Direct Effects Of Growth Hormone Research Articles

Acromegaly and it's cardiovascular implications

Acromegaly is a chronic and slowly progressive disease that results from the hypersecretion of growth hormone (GH) and consequently insulin-like growth factor type 1 (IGF-1), due to a GH-secreting pituitary adenoma in 95-98% of cases. There are several complications or co-morbidities associated with acromegaly, the most frequent being cardiovascular, metabolic and neoplastic. The cardiovascular complications of acromegaly go from arterial hypertension to a peculiar form of cardiomyopathy and are the result of the long-standing exposure to high GH and IGF-1 levels. The pathophysiology of these complications is complex and includes an increased tubular reabsorption of sodium and the direct effects of GH and IGF-1 on the endothelium and the cardiac tissue itself. Frequently, the cardiovascular comorbidities of acromegaly occur concomitantly with metabolic complications such as diabetes and respiratory abnormalities such as the sleep apnea syndrome. In this brief review we analyze the pathophysiology, the clinical manifestations and the management of the cardiovascular complications of acromegaly.

Hypermobility in individuals with Kabuki syndrome: The effect of growth hormone treatment.

Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D‐associated, autosomal‐dominant KS type 1 (KS1; OMIM 147920); and KDM6A‐associated, X‐linked‐dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS.

GH indirectly enhances the regeneration of transgenic zebrafish fins through IGF2a and IGF2b.

The somatotropic axis, composed essentially of the growth hormone (GH) and insulin-like growth factors (IGFs), is the main regulator of somatic growth in vertebrates. However, these protein hormones are also involved in various other major physiological processes. Although the importance of IGFs in mechanisms involving tissue regeneration has already been established, little is known regarding the direct effects of GH in these processes. In this study, we used a transgenic zebrafish (Danio rerio) model, which overexpresses GH from the beta-actin constitutive promoter. The regenerative ability of the caudal fin was assessed after repeated amputations, as well as the expression of genes related to the GH/IGF axis. The results revealed that GH overexpression increased the regenerated area of the caudal fin in transgenic fish after the second amputation. Transgenic fish also presented a decrease in gene expression of the GH receptor (ghrb), in opposition to the increased expression of the IGF1 receptors (igf1ra and igf1rb). These results suggest that transgenic fish have a higher sensitivity to IGFs than to GH during fin regeneration. With respect to the different IGFs produced locally, a decrease in igf1a expression and a significant increase in both igf2a and igf2b expression was observed, suggesting that igf1a is not directly involved in fin regeneration. Overall, the results revealed that excess GH enhances fin regeneration in zebrafish through igf2a and igf2b expression, acting indirectly on this major physiological process.

Effects of growth hormone therapeutic supplementation on hematopoietic stem/progenitor cells in children with growth hormone deficiency: focus on proliferation and differentiation capabilities.

We investigated the direct effects of growth hormone (GH) replacement therapy (GH-RT) on hematopoiesis in children with GH deficiency (GHD) with the special emphasis on proliferation and cell cycle regulation. Peripheral blood (PB) was collected from sixty control individuals and forty GHD children before GH-RT and in 3rd and 6th month of GH-RT to measure hematological parameters and isolate CD34+-enriched hematopoietic progenitor cells (HPCs). Selected parameters of PB were analyzed by hematological analyzer. Moreover, collected HPCs were used to analyze GH receptor (GHR) and IGF1 expression, clonogenicity, and cell cycle activity. Finally, global gene expression profile of collected HPCs was analyzed using genome-wide RNA microarrays. GHD resulted in a decrease in several hematological parameters related to RBCs and significantly diminished clonogenicity of erythroid progenies. In contrast, GH-RT stimulated increases in clonogenic growth of erythroid lineage and RBC counts as well as significant up-regulation of cell cycle-propagating genes, including MAP2K1, cyclins D1/E1, PCNA, and IGF1. Likewise, GH-RT significantly modified GHR expression in isolated HPCs and augmented systemic IGF1 levels. Global gene expression analysis revealed significantly higher expression of genes associated with cell cycle, proliferation, and differentiation in HPCs from GH-treated subjects. (i) GH-RT significantly augments cell cycle progression in HPCs and increases clonogenicity of erythroid progenitors; (ii) GHR expression in HPCs is modulated by GH status; (iii) molecular mechanisms by which GH influences hematopoiesis might provide a basis for designing therapeutic interventions for hematological complications related to GHD.Electronic supplementary materialThe online version of this article (doi:10.1007/s12020-015-0591-0) contains supplementary material, which is available to authorized users.

