High 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.

High Anxiety Levels and Growth Hormone Secretion in Children with Short Stature

Growth hormone (GH) provocation test, which includes repeated blood measurements following pharmacological stimuli, may be stressful for the children and their family. Thirty-three short stature children with impaired growth rate were studied during GH provocation tests to determine if the test is associated with increased anxiety and if increased anxiety affects the test results.

Metabolic and hormonal control of energy utilization and partitioning from early to mid lactation in Sarda ewes and Saanen goats

In a recent study, we observed that starch-rich diets used in mid lactation induced lower milk production persistency and higher body fat accumulation in dairy ewes compared with dairy goats. Because these species differences could be linked to hormonal mechanisms that drive energy partitioning, in the same experiment, we explored the evolution of metabolic and hormonal status during lactation to test this hypothesis. Twenty mature Sarda dairy ewes and 20 mature Saanen goats [15-134 ± 11 d in milk (DIM), mean ± SD] were compared simultaneously. In early lactation, each species was allocated to one dietary treatment: high-starch diet [HS: 20.4% starch, on dry matter (DM) basis], whereas from 92 ± 11 DIM, each species was allocated to 1 of 2 dietary treatments: HS (20.0% starch, on DM basis) and low-starch (LS: 7.8% starch, on DM basis) diets. Blood samples were collected in the morning to analyze glucose, nonesterified fatty acids (NEFA), growth hormone (GH), insulin, and insulin-like growth factor I (IGF-I). Data were analyzed using the PROC MIXED procedure of SAS with repeated measurements (SAS Version 9.0). The HS and LS diets applied in mid lactation did not affect metabolic status of the animal within species; thus, only a comparison between species was carried out. From early to mid lactation, plasma glucose concentration was higher in ewes than in goats (54.57 vs. 48.35 ± 1.18 mg/dL), whereas plasma NEFA concentration was greater in goats than in ewes (0.31 vs. 0.25 ± 0.03 mmol/L). Goats had higher plasma GH concentration and lower plasma insulin content than ewes (4.78 vs. 1.31 ng/mL ± 0.47; 0.11 vs. 0.26 μg/L ± 0.02). Plasma IGF-I concentration did not vary between species. The comparison of metabolic and hormonal status of lactating Sarda dairy ewes and Saanen goats, carried out by studying simultaneously the 2 species in the same stage of lactation and experimental conditions, suggests that the higher insulin and glucose concentration observed in Sarda ewes explains why they partitioned more energy toward body reserves than to the mammary gland, especially in mid lactation. This can justify the negative effect of high-starch diets in mid-lactating Sarda ewes. Conversely, the highest GH and NEFA concentration observed in Saanen goats explain why they partitioned more energy of starch diets toward the mammary gland than to body reserves and justify the positive effect of high-starch diet in mid lactation. Together, these different responses contribute to explain why specialized dairy goats, such as the Saanen breed, have a higher milk production persistency than specialized dairy sheep breeds, such as the Sarda.

Variants of FOXO3 and RPA3 genes affecting IGF-1 levels alter the risk of development of primary osteoarthritis.

Pathologically high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels in patients with acromegaly are associated with arthropathy. Several studies highlight the potential role of the GH/IGF-1 axis in primary osteoarthritis (OA). We aimed to disentangle the role of IGF-1 levels in primary OA pathogenesis. Patients from the Genetics osteoARthritis and Progression (GARP) Study with familial, generalized, symptomatic OA (n = 337, mean age: 59.8 ± 7.4 years, 82% female) were compared to Leiden Longevity Study (LLS) controls (n = 456, mean age: 59.8 ± 6.8 years, 51% female). Subjects were clinically and radiographically assessed, serum IGF-1 levels were measured, and 10 quantitative trait loci (QTL) in the FOXO3, IGFBP3/TNS3, RPA3, SPOCK2 genes, previously related to serum IGF-1 levels, were genotyped. Linear or binary logistic generalized estimating equation models were performed. Serum IGF-1 levels were increased in OA patients, with male patients exhibiting the strongest effect (males OR = 1.10 (1.04-1.17), P=0.002 vs females OR = 1.04 (1.01-1.07), P = 0.02). Independent of the increased IGF-1 levels, male carriers of the minor allele of FOXO3 QTL rs4946936 had a lower risk to develop hip OA (OR = 0.41 (0.18-0.90), P = 0.026). Additionally, independent of IGF-1 levels, female carriers of the minor alleles of RPA3 QTL rs11769597 had a higher risk to develop knee OA (OR = 1.90 (1.20-2.99), P = 0.006). Patients with primary OA had significantly higher IGF-1 levels compared to controls. Moreover, SNPs in the FOXO3 and RPA3 genes were associated with an altered risk of OA. Therefore, altered IGF-1 levels affect the development of OA, and are potentially the result of the pathophysiological OA process.

