Specific Growth Hormone Research Articles

FRI671 Association Of Insulin-like Growth Factor-1 (igf-1) With Bone Mineral Density (bmd) In Survivors Of Childhood Acute Leukemia

Abstract Disclosure: S. Kim: None. S. Park: None. S. Sim: None. S. Kim: None. M. Ahn: None. K. Shin Hee: None. W. Cho: None. C. Kyung Soon: None. M. Jung: None. B. Suh: None. Purpose: To investigate bone mineral deficit in children survivors of childhood acute leukemia and analyze the association of IGF-1 with BMD status Methods : A total 214 patients (aged 8.47±4.42 for girls and 8.31±4.09 for boys at diagnosis) who were treated for acute leukemia were retrospectively reviewed. Types of leukemia, transplantation, and radiation therapy were investigated. Standard deviation scores (SDSs) of height, weight, body mass index (BMI), and lumbar spine BMD were measured at the end of treatment. Lumbar spine BMD was measured using dual-energy x-ray absorptiometry (DXA). Its relationships with calcium, phosphorus, alkaline phosphatase, bone specific alkaline phosphatase, calcitriol, parathyroid hormone, growth hormone, IGF-1, and insulin-like growth factor-binding protein-3 (IGFBP-3) were analyzed. Low BMD was defined lumbar spine BMD SDS less than -2.0 according to International Society for Clinical Densitometry guideline. Results: The overall prevalence of low BMD was found to be 15% (32/214). Age at diagnosis, transplantation, and radiation therapy were not significantly different between low BMD and normal BMD groups, however, BMI SDS and IGF-1 SDS were different between those two groups (-0.84±1.94 vs. 0.17±2.09, P = 0.012; -1.23 ±0.82 vs. -0.72 ± 0.78, P = 0.001, respectively). Correlation analysis showed that IGF-1 SDS is associated with BMI SDS and lumbar spine BMD SDS (rho=0.19, P=0.006; rho=0.248, P=0.001, respectively). Lumbar spine BMD SDS was related to BMI SDS and IGF-1 SDS by multivariate linear regression analysis (β = 0.15, P = 0.003; β = 0.31, P = 0.021, respectively). Multivariate logistic regression analysis showed that higher IGF-1 SDS was associated with a decreased of prevalence of low BMD (odds ratio: 0.42, 95% confidence interval: 0.24-0.75, P = 0.003). Conclusion: IGF-1 SDS was related to BMD, especially lumbar spine BMD, and a risk of prevalence of low BMD in children and adolescents. IGF-1 SDS seems to be a good tool for evaluating and predicting osteoporosis in children and adolescents. Presentation: Friday, June 16, 2023

Deletion of hepatic growth hormone receptor (GHR) alters the mouse gut microbiota by affecting bile acid metabolism

ABSTRACT Both growth hormone (GH) and gut microbiota play significant roles in diverse physiological processes, but the crosstalk between them is poorly understood. Despite the regulation of GH by gut microbiota, study on GH’s influence on gut microbiota is limited, especially on the impacts of tissue specific GH signaling and their feedback effects on the host. In this study, we profiled gut microbiota and metabolome in tissue-specific GHR knockout mice in the liver (LKO) and adipose tissue (AKO). We found that GHR disruption in the liver rather than adipose tissue affected gut microbiota. It changed the abundance of Bacteroidota and Firmicutes at phylum level as well as abundance of several genera, such as Lactobacillus, Muribaculaceae, and Parasutterella, without affecting α-diversity. Moreover, the impaired liver bile acid (BA) profile in LKO mice was strongly associated with the change of gut microbiota. The BA pools and 12-OH BAs/non-12-OH BAs ratio were increased in the LKO mice, which was due to the induction of CYP8B1 by hepatic Ghr knockout. Consequently, the impaired BA pool in cecal content interacted with gut bacteria, which in turn increased the production of bacteria derived acetic acid, propionic acid, and phenylacetic acid that were possible to participate in the impaired metabolic phenotype of the LKO mice. Collectively, our findings suggested that the liver GH signaling regulates BA metabolism by its direct regulation on CYP8B1, which is an important factor influencing gut microbiota. Our study is significant in exploring gut microbiota modification effects of tissue-specific GH signaling as well as its involvement in gut microbiota–host interaction.