Differential effects of exogenous and autocrine growth hormone on LNCaP prostate cancer cell proliferation and survival

The prostate gland is regulated by multiple hormones and growth factors that may also affect prostate tumorigenesis. Growth hormone (GH) contributes to prostate development and function, but the direct effects of GH on prostate cancer cells are not well understood. The expression of endogenous GH in prostate cancer cell lines has also been observed, suggesting the potential for an effect of autocrine GH. In the present study, we measure the levels of GH and GH receptor (GHR) mRNA in multiple prostate cancer and normal prostate-derived cell lines, and compare the effects of exogenous and autocrine GH on LNCaP prostate cancer cell proliferation and apoptosis, and the associated signal transduction pathways. We found that GHR and GH expression were higher in the prostate cancer cell lines, and that exogenous GH increased LNCaP cell proliferation, but had no effect on apoptosis. In contrast, autocrine GH overexpression reduced LNCaP cell proliferation and increased apoptosis. The distinct actions of exogenous and autocrine GH were accompanied by differences in the involvement of GHR-associated signal transduction pathways, and were paralleled by an alteration in the subcellular localization of GHR, in which autocrine GH appeared to sequester GHR in the Golgi and endoplasmic reticulum. This alteration of GHR trafficking may underlie a distinct mode of GH-mediated signaling associated with the effect of autocrine GH. These findings clarify the potential effects of GH on prostate cancer cell function, and indicate that the activity of autocrine GH may be distinct from that of endocrine GH in prostate cancer cells.

Hypertensive emergency: A unique manifestation of a pituitary disorder

Acromegaly a common pituitary disorder has significant adverse effects on well-being and survival. The slight increase in the prevalence of hypertension in acromegaly is well known and is proposed to be the direct effects of growth hormone. The hypertension for calculating the prevalence in most series was defined as diastolic more than 100 mmHg, but hypertensive emergency is rarely ever described in the literature. Growth hormone excess has been associated with renal manifestations such as hypercalciuria and nephrolithiasis, but never with renal failure. We present a case referred to a tertiary care nephrology center with malignant hypertension. This is the first case of a patient of acromegaly presenting with hypertensive emergency progressing to malignant nephrosclerosis and renal failure.

Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice

Insulin, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) play key roles in the regulation of β cell growth and function. Although β cells express the GH receptor, the direct effects of GH on β cells remain largely unknown. Here we have employed a rat insulin II promoter-driven (RIP-driven) Cre recombinase to disrupt the GH receptor in β cells (βGHRKO). βGHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in β cell mass. When challenged with a high-fat diet, βGHRKO mice showed evidence of a β cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucose-stimulated insulin secretion. Interestingly, βGHRKO mice were impaired in β cell hyperplasia in response to a high-fat diet, with decreased β cell proliferation and overall reduced β cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and β cell compensation in response to a high-fat diet.

Prognostic significance of aortic stiffness index in acromegaly—Results from a 4-year follow-up

The elevated growth hormone (GH) and insuline-like growth-factor 1 (IGF-I) levels lead to a wide range of cardiovascular, respiratory, endocrine, and metabolic morbidities [ [1] Melmed S. Acromegaly. N Engl J Med. 1990; 322: 966-977 Crossref PubMed Scopus (509) Google Scholar ]. Direct effects of GH and IGF-1 on vasculature over traditional risk factors were suggested. In recent studies, early alterations in aortic distensibility have been demonstrated in acromegalics [ 2 Smith J.C. Lane H. Davies N. et al. The effects of depot long-acting somatostatin analog on central aortic pressure and arterial stiffness in acromegaly. J Clin Endocrinol Metab. 2003; 88: 2556-2561 Crossref PubMed Scopus (36) Google Scholar , 3 Nemes A. Gavallér H. Csajbók E. Julesz J. Forster T. Csanády M. Aortic stiffness is increased in acromegaly—a transthoracic echocardiographic study. Int J Cardiol. 2008; 124: 121-123 Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar , 4 Nemes A. Gavallér H. Csajbók E. Lengyel C. Forster T. Csanády M. Does diabetes mellitus facilitate aortic stiffening in acromegaly?. Diabetes Res Clin Pract. 2007; 78: e7-e8 Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar ]. However, prognostic information on vascular distensibility alterations in this patient population has never been investigated. Therefore the present study was designed to assess whether echocardiography-derived ascending aortic stiffness index (ASI) in acromegaly patients has a prognostic significance to assess event-free survival during a long-term follow-up.

