recovery of energy stores; and 4) affecting the activity of neuronal populations involved in the control of metabolism and stress response. Thus, the central and peripheral effects of GH coordinate multiple adaptations during situations of metabolic stress that ultimately help the organism restore homeostasis, increasing the chances of survival.

Lipotoxicity suppresses the synthesis of growth hormone in pituitary somatotrophs via endoplasmic reticulum stress.

Lipotoxicity has been shown to cause dysfunction of many organs and tissues. However, it is unclear whether lipotoxicity is harmful to the somatotrophs, a kind of cell that synthesize growth hormone (GH) in the pituitary. In this study, we performed an epidemiological study, serum levels of triglyceride (TG) and GH showed a negative correlation, even after adjustment for potential confounders. In an animal study, male Sprague‐Dawley rats were fed a high‐fat diet (HFD) or a control diet for 28 weeks. HFD rats showed impaired GH synthesis, resulting in a decrease in circulating GH levels. The expression of pituitary Pit‐1, a key transcription factor of GH, was inhibited. We found that the inositol‐requiring enzyme 1α (IRE1α) pathway of endoplasmic reticulum (ER) stress was triggered in HFD rat pituitary glands and palmitic acid‐treated GH3 cells, respectively. On the contrary, applying 4‐phenyl butyric acid (4‐PBA) to alleviate ER stress or 4µ8c to specifically block the IRE1α pathway attenuated the impairment of both Pit‐1 and GH expression. In conclusion, we demonstrated that lipotoxicity directly inhibits the synthesis of GH, probably by reducing Pit‐1 expression. The IRE1α signaling pathway of ER stress may play an important role in this process.

Pregnancy-related plasticity of gastric vagal afferent signals in mice.

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake. This study aimed to determine the mechanosensitivity of GVAs and food intake during early, mid-, and late stages of pregnancy in mice. Pregnant mice consumed more food compared with nonpregnant mice, notably in the light phase during mid- and late pregnancy. The increased food intake was predominantly due to light-phase increases in meal size across all stages of pregnancy. The sensitivity of GVA tension receptors to gastric distension was significantly attenuated in mid- and late pregnancy, whereas the sensitivity of GVA mucosal receptors to mucosal stroking was unchanged during pregnancy. To determine whether pregnancy-associated hormonal changes drive these adaptations, the effects of estradiol, progesterone, prolactin, and growth hormone on GVA tension receptor mechanosensitivity were determined in nonpregnant female mice. The sensitivity of GVA tension receptors to gastric distension was augmented by estradiol, attenuated by growth hormone, and unaffected by progesterone or prolactin. Together, the data indicate that the sensitivity of GVA tension receptors to tension is reduced during pregnancy, which may attenuate the perception of gastric fullness and explain increased food intake. Further, these adaptations may be driven by increases in maternal circulating growth hormone levels during pregnancy.NEW & NOTEWORTHY This study provides first evidence that gastric vagal afferent signaling is attenuated during pregnancy and inversely associated with meal size. Growth hormone attenuated mechanosensitivity of gastric vagal afferents, adding support that increases in maternal growth hormone may mediate adaptations in gastric vagal afferent signaling during pregnancy. These findings have important implications for the peripheral control of food intake during pregnancy.

Downregulation of growth hormone in postural orthostatic tachycardia syndrome: insights from the SYSTEMA cohort