Isolated growth hormone deficiency in children with vertically transmitted short stature: What do the genes tell us?

The growth hormone deficiency (GHD) diagnosis is controversial especially due to low specificity of growth hormone (GH) stimulation tests. It is therefore believed that children diagnosed with GHD form a heterogeneous group with growth disorder frequently independent on GH function. No study evaluating the complex etiology of growth failure in children with diagnosed GHD has been performed thus far. To discover genetic etiology of short stature in children with diagnosed GHD from families with short stature. Fifty-two children diagnosed with primary GHD and vertically transmitted short stature (height SDS in the child and his/her shorter parent <-2 SD) were included to our study. The GHD diagnosis was based on growth data suggestive of GHD, absence of substantial disproportionality (sitting height to total height ratio <-2 SD or >+2 SD), IGF-1 levels <0 for age and sex specific SD and peak GH concentration <10 ug/L in two stimulation tests. All children were examined using next-generation sequencing methods, and the genetic variants were subsequently evaluated by American College of Medical Genetics standards and guidelines. The age of children at enrollment into the study was 11 years (median, IQR 9-14 years), their height prior to GH treatment was -3.0 SD (-3.6 to -2.8 SD), IGF-1 concentration -1.4 SD (-2.0 to -1.1 SD), and maximal stimulated GH 6.3 ug/L (4.8-7.6 ug/L). No child had multiple pituitary hormone deficiency or a midbrain region pathology. Causative variant in a gene that affects growth was discovered in 15/52 (29%) children. Of them, only 2 (13%) had a genetic variant affecting GH secretion or function (GHSR and OTX2). Interestingly, in 10 (67%) children we discovered a primary growth plate disorder (ACAN, COL1A2, COL11A1, COL2A1, EXT2, FGFR3, NF1, NPR2, PTPN11 [2x]), in one (7%) a genetic variant impairing IGF-1 action (IGFALS) and in two (12%) a variant in miscellaneous genes (SALL4, MBTPS2). In children with vertically transmitted short stature, genetic results frequently did not correspond with the clinical diagnosis of GH deficiency. These results underline the doubtful reliability of methods standardly used to diagnose GH deficiency.

Changes in Juvenile Rainbow Trout (Oncorhynchus mykiss) Growth Performance, Digestive Enzyme Activity, Hematological Profile and Serum Biochemical Markers After Dietary Administration of γ-irradiated Cinnamon (Cinnamomum verum) Ethanolic Extract

The aim of this study was to investigate the effects of dietary supplementation of γ-irradiated cinnamon ethanolic extract on the growth performance, digestive enzymes, lysozyme activity level and hematological factors in the juvenile rainbow trout. The fish were divided into five groups, including control group and four experimental groups (received diets enriched with 10 g/kg of non-irradiated or irradiated CEE at the radiation doses of 10, 20 and 40 KGy. At the end of the feeding trial (60` days), 10 fish were sampled from each tank after 12 h of feed deprivation. The results showed that the fish dietary irradiated CEE at doses of 10 KGy and 20 KGy had significantly higher final weights, weight gain, specific growth rates and growth hormone levels, and lower feed conversion ratios compared to the other groups (P≤0.05). The blood glucose level significantly lowered in the fish group fed with dietary γ-irradiated CEE, and increased the activity of lysozyme activity level and digestive enzymes compared to the control group (P≤0.05). In conclusion, dietary supplementation of γ-irradiated CEE at a dose of 10 KGy can enhance the positive effects of cinnamon extract and improve the growth performance, digestion and lysozyme activity in juvenile rainbow trout.

Growth Hormone Cut-Off Post Glucagon Stimulation Test in an Indian Cohort of Overweight/Obese Hypopituitary Patients for the Diagnosis of Adult Growth Hormone Deficiency.