DIFFERENTIAL EFFECTS OF GROWTH HORMONE FAMILY PEPTIDES ON THE EXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 AND 2 mRNAs

Event Abstract Back to Event DIFFERENTIAL EFFECTS OF GROWTH HORMONE FAMILY PEPTIDES ON THE EXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 AND 2 mRNAs Chad Walock1*, Lincoln Martin2, Jeffrey Kittilson2 and Mark Sheridan1, 2 1 North Dakota State University, Cell and Molecular Biology, United States 2 North Dakota State University, Biological Sciences, United States The growth of vertebrates is primarily controlled by the growth hormone (GH)-insulin-like growth factor (IGF) system. In mammals, postembryonic growth is mediated by IGF-1 produced under the influence of GH, whereas embryonic growth is mediated by IGF-2, the production of which is not influenced by GH. Recent reports of IGF-2 expression in tissues of juvenile and adult fish suggest that it may play a role in regulating post-embryonic growth in this group. In this study, we used juvenile (postembryonic) rainbow trout to examine the influence of GH family peptides on the expression of IGF-1 and IGF-2 mRNAs and to assess the mechanism(s) through which GH exerts its actions. Fish were implanted with mini osmotic pumps containing GH or saline for 21 days. GH significantly increased mRNA levels of IGF-1 and IGF-2 in both liver and muscle of levels observed in saline-implanted fish. The direct effects of GH, prolactin (PRL), and somatolactin (SL) were assessed on isolated hepatocytes incubated in vitro. GH stimulated expression of IGF-1 and IGF-2 mRNAs in a concentration- and time-related manner; GH was more potent and more efficacious in stimulating IGF-2 expression than IGF-1 expression. The extracellualar signal-regulated kinase (ERK) pathways inhibitor, U0126, and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibitor, LY294002, blocked GH-stimulated IGF-1 and IGF-2 expression. PRL had slight but significant effects on the expression of IGF-1 and IGF-2; PRL-stimulated expression of IGF mRNAs also was blocked by U0126 and LY294002. SL had no effect on the expression of either IGF-1 or IGF-2 mRNA. These findings indicate that GH stimulates IGF-2 expression to a greater extent than IGF-1 expression and support a role of IGF-2 in postembryonic growth of fish. These findings also indicate that GH-stimulated IGF-1 and IGF-2 expressed involve activation of the ERK and PI3K/Akt signaling pathways. (Supported by NSF IOS 0920116) Acknowledgements We would like to thank Heather Bergan, Mike Caruso, Andrea Hanson, Elle Kvam, Dillon Marquart, and Lindsey Norbeck for their assistance. Prof. Akiyosi Takahasi and Dr. Shiunsuke Moriyama generously provided salmonid GH, PRL, and SL. Supported by NSF grant IOS 0920116 to M. A. Sheridan. Keywords: Akt, ERK, Growth Hormone, insulin-like growth factors, PI3K, Prolactin, Somatolactin Conference: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology, Ann Arbor, United States, 13 Jul - 16 Jul, 2011. Presentation Type: Poster Topic: Metabolism and feeding Citation: Walock C, Martin L, Kittilson J and Sheridan M (2011). DIFFERENTIAL EFFECTS OF GROWTH HORMONE FAMILY PEPTIDES ON THE EXPRESSION OF INSULIN-LIKE GROWTH FACTOR 1 AND 2 mRNAs. Front. Endocrinol. Conference Abstract: NASCE 2011: The inaugural meeting of the North American Society for Comparative Endocrinology. doi: 10.3389/conf.fendo.2011.04.00059 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 22 Jul 2011; Published Online: 09 Aug 2011. * Correspondence: Mr. Chad Walock, North Dakota State University, Cell and Molecular Biology, Fargo, North Dakota, United States, chad.walock@my.ndsu.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Chad Walock Lincoln Martin Jeffrey Kittilson Mark Sheridan Google Chad Walock Lincoln Martin Jeffrey Kittilson Mark Sheridan Google Scholar Chad Walock Lincoln Martin Jeffrey Kittilson Mark Sheridan PubMed Chad Walock Lincoln Martin Jeffrey Kittilson Mark Sheridan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Long-Term Effects of Growth Hormone on Infarct Size and Left Ventricular Function in Sheep With Coronary Artery Occlusion