Abstract Background Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular autonomic disorder occurring predominantly in young women. POTS is characterized by an excessive heart rate increase when assuming upright posture accompanied by symptoms of orthostatic intolerance. The pathophysiology of POTS has not been fully established and is believed to be multifactorial. Purpose We aimed to investigate the alterations in circulating growth hormone level in POTS. Methods We conducted an age-matched case-control study enrolling 42 patients with POTS (age 31±9 years; 36 women) verified by positive head-up tilt testing and cardiovascular autonomic tests, and 46 controls (32±9 years; 35 women) with negative active standing test and no history of syncope, orthostatic intolerance and endocrine disease. We measured plasma levels of growth hormone using a high-sensitivity chemiluminescence immunoassay in relation to presence of POTS diagnosis. All study participants completed the validated Orthostatic Hypotension Questionnaire (OHQ), consisting of two components: the symptoms assessment scale (OHSA) and daily activity scale (OHDAS) to evaluate the burden of symptoms. We applied standard statistical tests for group differences. Growth hormone values were log-transformed and standardized before the group comparison. Results POTS patients had significantly lower plasma levels of growth hormone (ng/mL) (median=0.53, IQR, 0.10–2.83 vs. median=2.33, IQR, 0.26–7.2, p=0.04) than controls. Levels of growth hormone were reversely related to OHDAS (p=0.049) among POTS patients. Supine heart rate was significantly higher in POTS patients (69.0±11.1 beats/min vs. 63.3±10.8 beats/min, p=0.02), as well as diastolic blood pressure (72.9±9.1 mmHg vs. 69.0±8.5 mmHg, p=0.04). We observed no significant difference in supine systolic blood pressure (116.6±13.3 mmHg vs. 115.2±10.0 mmHg, p=0.60). POTS patients had a significantly higher composite OHQ score than controls (60.0±18.6 vs. 4.2±7.5, p&amp;lt;0.001), as well as OHSA (36.2±10.0 vs. 3.6±6.4, p&amp;lt;0.001) and OHDAS (23.8±9.7 vs. 0.6±1.3, p&amp;lt;0.001). Conclusion(s) Our study shows that patients with POTS have significantly reduced plasma levels of circulating growth hormone. Lower growth hormone levels among POTS patients are associated with increased impairment of daily life activities. Further studies are necessary to confirm our findings in the independent populations and explain the mechanisms behind this alteration. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Crafoord Foundation, Swedish Heart and Lung Foundation

Early overnutrition sensitizes the growth hormone axis to the impact of diet-induced obesity via sex-divergent mechanisms

In addition to its essential role in the physiological control of longitudinal growth, growth-hormone (GH) is endowed with relevant metabolic functions, including anabolic actions in muscle, lipolysis in adipose-tissue and glycemic modulation. Adult obesity is known to negatively impact GH-axis, thereby promoting a vicious circle that may contribute to the exacerbation of the metabolic complications of overweight. Yet, to what extent early-overnutrition sensitizes the somatotropic-axis to the deleterious effects of obesity remains largely unexplored. Using a rat-model of sequential exposure to obesogenic insults, namely postnatal-overfeeding during lactation and high-fat diet (HFD) after weaning, we evaluated in both sexes the individual and combined impact of these nutritional challenges upon key elements of the somatotropic-axis. While feeding HFD per se had a modest impact on the adult GH-axis, early overnutrition had durable effects on key elements of the somatotropic-system, which were sexually different, with a significant inhibition of pituitary gene expression of GH-releasing hormone-receptor (GHRH-R) and somatostatin receptor-5 (SST5) in males, but an increase in pituitary GHRH-R, SST2, SST5, GH secretagogue-receptor (GHS-R) and ghrelin expression in females. Notably, early-overnutrition sensitized the GH-axis to the deleterious impact of HFD, with a significant suppression of pituitary GH expression in both sexes and lowering of circulating GH levels in females. Yet, despite their similar metabolic perturbations, males and females displayed rather distinct alterations of key somatotropic-regulators/ mediators. Our data document a synergistic effect of postnatal-overnutrition on the detrimental impact of HFD-induced obesity on key elements of the adult GH-axis, which is conducted via mechanisms that are sexually-divergent.

Tyrosine Hydroxylase Neurons Regulate Growth Hormone Secretion via Short-Loop Negative Feedback.