Obesity has been associated with reduced growth hormone (GH) secretion, which might lead to the over diagnosis of adult GH deficiency (GHD) in overweight (OW)/obese hypopituitary patients. Currently, there are no body mass index (BMI)-specific peak GH cut-offs for the glucagon stimulation test (GST) for assessing adult GHD in India, given the BMI cut-offs vary for Asians. The study's main objective was to determine a peak GH cut-off level for the diagnosis of adult GHD in overweight (OW)/obese individuals utilizing the GST. Forty OW/obese subjects were studied in two groups of 20 each. The first group included 20 OW/obese hypopituitary adults and the second group included 20 control subjects. The intervention consisted of a 3 h GST. The main outcome measured was the peak GH level on GST. The mean age of control subjects was lower (33.15 ± 7.67 v/s. 42.10 ± 13.70 years; P = 0.017) in comparison with hypopituitary adults. The mean BMI (27.93 ± 1.63 v/s. 25.81 ± 1.66 kg/m2; P < 0.001), mean IGF1 (272.81 ± 38.57 v/s. 163.75 ± 42.42; P < 0.001, and mean HOMA IR (11.8 ± 9.7 v/s. 6.02 ± 3.14; P = 0.02) was greater in OW/obese controls. The mean GH peak was significantly higher in control subjects (5.41 ± 3.59 ng/mL v/s. 1.49 ± 1.25 ng/mL; P < 0.001) compared to hypopituitary subjects. ROC curve analysis demonstrated a GH cut-off of 3.3 ng/mL with a moderate sensitivity of 70% and high specificity of 95%, with an AUC of 0.838 (P < 0.001; 95% confidence interval [CI] of 0.710-0.965) for the diagnosis of GHD in overweight/obese hypopituitary adults. This study demonstrates that a cut-off of 3.3 ng/mL would diagnose GHD in Indian overweight/obese hypopituitary adults.

Neuroprotective and Regenerative Effects of Growth Hormone (GH) in the Embryonic Chicken Cerebral Pallium Exposed to Hypoxic-Ischemic (HI) Injury.

Prenatal hypoxic–ischemic (HI) injury inflicts severe damage on the developing brain provoked by a pathophysiological response that leads to neural structural lesions, synaptic loss, and neuronal death, which may result in a high risk of permanent neurological deficits or even newborn decease. It is known that growth hormone (GH) can act as a neurotrophic factor inducing neuroprotection, neurite growth, and synaptogenesis after HI injury. In this study we used the chicken embryo to develop both in vitro and in vivo models of prenatal HI injury in the cerebral pallium, which is the equivalent of brain cortex in mammals, to examine whether GH exerts neuroprotective and regenerative effects in this tissue and the putative mechanisms involved in these actions. For the in vitro experiments, pallial cell cultures obtained from chick embryos were incubated under HI conditions (<5% O2, 1 g/L glucose) for 24 h and treated with 10 nM GH, and then collected for analysis. For the in vivo experiments, chicken embryos (ED14) were injected in ovo with GH (2.25 µg), exposed to hypoxia (12% O2) for 6 h, and later the pallial tissue was obtained to perform the studies. Results show that GH exerted a clear anti-apoptotic effect and promoted cell survival and proliferation in HI-injured pallial neurons, in both in vitro and in vivo models. Neuroprotective actions of GH were associated with the activation of ERK1/2 and Bcl-2 signaling pathways. Remarkably, GH protected mature neurons that were particularly harmed by HI injury, but was also capable of stimulating neural precursors. In addition, GH stimulated restorative processes such as the number and length of neurite outgrowth and branching in HI-injured pallial neurons, and these effects were blocked by a specific GH antibody, thus indicating a direct action of GH. Furthermore, it was found that the local expression of several synaptogenic markers (NRXN1, NRXN3, GAP-43, and NLG1) and neurotrophic factors (GH, BDNF, NT-3, IGF-1, and BMP4) were increased after GH treatment during HI damage. Together, these results provide novel evidence supporting that GH exerts protective and restorative effects in brain pallium during prenatal HI injury, and these actions could be the result of a joint effect between GH and endogenous neurotrophic factors. Also, they encourage further research on the potential role of GH as a therapeutic complement in HI encephalopathy treatments.