The effects of growth hormone (GH) on infarct size and left ventricular (LV) function in experimental acute myocardial infarction (AMI) have been controversial. Moreover, little, if any, information exists regarding long-term evaluation of therapeutic doses of GH in large mammalian models of AMI. We therefore aimed to assess the effect of therapeutic doses of GH over 3.5 months on infarct size and heart function in sheep with AMI. After coronary artery ligation, sheep received subcutaneous human GH 8 IU/d (n = 8) or vehicle (n = 8) over 100 days. Infarct area was similar in GH (16.9% +/- 3% of LV area) and placebo (16.5% +/- 3.7%, P = not significant) sheep. At 3 days of treatment onset, but not at later times, GH sheep had higher LV shortening fraction (30.7% +/- 3.5% vs. 24.8% +/- 6.1%, P < 0.04), systolic anterior wall thickness (10.1 +/- 0.8 vs. 8.6 +/- 1.2 mm, P < 0.02), and cardiac index (3.8 +/- 0.6 vs. 2.8 +/- 0.7 L x min x m, P < 0.01). This evolution of function parameters paralleled that of serum insulin-like growth factor 1 levels, which differed significantly only during the first week, suggesting a direct effect of GH on LV contractility. These results may suggest the usefulness of therapeutic doses of GH at the early phases of AMI but do not support maintaining the treatment for longer time.

Investigation of early atherosclerotic changes in acromegalic patients

Functional and morphological changes of endothelium were risk factors for mortality attributed to atherosclerosis. Studies investigating early atherosclerotic alterations and the effect of the treatment of acromegaly on these alterations gave conflicting results. Surrogate markers of early atherosclerotic changes, i.e. brachial artery flow-mediated dilation (FMD) and carotid artery intima-media-thickness (IMT) in active and inactive acromegalic patients were compared with control subjects matched to patients for age, sex and cardiovascular risk factors to find out the direct effects of growth hormone (GH)/insulin-like growth factor-1 excess. In 14 active acromegalics and their 14 matched controls, 14 inactive acromegalics and their 14 matched controls, carotid artery IMT and FMD of brachial artery were measured. Inactive acromegalics were in remission for at least 1 year. Active acromegalics had higher IMT than matched controls and inactive acromegalics (0.85 +/- 0.20 mm, 0.64 +/- 1.77 mm, 0.66 +/- 0.20 mm respectively; p < 0.005, p < 0.05) and IMT of inactive acromegalics was not different from their matched controls (0.61 +/- 0.12 mm). FMD was significantly lower in active acromegalics than in matched controls and inactive acromegalics (2.910 +/- 2.00 mm, 6.5 +/- 2.81 mm, 5.68 +/- 2.9 mm respectively; p < 0.005, p < 0.05). FMD of inactive acromegalics was not significantly different from their matched controls (7.96 +/- 3.12 mm). A significant inverse relationship was found between GH and FMD in active acromegalics (r = -0.659, p = 0.010). In active acromegalics, early atherosclerotic changes are not only attributed to the high prevalence of risk factors, but also to the abnormal GH secretion itself.

The role of recombinant insulin-like growth factor I in the treatment of the short child

Commercial preparations of recombinant human insulin-like growth factor I became available in 2005. Off-label use has been promoted because of the paucity of patients having approved indications; I review the background and rationale for such use. Attempts to identify growth hormone unresponsiveness in children with idiopathic short stature have been nonproductive. Treatment with insulin-like growth factor I for unequivocal growth hormone insensitivity improves but does not correct growth failure, in contrast to the typical experience with growth hormone replacement of growth hormone deficiency. This emphasizes the importance of direct effects of growth hormone at the growth plate, which cannot be duplicated by administration of recombinant insulin-like growth factor I. Adverse effects testify to the more than adequate delivery of administered recombinant human insulin-like growth factor I to other tissues, including lymphoid hyperplasia, coarsening of the facies, and increased body fat. In view of the risk profile, the limited ability of endocrine insulin-like growth factor I to restore normal growth, and the suppression of endogenous growth hormone (and therefore local effects on growth) that occurs with insulin-like growth factor I administration, the use of recombinant insulin-like growth factor I should be limited to those with well-documented growth hormone unresponsiveness and severe short stature.