Classical studies suggest that growth hormone (GH) secretion is controlled by negative-feedback loops mediated by GH-releasing hormone (GHRH)- or somatostatin-expressing neurons. Catecholamines are known to alter GH secretion and neurons expressing TH are located in several brain areas containing GH-responsive cells. However, whether TH-expressing neurons are required to regulate GH secretion via negative-feedback mechanisms is unknown. In the present study, we showed that between 50% and 90% of TH-expressing neurons in the periventricular, paraventricular, and arcuate hypothalamic nuclei and locus ceruleus of mice exhibited STAT5 phosphorylation (pSTAT5) after an acute GH injection. Ablation of GH receptor (GHR) from TH cells or in the entire brain markedly increased GH pulse secretion and body growth in both male and female mice. In contrast, GHR ablation in cells that express the dopamine transporter (DAT) or dopamine β-hydroxylase (DBH; marker of noradrenergic/adrenergic cells) did not affect body growth. Nevertheless, less than 50% of TH-expressing neurons in the hypothalamus were found to express DAT. Ablation of GHR in TH cells increased the hypothalamic expression of Ghrh mRNA, although very few GHRH neurons were found to coexpress TH- and GH-induced pSTAT5. In summary, TH neurons that do not express DAT or DBH are required for the autoregulation of GH secretion via a negative-feedback loop. Our findings revealed a critical and previously unidentified group of catecholaminergic interneurons that are apt to sense changes in GH levels and regulate the somatotropic axis in mice.SIGNIFICANCE STATEMENT Textbooks indicate until now that the pulsatile pattern of growth hormone (GH) secretion is primarily controlled by GH-releasing hormone and somatostatin neurons. The regulation of GH secretion relies on the ability of these cells to sense changes in circulating GH levels to adjust pituitary GH secretion within a narrow physiological range. However, our study identifies a specific population of tyrosine hydroxylase-expressing neurons that is critical to autoregulate GH secretion via a negative-feedback loop. The lack of this mechanism in transgenic mice results in aberrant GH secretion and body growth. Since GH plays a key role in cell proliferation, body growth, and metabolism, our findings provide a major advance to understand how the brain regulates the somatotropic axis.

Effect of growth rate on transcriptomic responses to immune stimulation in wild-type, domesticated, and GH-transgenic coho salmon

BackgroundTranscriptomic responses to immune stimulation were investigated in coho salmon (Oncorhynchus kisutch) with distinct growth phenotypes. Wild-type fish were contrasted to strains with accelerated growth arising either from selective breeding (i.e. domestication) or genetic modification. Such distinct routes to accelerated growth may have unique implications for relationships and/or trade-offs between growth and immune function.ResultsRNA-Seq was performed on liver and head kidney in four ‘growth response groups’ injected with polyinosinic-polycytidylic acid (Poly I:C; viral mimic), peptidoglycan (PGN; bacterial mimic) or PBS (control). These groups were: 1) ‘W’: wild-type, 2) ‘TF’: growth hormone (GH) transgenic salmon with ~ 3-fold higher growth-rate than W, 3) ‘TR’: GH transgenic fish ration restricted to possess a growth-rate equal to W, and 4) ‘D’: domesticated non-transgenic fish showing growth-rate intermediate to W and TF. D and TF showed a higher similarity in transcriptomic response compared to W and TR. Several immune genes showed constitutive expression differences among growth response groups, including perforin 1 and C-C motif chemokine 19-like. Among the affected immune pathways, most were up-regulated by Poly I:C and PGN. In response to PGN, the c-type lectin receptor signalling pathway responded uniquely in TF and TR. In response to stimulation with both immune mimics, TR responded more strongly than other groups. Further, group-specific pathway responses to PGN stimulation included NOD-like receptor signalling in W and platelet activation in TR. TF consistently showed the most attenuated immune response relative to W, and more DEGs were apparent in TR than TF and D relative to W, suggesting that a non-satiating ration coupled with elevated circulating GH levels may cause TR to possess enhanced immune capabilities. Alternatively, TF and D salmon are prevented from acquiring the same level of immune response as TR due to direction of energy to high overall somatic growth. Further study of the effects of ration restriction in growth-modified fishes is warranted.ConclusionsThese findings improve our understanding of the pleiotropic effects of growth modification on the immunological responses of fish, revealing unique immune pathway responses depending on the mechanism of growth acceleration and nutritional availability.