Serum Levels of Asprosin, a Novel Adipokine, Are Significantly Lowered in Patients with Acromegaly.

Background Asprosin is a novel identified adipokine secreted mainly by white adipose tissue, which is elevated in metabolic diseases such as diabetes and obesity. Acromegaly is a syndrome caused by pituitary growth hormone (GH) cell adenoma with excessive GH secretion. Serum adipocytokines levels may be involved in abnormal glycolipid metabolism in acromegaly patients. Objectives To investigate serum asprosin levels in acromegaly patients and its correlation with high GH levels and glucolipid metabolic parameters. Methods A retrospective case-control study was conducted and 68 acromegaly patients and 121 controls were included in this study. Clinical information and laboratory examinations were collected and serum asprosin levels were measured by commercial ELISA kits. Results Serum asprosin levels in acromegaly patients were significantly lower than controls (P < 0.001). Serum asprosin levels in patients with the course of acromegaly ≥5 years (compared with <5 years), high area under curve of growth hormone (GH-AUC) after 75 g oral glucose tolerance test (OGTT) (compared with low GH-AUC patients), and high IGF-1 SDS group (compared with low IGF-1 SDS group) were significantly reduced (all P < 0.05). Serum asprosin levels in acromegaly patients were negatively correlated with the course of acromegaly, IGF-1 SDS, nadir growth hormone value (GH-Nadir), and GH-AUC after OGTT. Multiple stepwise linear regression indicated that acromegaly was an independent influencing factor of serum asprosin levels. According to serum asprosin levels tertiles, the risk of acromegaly in the lowest group was 2.67 times higher than the highest group (OR ＝ 3.665, 95% CI 1.677 ∼ 8.007, P=0.001), and the increased risk of the lowest group still existed after adjusting for gender, age, BMI, and TC (Model 2). Conclusions Serum asprosin levels in acromegaly patients are lowered, which may be related to increased blood glucose and reduced body fat mass caused by long-term high GH levels exposure.

Growth Hormone Upregulates Mediators of Melanoma Drug Efflux and Epithelial-to-Mesenchymal Transition In Vitro and In Vivo.

Simple SummaryGrowth hormone (GH) action is strongly implicated in the progression and therapy resistance in several types of solid tumors which overexpress the GH receptor (GHR). The aim of our study was to characterize the effects of GH and its downstream effector insulin-like growth factor 1 (IGF-1) on melanoma using in vitro and in vivo models. We confirmed an IGF-1-independent role of elevated circulating GH in upregulating key mechanisms of therapy resistance and malignancy with analyses conducted at the molecular and cellular level. We identified that GH upregulates key mechanisms of therapy resistance and metastases in melanoma tumors in an IGF-1 dependent and independent manner by upregulating multidrug efflux pumps and EMT transcription factors. Our study reveals that GH action renders an intrinsic drug resistance phenotype to the melanoma tumors—a clinically crucial property of GH verifiable in other human cancers with GHR expression.Growth hormone (GH) and the GH receptor (GHR) are expressed in a wide range of malignant tumors including melanoma. However, the effect of GH/insulin-like growth factor (IGF) on melanoma in vivo has not yet been elucidated. Here we assessed the physical and molecular effects of GH on mouse melanoma B16-F10 and human melanoma SK-MEL-30 cells in vitro. We then corroborated these observations with syngeneic B16-F10 tumors in two mouse lines with different levels of GH/IGF: bovine GH transgenic mice (bGH; high GH, high IGF-1) and GHR gene-disrupted or knockout mice (GHRKO; high GH, low IGF-1). In vitro, GH treatment enhanced mouse and human melanoma cell growth, drug retention and cell invasion. While the in vivo tumor size was unaffected in both bGH and GHRKO mouse lines, multiple drug-efflux pumps were up regulated. This intrinsic capacity of therapy resistance appears to be GH dependent. Additionally, epithelial-to-mesenchymal transition (EMT) gene transcription markers were significantly upregulated in vivo supporting our current and recent in vitro observations. These syngeneic mouse melanoma models of differential GH/IGF action can be valuable tools in screening for therapeutic options where lowering GH/IGF-1 action is important.