Analysis of Intestinal Mucosa Integrity and GLP-2 Gene Functions upon Porcine Epidemic Diarrhea Virus Infection in Pigs

Simple SummaryPorcine epidemic diarrhea virus causes serious diarrhea in suckling piglets, resulting in huge economic losses in the pig industry. A better understanding of porcine epidemic diarrhea virus (PEDV) pathogenesis and identification of the responsive genes will contribute to controlling PEDV infection. Therefore, screening and identifying PEDV-resistance functional genes and then implementing disease resistance breeding have important scientific significance. This study explores the regulatory roles of the GLP-2 gene in regulating PEDV infection and in repairing the intestinal mucosa damage associated with PEDV infection. The findings may contribute to the identification of resistant genes or genetic markers for disease resistance breeding in pigs.Porcine epidemic diarrhea virus (PEDV) infects intestinal epithelial cells, destroys the intestinal mucosal barrier and then causes diarrhea in piglets. Glucagon-like peptide-2 (GLP-2) is a specific intestinal growth hormone that promotes the repair of damaged intestinal mucosa and improves the intestinal barrier. In this study, we investigated the functions of porcine GLP-2 gene in regulating PEDV infection. The intestinal tissues with damaged intestinal structures caused by PEDV infection were first confirmed and collected. Expression analysis indicated that the GLP-2 gene was expressed in the duodenum, jejunum and ileum tissues, and the mRNA level was significantly down-regulated in jejunum and ileum of piglets with damaged intestinal mucosa. Infection of PEDV to porcine small intestinal epithelial cells in vitro showed that GLP-2 gene was significantly decreased, which was consistent with the expression pattern in intestinal tissues. In addition, we silenced the GLP-2 gene by shRNA interfering and found that the copy numbers of PEDV were remarkably increased in the GLP-2 gene silencing cells. Our findings suggest that the GLP-2 gene was potentially involved in regulating PEDV infection and in maintaining the integrity of the intestinal mucosal barrier structure, which could contribute to our understanding of the mechanisms of PEDV pathogenesis and provide a theoretical basis for the identification and application of resistant genes in pig selective breeding for porcine epidemic diarrhea.

Autoimmune Pituitary Disease: New Concepts With Clinical Implications.

Some endocrine disorders, including hypophysitis and isolated adrenocorticotropic hormone (ACTH) deficiency, are caused by an autoimmune response to endocrine organs. Although the pathogenesis of some autoimmune endocrine diseases has been elucidated, it remains obscure for most. Anti-PIT-1 hypophysitis (anti-PIT-1 antibody syndrome) is a newly described pituitary autoimmune disease characterized by acquired and specific growth hormone (GH), prolactin (PRL), and thyroid-stimulating hormone (TSH) deficiencies. This disorder is associated with a thymoma or neoplasm that ectopically expresses pituitary-specific transcription factor 1 (PIT-1) protein. Circulating anti-PIT-1 antibody is a disease marker, and PIT-1-reactive cytotoxic T cells (CTLs) play a pivotal role in disease development. In addition, isolated ACTH deficiency appears to be caused by autoimmunity to corticotrophs; however, the pathogenesis remains unclear. A recently described case of isolated ACTH deficiency with large cell neuroendocrine carcinoma (LCNEC) showed ectopically expressed proopiomelanocortin (POMC), and circulating anti-POMC antibody and POMC-reactive CTLs were also detected. As CTL infiltrations around corticotrophs were also observed, isolated ACTH deficiency may be associated at least in part with a paraneoplastic syndrome. Although several underlying mechanisms for pituitary autoimmunity have been proposed, these observations highlight the importance of paraneoplastic syndrome as a cause of pituitary autoimmune disease. In this review, we focus on the pathophysiology and connection of anti-PIT-1 hypophysitis and isolated ACTH deficiency and discuss the state-of-art knowledge for understanding pituitary autoimmunity.