SAT-181 Characterization of Adult Growth Hormone Receptor Gene-Disrupted Mice

Reduced growth hormone (GH) action can extend life- and health-span. Mice with a disrupted GHR gene since birth are dwarf and obese with low levels of IGF-1 and insulin; high levels of GH; and hold the record for the longest-lived laboratory mouse. They are also somewhat resistant to several age-related diseases including cancer and diabetes. In order to determine if disruption of GHR after birth can also extend lifespan, we previously disrupted the GHR gene at 6 weeks of age and found that females have extended maximal lifespans. In the current study, we wanted to evaluate if disrupting GH action at an adult age (6 months) will lead to the same lifelong benefits seen mice with no GH action since birth, but without dwarfism. In this study, we used the Cre-lox system to ablate the GHR in mice of 6 months (a6mGHRKO mice). Following this, we determined body weights, composition and glucose homeostatic criteria including glucose and insulin tolerance testing. We then dissected the mice 6 months after GHR disruption (1 year of age) to measure circulatory GH, Insulin growth factor 1 (IGF-1), inflammatory factors, as well as the GHR expression levels in different tissues including liver, skeletal muscle and adipose tissue. We found that, the a6mGHRKO mice were not dwarf and have decreased IGF-1 and increased circulating GH levels. We also found that the GHR gene expression was decreased in all the tissues tested, and IGF-1 mRNA levels were reduced in adipose tissue liver and heart, but not in muscle or kidneys when compared to WT mice. Also, circulatory levels of interleukin-6, tumor necrosis alpha and monocyte chemoattractant protein 1 were unchanged between a6mGHRKO mice and controls. Moreover, differences in glucose metabolism can be seen in male and female a6mGHRKO mice. While glucose tolerance was not changed between experimental mice and controls, male a6mGHRKO mice showed increased insulin sensitivity, whereas female a6mGHRKO mice showed no difference in insulin sensitivity with respect to littermate controls. Studies that assess the status of age-related mechanisms such as mechanistic target of rapamycin (mTOR) activity and oxidative stress are being performed. Finally, a separate cohort of the a6mGHRKO mice have been generated and are being evaluated for the life span of these mice. In conclusion, mice that have the GHR gene ablated at 6 months of age have a normal body length, improved insulin sensitivity in males and normal inflammatory status when compared to controls. Molecular mechanisms to determine age-related effects of GH including longevity studies are ongoing.

Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release.

Exercise is an effective intervention for the prevention and treatment of type 2 diabetes. Skeletal muscle combines multiple signals that contribute to the beneficial effects of exercise on cardiometabolic health. Inorganic nitrate increases exercise efficiency, tolerance, and performance. The transcriptional regulator peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) coordinates the exercise-stimulated skeletal muscle fiber-type switch from glycolytic fast-twitch (type IIb) to oxidative slow-twitch (type I) and intermediate (type IIa) fibers, an effect reversed in insulin resistance and diabetes. We found that nitrate induces PGC1α expression and a switch toward type I and IIa fibers in rat muscle and myotubes in vitro. Nitrate induces the release of exercise/PGC1α-dependent myokine FNDC5/irisin and β-aminoisobutyric acid from myotubes and muscle in rats and humans. Both exercise and nitrate stimulated PGC1α-mediated γ-aminobutyric acid (GABA) secretion from muscle. Circulating GABA concentrations were increased in exercising mice and nitrate-treated rats and humans; thus, GABA may function as an exercise/PGC1α-mediated myokine-like small molecule. Moreover, nitrate increased circulating growth hormone levels in humans and rodents. Nitrate induces physiological responses that mimic exercise training and may underlie the beneficial effects of this metabolite on exercise and cardiometabolic health.

Reproductive parameters of double transgenic zebrafish (Danio rerio) males overexpressing both the growth hormone (GH) and its receptor (GHR).