Aortic stiffness is increased in acromegaly — A transthoracic echocardiographic study

Background Acromegaly is associated with increased cardiovascular risk. Recent studies suggested a direct effect of growth hormone and insuline-like growth factor 1 excess on the vasculature over the conventional risk factors. The aim of the present study was to evaluate the stiffness of ascending aorta by means of transthoracic echocardiography (TTE) in patients with acromegaly. Patients and methods The following patient populations were compared: 20 subjects with negative coronary angiograms, 16 acromegalics and 21 patients with significant coronary artery disease (CAD). Aortic stiffness index ( β) was evaluated by means of TTE by use of the formula: β = ln (SBP / DBP) / (Δ D / DD), where SBP and DBP are the systolic and diastolic blood pressures, DD is the diastolic aortic diameter, Δ D is the pulsatile change in aortic diameter (systolic diameter minus diastolic diameter) and ‘ln’ is the natural logarithm. Results The average time from diagnosis was 162 ± 127 days in acromegalic patients. Transsphenoidal hypophysectomy was performed in 12 patients, while the mean growth hormone level was 10.8 ± 11.7 mIU/ml. β was similarly increased in acromegalics and in CAD patients as compared to controls (6.23 ± 3.29 vs 16.47 ± 14.53 and 16.66 ± 15.49, p < 0.05, respectively). Conclusions Stiffness of ascending aorta evaluated by a routine TTE examination is increased in acromegalics without overt cardiovascular disease as compared to controls and similar to CAD patients.

Increased atherosclerotic lesion area in apoE deficient mice overexpressing bovine growth hormone

Human growth hormone (GH) excess is linked to increased cardiovascular morbidity and mortality. However, little is known about the effect of GH excess on atherosclerosis. We developed a new mouse model to assess the hypothesis that GH overexpression accelerates atherosclerotic lesion formation. apoE −/− mice were crossed with bovine GH (bGH) transgenic mice to yield apoE −/− mice overexpressing bGH (apoE −/−/bGH). The mice were fed either standard or Western diet. At 22 weeks, atherosclerotic lesion area of thoracic aorta was larger in apoE −/−/bGH mice compared with littermate apoE −/− mice fed either diet (standard: +161 ± 50%, Western: +430 ± 134%). Aortic sinus lesions were more severe in apoE −/−/bGH mice fed standard diet compared with littermate apoE −/− mice. apoE −/−/bGH mice had lower (VLDL + LDL)/HDL ratios compared with littermate apoE −/− mice, while systolic blood pressure was higher in apoE −/−/bGH mice, irrespective of diet. The levels of serum amyloid A and hepatic CRP mRNA were higher in apoE −/−/bGH mice than in littermate apoE −/− mice. In conclusion, this study shows that excess GH augments the development of atherosclerosis in apoE −/− mice. The mechanisms could be direct effects of GH on cellular processes in the vessel wall or the result of concomitant processes such as hypertension or a general inflammatory state.

Growth hormone, vascular reactivity, and heart failure

The growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis plays a relevant role in the regulation of vascular growth and function, as demonstrated by the data obtained in GH-deficient patients, in whom endothelial function is severely impaired. The treatment of these patients with GH is able to restore a normal endothelial function. Patients affected by congestive heart failure (CHF) are also characterized by endothelial dysfunction. Such a defect represents a key factor in the progression of the disease. Therefore, the possibility of using GH to correct endothelial dysfunction in patients with CHF has been proposed. Experimental data have demonstrated that chronic GH administration improves endothelial dysfunction in CHF patients. On the other hand, GH administration in normal healthy volunteers has been shown to positively affect endothelial function after a few hours of infusion, suggesting that GH can rapidly modify vascular functions. The mechanisms involved in the regulation of vascular function by GH are at the moment not completely clear. However, the positive effect of GH on endothelial dysfunction may be linked to a direct effect of GH on endothelial cells, an IGF-I-mediated effect, an increase in cardiac output, and a decrease of cytokine activation.

Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver.

We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.

From hormones to immunity: the physiology of immunology

Discoveries in the physiology of immunology have increased at an increasing rate during the past two decades. It is now recognized that the immune system is just another physiological system that regulates, and is regulated by, other physiological systems such as the brain. These advances make it clear that recent findings in genomic biology must be interpreted in the context of the environment in which animals and humans live. Lack of a strong genetic basis for significant human mental health disorders, such as major depression, points to the critical importance of interactions. Several examples of environmental × genetic × disease interactions are presented. Regulation of cells of the hematopoietic lineage by two genes that control over 80% of postnatal growth, growth hormone and IGF-I, are then highlighted. The reciprocal relationship of how proinflammatory cytokines from the immune system regulate the growth hormone/IGF-I axis is also summarized. Particular emphasis is placed upon TNFα-induced IGF-I resistance in neurons, muscle cells and epithelial cells. This cytokine regulation of hormone action may ultimately be more important for human and animal health than direct effects of growth hormone and IGF-I on hematopoietic cells. Wasting of AIDS patients is given as an important clinical example of how TNFα from an activated immune system reduces IGF-I sensitivity in multiple physiologic systems, including muscle, nervous and hematopoietic tissues.

Growth hormone-related effects on apoptosis, mitosis, and expression of connexin 43 in bovine in vitro maturation cumulus-oocyte complexes.

Pituitary LH and FSH are known to be the major regulators of ovarian function. In the last few years, however, there has been evidence that growth hormone (GH) is also involved in ovarian regulation. Therefore, the aim of our study was to elucidate the mechanisms of GH action during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs). As shown by detection of the nuclear cell proliferation-associated antigen Ki-67, COCs matured in vitro in the presence of GH revealed a significantly (P < 0.05) higher proportion of proliferating cumulus cells (12.6%) compared with the COCs matured in the control medium TCM 199 (9.9%). In contrast, the percentage of proliferating cells was not increased by supplementation of the medium with a combination of GH and insulin-like-growth factor I (IGF-I). Apoptosis as determined by TUNEL (terminal doxynucleotidyl transferase mediated dUTP nick-end labeling) was significantly (P < 0.05) reduced in the cumulus cells by GH treatment. COCs matured with a combination of GH and IGF-I revealed the lowest percentage of apoptotic cells (11%). The localization and quantification of the gap junction protein connexin 43 (Cx 43) demonstrated that GH induced a significant decrease in the synthesis of the Cx 43 protein in the cumulus cells. Our results imply that GH increases cumulus expansion by promotion of cell proliferation and inhibition of apoptosis. Whereas the increase in cell proliferation is a direct effect of GH, the antiapoptotic effects of GH during in vitro maturation are modulated by IGF-I. Stimulatory effects of GH on oocyte maturation are correlated with changes in the synthesis of gap junction proteins.

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

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

Demonstration of Direct Effects of Growth Hormone on Neonatal Cardiomyocytes

The cellular and molecular basis of growth hormone (GH) actions on the heart remain poorly defined, and it is unclear whether GH effects on the myocardium are direct or mediated at least in part via insulin-like growth factor (IGF-1). Here, we demonstrate that the cultured neonatal cardiomyocyte is not an appropriate model to study the effects of GH because of artifactual loss of GH receptors (GHRs). To circumvent this problem, rat neonatal cardiomyocytes were infected with a recombinant adenovirus expressing the murine GHR. Functional integrity of GHR was suggested by GH-induced activation of the cognate JAK2/STAT5, MAPK, and Akt intracellular pathways in the cells expressing GHR. Although exposure to GH resulted in a significant increase in the size of the cardiomyocyte and increased expression of c-fos, myosin light chain 2, and skeletal alpha-actin mRNAs, there were no significant changes in IGF-1 or atrial natriuretic factor mRNA levels in response to GH stimulation. In this model, GH increased incorporation of leucine, uptake of palmitic acid, and abundance of fatty acid transport protein mRNA. In contrast, GH decreased uptake of 2-deoxy-d-glucose and levels of Glut1 protein. Thus, in isolated rat neonatal cardiomyocytes expressing GHR, GH induces hypertrophy and causes alterations in cellular metabolic profile in the absence of demonstrable changes in IGF-1 mRNA, suggesting that these effects may be independent of IGF-1.