Discordant GH and IGF-1 Results in Treated Acromegaly: Impact of GH Cutoffs and Mean Values Assessment.

Discordant growth hormone (GH) and insulin-like growth factor-1 (IGF-1) values are frequent in acromegaly. To evaluate the impact of different GH cutoffs on discordance rate. To investigate whether the mean of consecutive GH measurements impacts discordance rate when matched to the last available IGF-1 value. Retrospective study. Referral center for pituitary diseases. Ninety acromegaly patients with at least 3 consecutive evaluations for GH and IGF-1 using the same assay in the same laboratory (median follow-up 13 years). Multimodal treatment of acromegaly. Single fasting GH (GHf) and IGF-1 (IGF-1f). Mean of 3 GH measurements (GHm), collected during consecutive routine patients' evaluations. At last evaluation GHf values were 1.99 ± 2.79 µg/L and age-adjusted IGF-1f was 0.86 ± 0.44 × upper limit of normality (mean ± SD). The discordance rate using GHf was 52.2% (cutoff 1 µg/L) and 35.6% (cutoff 2.5 µg/L) (P = 0.025). "High GH" discordance was more common for GHf <1.0 µg/L, while "high IGF-1" was predominant for GHf <2.5 µg/L (P < 0.0001). Using GHm mitigated the impact of GH cutoffs on discordance (GHm <1.0 µg/L: 43.3%; GHm <2.5 µg/L: 38.9%; P = 0.265). At receiver-operator characteristic curve (ROC) analysis, both GHf and GHm were poor predictors of IGF-1f normalization (area under the curve [AUC] = 0.611 and AUC = 0.645, respectively). The prevalence of disease-related comorbidities did not significantly differ between controlled, discordant, and active disease patients. GH/IGF-1 discordance strongly depends on GH cutoffs. The use of GHm lessen the impact of GH cutoffs. Measurement of fasting GH levels (both GHf and GHm) is a poor predictor of IGF-1f normalization in our cohort.

OUTCOMES AFTER ADJUNCT GROWTH HORMONE TREATMENT WITH A LOW, INTERMEDIATE, OR HIGH DOSE PROTOCOL IN IVF CYCLES WITH POOR RESPONDERS

Adjunct growth hormone (GH) is used in poor responders to improve IVF cycle and pregnancy outcomes. There is no consensus on the ideal GH protocol. We compared the extended low, intermediate, and high dose GH protocols used at our center to determine if there was a difference in IVF and pregnancy outcomes.

Strong Positive Correlation between TSH and Ghrelin in Euthyroid Non-Growth Hormone-Deficient Children with Short Stature.

The growth processes in children depend on the proper functioning of some hormones and growth factors. Recently, a positive correlation between ghrelin and TSH (thyroid stimulating hormone) in patients with hyper- and hypothyroidism was proved. Moreover, in hypothyroid rats with high ghrelin concentration, growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion was suppressed. We analyzed these relationships in euthyroid prepubertal children with idiopathic short stature (ISS). The analysis comprised concentration of ghrelin, GH in stimulating tests and during the night, as well as IGF-I, TSH, free thyroxine (FT4) and free triiodothyronine (FT3) in 85 children with ISS (36 girls, 49 boys) aged 9.65 ± 3.02 years (mean ± SD). A strong positive correlation between ghrelin and TSH was confirmed (r = +0.44, p < 0.05). A higher ghrelin but lower nocturnal GH and lower IGF-I were observed in children with higher normal TSH concentration than those in children with lower normal TSH. Interestingly, alterations of TSH level were without any impact on FT4 and FT3 concentrations. Summing up, in ISS prepubertal euthyroid children, ghrelin and TSH secretion are closely related. On the other hand, the higher the TSH, the lower the nocturnal GH and IGF-I levels. The contribution of the above findings in deterioration of growth processes requires further studies.