Increased fibrosis: A novel means by which GH influences white adipose tissue function

ObjectiveWhite adipose tissue (WAT) fibrosis – the buildup of extracellular matrix (ECM) proteins, primarily collagen – is now a recognized hallmark of tissue dysfunction and is increased with obesity and lipodystrophy. While growth hormone (GH) is known to increase collagen in several tissues, no previous research has addressed its effect on ECM in WAT. Thus, the purpose of this study is to determine if GH influences WAT fibrosis. DesignThis study examined WAT from four distinct strains of GH-altered mice (bGH and GHA transgenic mice as well as two tissue specific GH receptor gene disrupted lines, fat growth hormone receptor knockout or FaGHRKO and liver growth hormone receptor knockout or LiGHRKO mice). Collagen content and adipocyte size were studied in all cohorts and compared to littermate controls. In addition, mRNA expression of fibrosis-associated genes was assessed in one cohort (6month old male bovine GH transgenic and WT mice) and cultured 3T3-L1 adipocytes treated with GH. ResultsCollagen stained area was increased in WAT from bGH mice, was depot-dependent, and increased with age. Furthermore, increased collagen content was associated with decreased adipocyte size in all depots but more dramatic changes in the subcutaneous fat pad. Notably, the increase in collagen was not associated with an increase in collagen gene expression or other genes known to promote fibrosis in WAT, but collagen gene expression was increased with acute GH administration in 3T3-LI cells. In contrast, evaluation of 6month old GH antagonist (GHA) male mice showed significantly decreased collagen in the subcutaneous depot. Lastly, to assess if GH induced collagen deposition directly or indirectly (via IGF-1), fat (Fa) and liver (Li) specific GHRKO mice were evaluated. Decreased fibrosis in FaGHRKO and increased fibrosis in LiGHRKO mice suggest GH is primarily responsible for the alterations in collagen. ConclusionsOur results show that GH action is positively associated with an increase in WAT collagen content as well as a decrease in adipocyte size, particularly in the subcutaneous depot. This effect appears to be due to GH and not IGF-1 and reveals a novel means by which GH regulates WAT accumulation.

Growth Hormone and the Epithelial-to-Mesenchymal Transition.

Previous studies have implicated growth hormone (GH) in the progression of several cancers, including breast, colorectal, and pancreatic. A mechanism by which GH may play this role in cancer is through the induction of the epithelial-to-mesenchymal transition (EMT). During the EMT process, epithelial cells lose their defining phenotypes, causing loss of cellular adhesion and increased cell migration. This review aims to carefully summarize the previous two decades of research that points to GH as an initiator of EMT, in both cancerous and noncancerous tissues. Sources were collected using PubMed and Google Scholar search engines by using specific GH- and/or EMT-related terms. Identified manuscripts were selected for further analysis based on presentation of GH-induced molecular markers of the EMT process in vivo or in vitro. Cellular mechanisms involved in GH-induced EMT are the focus of this review, both in cancerous and noncancerous epithelial cells. Our findings suggest that a myriad of molecular mechanisms are induced by GH that cause EMT and may point to potential therapeutic use of GH antagonists or any downregulator of GH action in EMT-related disease.

Plasma growth hormone-binding protein levels in Atlantic salmon Salmo salar during smoltification and seawater transfer.

Specific growth hormone (GH)-binding protein (Ghbp) was purified from Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss plasma with immunoprecipitation and characterized in cross-linking studies using autoradiography and western blots. The size of the Ghbp was estimated to be c. 53 kDa. A radioimmunoassay was established to measure Ghbp in salmonids, using antibodies specific against the extracellular segment of the S. salar growth hormone receptor 1 (grh1; GenBank AY462105). Plasma Ghbp levels were measured in S. salar smolts in fresh water and after transfer to seawater (SW; experiments 1 and 2), and in post-smolts kept at different salinities (0, 12, 22 and 34) for 3 months (experiment 3). A transient increase in plasma Ghbp, which lasted for 1 month or less, was noted in smolts after transfer to SW. Concomitantly, plasma GH and gill Na(+) -K(+) -ATPase activity increased during smoltification (in experiment 2). No difference in plasma Ghbp was evident between post-smolts kept at different salinities, although the fish kept at salinity 34 had higher plasma GH than the group kept at salinity 22 and higher hepatic ghr1 expression than post-smolts kept at salinity 12. This suggests that plasma Ghbp regulation may respond to salinity changes in the short term. The lack of correlation between Ghbp, plasma GH and hepatic ghr1 expression in the long-term post-smolt experiment indicates that Ghbp levels may be regulated independently of other components of the endocrine GH system in salmonids.