Growth hormone (GH) transgenesis presents a high potential application in aquaculture. However, excess GH may have serious consequences due to pleiotropic actions. In order to study these effects in zebrafish (Danio rerio), two transgenic lines were developed. The first expresses GH ubiquitously and constitutively (F0104 line), while the second expresses the GH receptor in a muscle-specific manner (Myo-GHR line). Results from the F0104 line showed accelerated growth but increased reproductive difficulties, while Myo-GHR did not show the expected increase in muscle mass. Since the two lines appeared to display complementary characteristics, a double transgenic (GH/GHR) was created via crossing between them. This double transgenic displayed accelerated growth, however reproductive parameters remained uncertain. The objective of the present study was to determine the reproductive capacity of males of this new line, by evaluating sperm parameters, expression of spermatogenesis-related genes, and reproductive tests. Double transgenics showed a strong recovery in almost all sperm parameters analyzed when compared to the F0104 line. Gene expression analyses revealed that Anti-Müllerian Hormone gene (amh) appeared to be primarily responsible for this recovery. Reproductive tests showed that double transgenic males did not differ from non-transgenics. It is possible that GHR excess in the muscle tissues of double transgenics may have contributed to lower circulating GH levels and thus reduced the negative effects of this hormone with respect to reproduction. Therefore, it is clear that GH-transgenesis technology should take into account the need to obtain adequate levels of circulating hormone in order to achieve maximum growth with minimal negative side effects.

Differential impact of selective GH deficiency and endogenous GH excess on insulin-mediated actions in muscle and liver of male mice.

A reciprocal relationship between insulin sensitivity and glucose tolerance has been reported in some mouse models and humans with isolated changes in growth hormone (GH) production and signaling. To determine if this could be explained in part by tissue-specific changes in insulin sensitivity, hyperinsulinemic-euglycemic clamps were performed in mice with adult-onset, isolated GH deficiency and in mice with elevated endogenous GH levels due to somatotrope-specific loss of IGF-I and insulin receptors. Our results demonstrate that circulating GH levels are negatively correlated with insulin-mediated glucose uptake in muscle but positively correlated with insulin-mediated suppression of hepatic glucose production. A positive relationship was also observed between GH levels and endpoints of hepatic lipid metabolism known to be regulated by insulin. These results suggest hepatic insulin resistance could represent an early metabolic defect in GH deficiency.

Effects of genistein on stereological and hormonal characteristics of the pituitary somatotrophs in rats.

The hypothalamic-pituitary somatotropic system plays a pivotal role in the regulation of physiological processes and metabolism, which is modulated by gonadal steroids. Considering that genistein belongs to the phytoestrogen family and acts via similar mechanisms to estrogens, the present study was designed to demonstrate whether genistein modulates the morphofunctional characteristic of somatotrophs [growth hormone (GH) cells] in adult rats in comparison with the effects of estradiol. In the study, the orchidectomized adult rats were used as an appropriate model system for testing the effects of this hormone-like substance. Changes in the pituitary somatotrophs were evaluated histologically and stereologically, while GH level was determined biochemically. Using immunolabelling and stereological methods, we showed that orchidectomy (Orx) provoked the decrease of GH cell volume density. After estradiol treatment of Orx rats, the most prominent change concerned the pituitary relative intensity of GH fluorescence and circulating GH level, which were elevated 77 % and 4.7-fold, respectively. Clearly, in contrast to orchidectomy, estradiol treatment enhanced the GH cells activity. Genistein treatment increased pituitary weight and volume, GH cell volume density, the total number of GH cells, and GH blood concentration (1.3-fold) in comparison to the Orx group. Although identical tendencies followed estradiol and genistein administration, the changes observed after genistein treatment were milder compared to estradiol treatment.