Quality of Life in Patients with Acromegaly before and after Transsphenoidal Surgical Resection

Objective We aimed to determine the perioperative changes in the quality of life (QoL) in patients with acromegaly and to reveal the relationship between biochemical indicators and quality of life change after tumor resection. Methods Patients with acromegaly were enrolled from a tertiary pituitary center. SF-36 scale and AcroQoL scale were used to determine the QoL before and after surgery. We analyzed changes in QoL using a generalized linear model for repeated measurements. We compared the changes in QoL among three groups (remission, active, and discordant group) based on postoperative growth hormone (GH) and insulin-like growth factor-1. Results 151 patients (75 males and 76 females) diagnosed with acromegaly were included. The average age was 43.9 ± 12.3 years. The median total SF-36 scale was 65.3% (IQR: 63.2%–69.2%). Overall AcroQoL score at baseline was 59.1% (IQR: 51.8%–71.8%). Nadir GH levels (coefficient −0.08, p=0.047), T3 levels (coefficient 2.8, p=0.001), and testosterone levels (coefficient −0.20, p=0.033) in males were independent predictive factors of the total SF-36 score. During the follow-up, the median overall SF-36 score increased to 66.1% at 3 months and 75.3% at 6 months (p < 0.001) after surgery. The median overall AcroQoL score increased to 74.5% at 3 months and 77.3% at 6 months (p < 0.001) after surgery. At 6-month follow-up, median scores were still less than 70% in appearance, vitality, and mental health dimensions. The QoL after surgery were similar among the three groups, although higher GH and more preoperative somatostatin analogs usage were observed in the active group. Conclusion In conclusion, acromegalic patients were associated with low QoL, which could be reversed partially by surgery. The improvement was independent of the endocrine remission. Appearance, vitality, and mental health were three major aspects that warrant further attention from physicians and caregivers after surgery.

MON-311 Glucose Metabolism in Acromegaly Patients Resistant to First Generation Somatostatin Receptor Ligands Treated with Pegvisomant And/Or Pasireotide Lar

Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

Proteomic analysis reveals sex-specific biomarker signature in postural orthostatic tachycardia syndrome

BackgroundPostural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular (CV) autonomic disorder of unknown etiology characterized by an excessive heart rate increase on standing and orthostatic intolerance. In this study we sought to identify novel CV biomarkers potentially implicated in POTS pathophysiology.MethodsWe conducted a nested case-control study within the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort including 396 patients (age range, 15–50 years) with either POTS (n = 113) or normal hemodynamic response during passive head-up-tilt test (n = 283). We used a targeted approach to explore changes in cardiovascular proteomics associated with POTS through a sequential two-stage process including supervised principal component analysis and univariate ANOVA with Bonferroni correction.ResultsPOTS patients were younger (26 vs. 31 years; p < 0.001) and had lower BMI than controls. The discovery algorithm identified growth hormone (GH) and myoglobin (MB) as the most specific biomarker fingerprint for POTS. Plasma level of GH was higher (9.37 vs 8.37 of normalised protein expression units (NPX); p = 0.002), whereas MB was lower (4.86 vs 5.14 NPX; p = 0.002) in POTS compared with controls. In multivariate regression analysis, adjusted for age and BMI, and stratified by sex, lower MB level in men and higher GH level in women remained independently associated with POTS.ConclusionsCardiovascular proteomics analysis revealed sex-specific biomarker signature in POTS featured by higher plasma level of GH in women and lower plasma level of MB in men. These findings point to sex-specific immune-neuroendocrine dysregulation and deconditioning as potentially key pathophysiological traits underlying POTS.

Autocrine/paracrine actions of growth hormone in human melanoma cell lines

Melanoma is the most aggressive skin cancer. Its aggressiveness is most commonly attributed to ERK pathway mutations leading to constitutive signaling. Though initial tumor regression results from targeting this pathway, resistance often emerges. Interestingly, interrogation of the NCI-60 database indicates high growth hormone receptor (GHR) expression in melanoma cell lines. To further characterize melanoma, we tested responsiveness to human growth hormone (GH). GH treatment resulted in GHR signaling and increased invasion and migration, which was inhibited by a GHR monoclonal antibody (mAb) antagonist in WM35, SK-MEL 5, SK-MEL 28 and SK-MEL 119 cell lines. We also detected GH in the conditioned medium (CM) of human melanoma cell lines. GHR, JAK2 and STAT5 were basally phosphorylated in these cell lines, consistent with autocrine/paracrine GH production. Together, our results suggest that melanomas are enriched in GHR and produce GH that acts in an autocrine/paracrine manner. We suggest that GHR may constitute a therapeutic target in melanoma.