Using growth hormone levels to detect macroadenoma in patients with acromegaly.

BackgroundThe aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and patients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma.MethodsWe performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves.ResultsCompared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass index, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. However, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve.ConclusionThe GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect macroadenoma at the time of diagnosis.

Evaluation of body composition and cartilage biomarkers in large-breed dogs fed two foods designed for growth

To evaluate cartilage and bone biomarkers and body composition in growing large-breed dogs consuming a diet designed for growth. 43 large-breed 2 month-old-puppies. Dogs were randomly assigned to receive 1 of 2 foods until 18 months of age. Dogs were evaluated at 2, 5, 12, and 18 months of age via dual energy x-ray absorptiometry (DEXA), CBC, serum biochemical profile, and concentrations or activities of taurine, vitamin E, fatty acids, glutathione peroxidase, C-propeptide of type II collagen (CPII), cartilage oligomeric matrix protein (COMP), carboxy-terminal cross-linked fragment of type II collagen (CTXII), bone specific alkaline phosphatase (BAP), osteocalcin, ghrelin, and growth hormone. Blood components largely reflected the composition of the foods. Dogs fed the food with a higher concentration of protein, calcium, n-3 fatty acids, and antioxidants had a lower percentage of body fat and greater percentage of lean body mass at 5, 12, and 18 months of age, and higher CPII:CTXII ratio and lower COMP at 18 months of age. The BAP activity, osteocalcin concentration, and CTXII concentration declined with age, whereas COMP concentration and CPII concentration were similar at all time points for both foods. The BAP activity, osteocalcin concentration, and CTXII concentration were greater during growth than at 18 months of age. The food that was proportionately higher in protein, calcium, n-3 fatty acids, and antioxidants increased lean body mass and may have positively affected cartilage turnover as maturity was attained. Whether the rate of cartilage turnover during growth affects development of orthopedic disease or arthritis in adulthood has yet to be determined.

Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response.

Understanding how the immune system decides between tolerance and activation by antigens requires addressing cytokine regulation as a highly dynamic process. We quantified the dynamics of interleukin-2 (IL-2) signaling in a population of T cells during an immune response by combining in silico modeling and single-cell measurements in vitro. We demonstrate that IL-2 receptor expression levels vary widely among T cells creating a large variability in the ability of the individual cells to consume, produce and participate in IL-2 signaling within the population. Our model reveals that at the population level, these heterogeneous cells are engaged in a tug-of-war for IL-2 between regulatory (T(reg)) and effector (T(eff)) T cells, whereby access to IL-2 can either increase the survival of T(eff) cells or the suppressive capacity of T(reg) cells. This tug-of-war is the mechanism enforcing, at the systems level, a core function of T(reg) cells, namely the specific suppression of survival signals for weakly activated T(eff) cells but not for strongly activated cells. Our integrated model yields quantitative, experimentally validated predictions for the manipulation of T(reg) suppression.

Pegvisomant: current and potential novel therapeutic applications

Background: Pegvisomant is a genetically engineered molecule, which exhibits specific growth hormone (GH) antagonism by directly interacting with the GH receptor. It is currently licensed for the treatment of acromegaly where surgery and medical therapy with somatostatin analogues have failed. Objective: To delineate the role of pegvisomant in the treatment of acromegaly and its novel application in other areas of clinical medicine where suppression of GH action may be of therapeutic benefit. Methods: A literature review from PubMed- and EMBASE-listed publications and the web-sites of licensing organisations for medicinal products. Conclusion: Pegvisomant is currently used as a second line therapy in the management of acromegaly. It is highly effective in suppressing the metabolic effects of elevated GH levels when used alone or in combination with somatostatin analogues. However, its long term efficacy and safety for this indication has yet to be established. Preliminary data indicate that pegvisomant may have a role in management of type 1 diabetes with beneficial effects on insulin sensitivity and in preventing the progression of microvascular complications. Additional roles as an adjunct to cancer chemotherapy regimens and for the diagnosis of GH deficiency have been proposed, but have yet to be confirmed.