Impaired renal growth hormone JAK/STAT5 signaling in chronic kidney disease

Treatment with recombinant human growth hormone (GH) is the standard therapy for short stature in children with chronic kidney disease (CKD). However, concerns have been raised on the potential renal fibrogenic effects of GH. There is no information regarding the renal GH receptor (GHR)-JAK-STAT signaling pathway in CKD. Subtotal nephrectomized (CKD) and pair-fed sham-operated control (C) juvenile rats were treated with subcutaneous GH or saline for 2 weeks. A single intravenous GH bolus or vehicle was provided prior to euthanasia. Reduced body weight in CKD was improved with GH therapy. The remnant kidney showed glomerular hypertrophy and early interstitial fibrosis without inflammatory infiltration. Treatment of CKD rats with GH did not worsen renal function or fibrosis. Kidney GHR mRNA and protein levels were reduced and basal phosphorylation of JAK2 and STAT5 was significantly impaired. However, intravenous GH administration prior to sacrifice normalized STAT5 phosphorylation. Basal renal IL6 mRNA and phosphorylation of its downstream signaling molecule STAT3 were increased as was the product of its action, the suppressor of cytokine signaling 3 (SOCS3) mRNA. Despite known unaltered circulating GH levels, remnant kidneys of uremic growth retarded juvenile rats show impaired basal signaling along the GH-activated JAK2/STAT5 signaling pathway. This may well be a consequence of the reduced GHR level and the inhibitory effect of the increase in IL-6-mediated SOCS3 expression. This renal GH insensitivity, if present in humans, may protect against the potential adverse renal effects of GH administration in CKD patients.

Role of Ghrelin in regulation of growth hormone secretion by Ghrelin-Pituitary-GH axis linkage

Background: Ghrelin is the endogenous ligand of the growth hormone (GH) secretagogue receptor and is the first hormone linking gastrointestinal-pituitary axis. Actions of ghrelin on GH secretion provide a strong force for envisioning that one of the major role of ghrelin could be the regulation of secretion of GH. Aims & Objective: To explore the intriguing dimensions on the possible physiological role of the Ghrelin /GHRP system. Materials and Methods: The search was performed in electronic databases (Medline, Embase, Cochrane, Google scholar) and by hand searching by 2 reviewers. Clinical trials (Randomised and non-randomised trials), review articles, systematic reviews, conference proceedings and meta-analysis were included in the study. Results: Ghrelin stimulates strong increase in circulating GH levels both in vitro and in vivo in a dose-dependent manner. Human or animal ghrelin was found to be significantly more potent than a synthetic GHS, hexarelin. The regulation of GH by Ghrelin is influenced by various other factors like autonomic nervous system, GHRH, IGF-1, anterior pituitary hormones, obesity, etc. Conclusion: Ghrelin is a specific endogenous ligand for the GHS receptor and suggests the existence of a GHS–GHS receptor signaling system in the regulation of GH secretion. Stomach-ghrelin - pituitary-GH axis links nutritional intake to regulation of GH secretion. However, the mechanism underlying the feedback actions of GH on the regulation of ghrelin remains unanswered. Under physiological conditions, ghrelin administered either centrally or peripherally, exerts a potent, time-dependent stimulation of pulsatile secretion of GH by ghrelin-pituitary-GH axis.

Influence of glucocorticoids and growth hormone on insulin sensitivity in humans

The seminal concept proposed by Sir Harold Himsworth more than 75 years ago that a large number of patients with diabetes were 'insulin insensitive', now termed insulin resistance, has now expanded to include several endocrine syndromes, namely those of glucocorticoid excess, and growth hormone excess and deficiency. Synthetic glucocorticoids are increasingly used to treat a wide variety of chronic diseases, whereas the beneficial effects of recombinant growth hormone replacement therapy in children and adults with growth hormone deficiency have now been well-recognized for over 25 years. However, clinical and experimental studies have established that increased circulating levels of glucocorticoids and growth hormone can also lead to worsening of insulin resistance, glucose intolerance, overt diabetes mellitus and cardiovascular disease. Improved understanding of the physiological 24-h rhythmicity of glucocorticoid and growth hormone secretion and its influence on the dawn phenomenon and the Staub-Trauggot effect has therefore led to renewed interest in studies on the mechanisms of insulin resistance induced by exogenous administration of glucocorticoids and growth hormone in humans. In this review, we describe the physiological events that result from the presence of resistance to insulin action at the level of skeletal muscle, adipose tissue, and liver, describe the known mechanisms of glucocorticoid- and growth hormone-mediated insulin resistance, and provide an update of the contributions of glucocorticoids and growth hormone to understanding the pathophysiology of insulin resistance and its effects on several endocrine syndromes.