1559-P: Differential Effects of Type 1 (T1D) and Type 2 Diabetes (T2D) on the Growth Hormone (GH)-Insulin-Like Growth Factor (IGF) Axis in Youth

T1D and T2D are characterized by hyperglycemia and insulin resistance (IR), but in T1D the IR occurs even in the absence of metabolic syndrome features. The loss of β-cell insulin secretion in T1D results in lower portal and thus hepatic insulin concentrations in T1D than in T2D or nondiabetic (non-DM) individuals, affecting the GH-IGF axis, as exogenous insulin is subcutaneously delivered in T1D. In this study, we examined how the GH-IGF axis differs by diabetes type, and how it relates to IR. This study included youth (mean age 15±2 years, 37% female) with T1D (n=16), T2D (n=27) and non-DM controls (n=38). A morning fasting blood sample was obtained to measure GH, IGF-1, and IGF binding proteins (IGF BP-1, 2 and 3). Hyperinsulinemic euglycemic clamps were performed to measure glucose infusion rate (GIR), an estimate of skeletal muscle IR, and serum free fatty acid (FFA) suppression. GH, IGF BP-1 and IGF BP-2 were higher in T1D compared to non-DM youth (Figure). Higher IGF BP-3 was associated with lower GIR (more muscle IR) in all youth, but lower IGF BP-1 and 2 were associated with lower GIR in non-DM youth only. Higher GH, IGF BP-1 and IGF BP-3 were associated with less FFA suppression (more adipose IR) in T1D youth only. The GH-IGF-1 axis is altered and is differentially correlated to IR in T1D versus T2D. These data provide clues regarding the unique phenotype of IR in T1D. Disclosure J.K. Snell-Bergeon: None. J.E.B. Reusch: Board Member; Self; American Diabetes Association. Other Relationship; Self; Merck &amp; Co., Inc. A.D. Baumgartner: None. M. Cree-Green: None. K.J. Nadeau: None. Funding American Diabetes Association (7-13-CD-10 to J.K.S-B.)

MON-476 Growth Hormone and the Glomerular Podocyte: Studies of Podocyte-Specific Growth Hormone Receptor Gene Deletion in Mice

Previous research has suggested a role for growth hormone (GH) in the development of kidney disease. Evidence of increased glomerular size and sclerosis in bovine GH (bGH) overproducing animals suggests that excess GH action may cause or exacerbate glomerular damage. Within the glomerulus, the podocyte plays the role of forming a filtration barrier called the slit diaphragm. This cell is known to be dysfunctional in many models of nephropathy and is also a direct target of GH. To explore the mechanisms by which GH impacts the glomerulus, we have developed a transgenic mouse, the podocyte-specific GH receptor gene-disrupted mouse (podGHR-/-). These mice were generated on a C57BL/6J background using Cre-Lox transgenic methods. To examine the effects of high GH levels on the podocyte, these mice were crossed with bovine GH (bGH) overproducing mice and studied at several time points over the course of a year, alongside wild-type control mice and podGHR-/- mice lacking bGH overexpression. Various metabolic and physiologic assays were performed on these mice, including glomerular filtration rate (GFR) testing, glucose and insulin tolerance testing, body composition analysis, and urine & serum analysis. Histological analyses were also performed. Podocyte-specific GHR gene-deletion was associated with increased GFR in male podGHR-/- mice at 54 weeks of age, and with decreased GFR in male podGHR-/- mice with bGH overexpression at 54 weeks of age. PodGHR-/- male mice exhibited significantly decreased total kidney hydroxyproline content at 54 weeks of age as well as decreased glomerular trichrome stain deposition. Both male and female podGHR-/- mice showed decreased glomerular periodic acid Schiff stain deposition at 54 weeks of age. These results suggest a role for podocyte GH activity in the regulation of GFR in the aging and diseased kidney, as well as a role for GH in directing the deposition of collagen and glycosaminoglycans in glomerulus via the podocyte.