INFLUENCE OF BREED, SEX AND GROWTH HORMONE AND HALOTHANE GENOTYPES ON CARCASS COMPOSITION AND MEAT QUALITY TRAITS IN PIGS

ABSTRACT The objective of this study was to verify the influence of the growth hormone (GH) and halothane (Hal) genotypes, breed and sex on carcass and meat quality. Ninety‐six pigs (Piétrain, Large White and Landrace) were dissected. For each breed, 16 were noncastrated males and 16 were females. The Piétrain animals presented the greatest lean meat percentage, the heaviest ham and shoulder and the lightest belly weight and fat thickness. Landrace presented the heaviest belly. Females presented the greatest drip loss; L*, b* and fat thickness; the heaviest ham and loin; and the lightest shoulder and tenderloin. Hal–NN and Nn presented greater loin weight than nn animals. Nn animals presented smaller belly weight than homozygotes. The nn animals presented greater drip loss than NN and Nn, and greater lean meat than NN. Interestingly, GH–D2D2 animals also showed higher drip loss than those with D1D1 genotype. This investigation presents relevant associations between important economic traits and specific GH and Hal genotypes.PRACTICAL APPLICATIONSThe identification of new molecular markers related to pig production has been increasing in importance, especially when these markers are related to carcass and meat quality traits, which are difficult to predict. When a marker is intensively used in a selection program, it reaches fixation, so it is important to identify new markers to replace it. This work shows, for the first time, the association of a GH polymorphism with an important meat quality trait and reinforces the possibility of its use in programs of marker‐assisted selection.

Resistance Training and Reduction of Treatment Side Effects in Prostate Cancer Patients

To examine the effect of progressive resistance training on muscle function, functional performance, balance, body composition, and muscle thickness in men receiving androgen deprivation for prostate cancer. Ten men aged 59-82 yr on androgen deprivation for localized prostate cancer undertook progressive resistance training for 20 wk at 6- to 12-repetition maximum (RM) for 12 upper- and lower-body exercises in a university exercise rehabilitation clinic. Outcome measures included muscle strength and muscle endurance for the upper and lower body, functional performance (repeated chair rise, usual and fast 6-m walk, 6-m backwards walk, stair climb, and 400-m walk time), and balance by sensory organization test. Body composition was measured by dual-energy x-ray absorptiometry and muscle thickness at four anatomical sites by B-mode ultrasound. Blood samples were assessed for prostate specific antigen (PSA), testosterone, growth hormone (GH), cortisol, and hemoglobin. Muscle strength (chest press, 40.5%; seated row, 41.9%; leg press, 96.3%; P < 0.001) and muscle endurance (chest press, 114.9%; leg press, 167.1%; P < 0.001) increased significantly after training. Significant improvement (P < 0.05) occurred in the 6-m usual walk (14.1%), 6-m backwards walk (22.3%), chair rise (26.8%), stair climbing (10.4%), 400-m walk (7.4%), and balance (7.8%). Muscle thickness increased (P < 0.05) by 15.7% at the quadriceps site. Whole-body lean mass was preserved with no change in fat mass. There were no significant changes in PSA, testosterone, GH, cortisol, or hemoglobin. Progressive resistance exercise has beneficial effects on muscle strength, functional performance and balance in older men receiving androgen deprivation for prostate cancer and should be considered to preserve body composition and reduce treatment side effects.