Modulation of the somatotropic axis, adiponectin and cytokine secretion during highly pathogenic porcine reproductive and respiratory syndrome virus type 1 (HP-PRRSV-1) infection

Porcine reproductive and respiratory syndrome virus (PRRSV) is known to be clinically responsible for reproductive failure in sows and post-weaning respiratory disease in growing piglets. During the last years, highly pathogenic PRRSV isolates have been discovered. In Italy, a PRRSV-1 subtype 1 strain (namely PR40/2014) characterized by high pathogenicity was isolated and experimental infection was characterized in terms of virological/clinical features and immune modulation (Canelli et al., 2017; Ferrari et al., 2018). The present study was performed in 4-week-old pigs experimentally infected with the highly pathogenic PRRSV1_PR40/2014 (HP-PR40) or with the conventional PRRSV1_PR11/2014 (PR11). The aim was to evaluate the interrelation between plasmatic hormones and cytokines in infected pigs compared to uninfected controls in order to address potential effects on the course of an experimental infection. The time-related changes of growth hormone (GH), insulin-like growth factor-1 (IGF-1), adiponectin, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels appear to be modulated by the infection depending on the PRRSV isolate (HP-PR40 vs. PR11). In particular, in HP-PR40 infected animals, the association between high GH levels and viremia may testify the need to block the anabolic action of GH in order to shift available energy towards the immune response. This need appeared to be delayed in PR11 animals, given the lower pathogenicity of the isolate. Adiponectin, IL-6 and TNF-α course supports the hypothesis of GH resistance mechanisms to guarantee homeostasis in HP-PR40 animals and underlines the key role of energy availability in events leading to an effective response to the virus.

Excess growth hormone suppresses DNA damage repair in epithelial cells.

Growth hormone (GH) decreases with age, and GH therapy has been advocated by some to sustain lean muscle mass and vigor in aging patients and advocated by athletes to enhance performance. Environmental insults and aging lead to DNA damage, which - if unrepaired - results in chromosomal instability and tumorigenesis. We show that GH suppresses epithelial DNA damage repair and blocks ataxia telangiectasia mutated (ATM) kinase autophosphorylation with decreased activity. Decreased phosphorylation of ATM target proteins p53, checkpoint kinase 2 (Chk2), and histone 2A variant led to decreased DNA repair by nonhomologous end-joining. In vivo, prolonged high GH levels resulted in a 60% increase in unrepaired colon epithelial DNA damage. GH suppression of ATM was mediated by induced tripartite motif containing protein 29 (TRIM29) and attenuated tat interacting protein 60 kDa (Tip60). By contrast, DNA repair was increased in human nontumorous colon cells (hNCC) where GH receptor (GHR) was stably suppressed and in colon tissue derived from GHR-/- mice. hNCC treated with etoposide and GH showed enhanced transformation, as evidenced by increased growth in soft agar. In mice bearing human colon GH-secreting xenografts, metastatic lesions were increased. The results elucidate a mechanism underlying GH-activated epithelial cell transformation and highlight an adverse risk for inappropriate adult GH treatment.

Effects of dietary leucine levels on growth, feed utilization, neuro-endocrine growth axis and TOR-related signaling genes expression of juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂)

A 9-week growth trial was conducted to evaluate the effects of dietary leucine (Leu) levels on growth, feed utilization, neuro-endocrine growth axis and TOR-related signaling genes expression of juvenile hybrid grouper (Epinephelus fuscoguttatus ♀ × Epinephelus lanceolatus ♂). Seven isoenergetic (340 kcal per 100 g of dry matter), isoproteic (53.5% of dry matter) and isolipidic (7% of dry matter) diets were formulated to contain graded Leu levels (1.83%, 2.23%, 2.78%, 3.28%, 3.70%, 4.40% and 4.71%, dry matter basis). Each experimental diet was fed to triplicate groups of 12 hybrid grouper juveniles (average initial body weight: 6.92 ± 0.03 g/fish) which were stocked into small floating cages (L 120 cm × W 70 cm × H 50 cm). Fish were fed twice daily (08:00 and 16:00) to apparent satiation.Results showed that weight gain% (WG%) was increased as dietary Leu level increased, reaching a peak value at the 3.28% dietary Leu level, and thereafter, it started to reduce as dietary Leu level continued to rise. Protein productive values (PPVs) of fish fed 3.28% and 3.70% dietary Leu levels were higher than those of fish fed other dietary Leu levels. The quadratic regression analysis of WG% or PPV against dietary Leu levels indicated that the optimal dietary Leu requirement for hybrid grouper was estimated to be 3.25% or 3.41% of dry matter. Fish fed 3.28% and 3.70% dietary Leu levels had higher growth hormone (GH) expression in pituitary than fish fed other dietary Leu levels. For genes of insulin like growth factor 1 (IGF-1) and growth hormone receptor 1 (GHR1) in liver, fish fed 3.28% dietary Leu had higher expression than fish fed other dietary Leu levels. Fish fed 3.28% dietary Leu had higher expression of target of rapamycin (TOR) and S6-kinase 1 (S6K1) in liver than fish fed other dietary Leu levels. Gut morphometric indices of experimental fish were improved by 3.28% or 3.70% dietary Leu supplementations. Generally, optimal dietary Leu requirement for best growth of hybrid grouper was estimated to be 3.25% of dry matter, corresponding to 6.07% % of dietary protein.

Partial dietary fish meal replacement with cotton seed meal and supplementation with exogenous protease alters growth, feed performance, hematological indices and associated gene expression markers (GH, IGF-I) for Nile tilapia, Oreochromis niloticus

A 12-week feeding trial was conducted to evaluate the effect of different ratios of fish meal (FM): cotton seed meal (CSM) without or with inclusion of exogenous protease in diets on growth performance, hematology, digestibility and selected gene expression markers (GH and I (IGF-I) of juvenile Nile tilapia. The experimental diets were categorized into three groups; the first group CSM1 which contained fish meal protein: cotton seed meal protein (FM: CSM = 2:1), the second group CSM2 which contained FM: CSM = 1:1 and the third one CSM3 contained FM: CSM = 1:2 on protein content based. All groups were supplemented with exogenous protease at 0 and 2500 U kg−1 diet, respectively. All diets were fed to fish (initial body weight 11.62 ± 0.03 g fish−1) in triplicate aquaria twice daily. The higher weight gain (WG), protein efficiency ratio (PER) and best feed conversion ratio (FCR) were recorded by fish fed CSM1 and CSM2 and supplemented with 2500 U protease/kg diet. The highest apparent digestibility coefficient of crude protein, crude lipid and digestible energy, and apparent availability coefficient of essential amino acids were obtained by fish receiving CSM1 and CSM2 supplemented with protease (2500 U protease kg−1 diet). The highest mean values of Hb, Htc and RBCs were recorded in fish fed CSM1 and CSM2 supplemented with protease enzyme (2500 U protease kg−1 diet). Serum of alanine and aspartate aminotransferase activities were improved due to dietary protease (2500 U protease kg−1 diet) supplementation, also, fish received the diets supplemented with protease 2500 U kg−1 diet generally had higher total protein, albumin, calcium and phosphorus than those fed diets without supplement. The highest growth hormone (GH) gene expression in brain and liver of tilapia were obtained in the group fed CSM3 and un-supplemented with protease enzyme followed by CSM2 (un-supplemented). On the other hand, tilapia fed CSM1 and CSM2 supplemented with protease enzyme showed the highest values of gene expression of insulin like growth factor I (IGF-I) in brain and liver of tilapia compared to other groups. Results above showed that supplementation of protease can improve growth, nutrient assimilation, and hematology and alter gene expression of GH and IGF-I of Nile tilapia.

The predictors of recovery from diabetes mellitus following neurosurgical treatment of acromegaly: A prospective study over a decade.

The natural history of glucose intolerance (GI) in patients with acromegaly undergoing surgical treatment has not been fully understood. This study was aimed to unravel the prevalence and predictors of recovery from GI in these patients in a prospective multivariate model. Patients with acromegaly treated between 2007 and 2016 were prospectively studied with respect to demographics, clinicoradiological features, comorbidities, and hormonal investigations before surgery and at regular follow-up. The independent predictors of recovery from diabetes were analyzed. There were a total of 151 patients with active acromegaly included in the study. The median baseline growth hormone (GH) and insulin-like growth factor (IGF)-1 levels were 25 and 811 ng/mL, respectively. Diabetes mellitus (DM) and pre-diabetes were noted in 93 (61.6%) and 20 (13.2%) patients, respectively. Following surgical treatment, the median HbA1c decreased significantly from 6.4% to 5.5% (P < 0.001), with 46.8% having complete recovery from DM or pre-diabetes. This glycemic recovery had significant association with both biochemical (P = 0.001) and radiological remission (P = 0.01). The recovery from DM had a greater association with post-operative IGF-1 than GH, especially among those with discordant GH and IGF-1 levels (60% in normal IGF-1 and high GH vs. 20% in high IGF-1 and normal GH). Post-operative IGF-1 had a significant impact on recovery from DM (P = 0.01) independent of age, body mass index, duration of DM, and pre-operative HbA1c. Nearly half of the patients with acromegaly with DM or pre-diabetes had glycemic recovery, influenced by biochemical and radiologic remission. Post-operative IGF-1 appears to be the strongest independent determinant of recovery from DM.