Circulating Growth Hormone Binding Protein Levels and Mononuclear Cell Growth Hormone Receptor Expression in Uremia

Resistance to growth hormone (GH) in end-stage renal disease (ESRD) causes growth retardation and muscle wasting. In humans, circulating GH binding protein (GHBP), the extracellular domain of the GH receptor that is shed into the circulation and is believed to reflect tissue GH receptor levels, is reduced in uremia and suggests that cellular GH receptor levels are correspondingly reduced. If true, this could be a cause of GH resistance. We set out to establish whether serum GHBP levels reflect cellular GH receptor levels and whether changes in serum GHBP levels are related to nutritional or inflammatory status. GH receptor protein expression in peripheral blood mononuclear cells (PBMC) from 21 ESRD and 14 normal subjects were analyzed by fluorochrome flow cytometry. The GH receptor density and percent total PBMCs expressing the GH receptor were similar in the 2 groups, and there was no difference in percent GH receptor positive T or B cells or monocytes. In contrast, serum GHBP levels were 80% lower in ESRD. GHBP levels did not correlate with serum albumin, body mass index, or muscle mass but seemed to be partly related to the log serum C-reactive protein levels. Serum GHBP levels are markedly reduced in ESRD; this seems to occur independent of nutritional status and may in part be caused by inflammation. Because GH receptor expression on PBMC of ESRD and control subjects was similar, our findings argue against a reduction in GH receptor as a cause of GH resistance and the use of serum GHBP levels as a reliable marker of specific tissue GH receptor levels.

Direct Effect of Ghrelin on Leptin Production by Cultured Rat White Adipocytes

Because ghrelin is known to stimulate adipogenesis, we tested whether ghrelin could contribute to the maintenance of homeostasis, directly affecting rat white adipocyte leptin production. Isolated retroperitoneal adipocytes were cultured for 0.5 to 48 hours without (baseline) or with (0.001 to 1 nM) ghrelin alone or in combination with insulin (0.01 to 10 nM) or dexamethasone (1 to 100 nM). Adipocytes were also incubated with ghrelin and inhibitors either of RNA (actinomycin D) or protein synthesis (cycloheximide) or with several concentrations (10 to 1000 nM) of a specific ghrelin antagonist. When cultures were terminated, we evaluated adipocyte leptin secretion and ob mRNA expression. Our data indicate that ghrelin directly enhanced adipocyte leptin release and ob mRNA expression, that the leptin-releasing activity of ghrelin was additive to the action of both insulin and dexamethasone and was abrogated by protein synthesis inhibitors, and that effects of ghrelin on adipocyte ob mRNA expression and release were blocked by coincubation with the specific growth hormone secretagogue receptor 1a antagonist. Our study supports the ability of ghrelin to enhance white adipose tissue leptin production by a direct receptor-mediated effect. This activity of ghrelin could play a potentially significant role in rapid restoration of homeostasis after food intake.

Expression of growth hormone and its receptor in the lungs of embryonic chicks

The lung is well established as being a postnatal target site for growth hormone (GH) action, since pathophysiological states of GH excess and deficiency are both associated with impaired pulmonary function. Pituitary GH is therefore probably involved in normal lung growth or development, although perinatal lung development occurs prior to the differentiation of pituitary somatotrophs and the ontogeny of pituitary GH secretion. The lung itself may, however, be a site of GH production during prenatal development, since a specific GH-response gene (a marker of GH activity) is expressed in the lungs of early chick embryos, in which GH immunoreactivity is widespread in many other peripheral tissues. We have assessed this possibility in embryonic chicks. A 690-bp cDNA, identical in size and nucleotide sequence to the full-length pituitary GH transcript, was amplified by reverse transcription/polymerase chain reaction from total RNA extracted from the lungs of embryos at 11, 13, 15, and 18 days of the 21-day incubation period. This transcript was localized by in situ hybridization to mesenchymal and epithelial cells of the developing lungs, in which specific GH immunoreactivity was similarly located. Intense GH immunoreactivity was also present after embryonic day 15 (ED15) in the smooth muscle surrounding blood vessels in the lung and surrounding the bronchioles. Lung GH immunoreactivity was primarily associated with a 15-kDa protein, rather than the 26-kDa protein in the pituitary gland. After the onset of pituitary GH secretion (at ED17), GH mRNA was barely detectable in the lungs of ED20 embryos, at the start of lung breathing. GH immunoreactivity was, however, still present in some cells in the lungs of ED20 embryos. GH-receptor mRNA and immunoreactivity were also widespread and abundant within the embryonic lung. Lung GH may thus have autocrine or paracrine roles in lung development or in pulmonary function prior to the ontogeny of the pituitary gland and the appearance of GH in peripheral plasma.