Prevalence of copy number variants (CNVs) and rhGH treatment efficacy in an Italian cohort of children born small for gestational age (SGA) with persistent short stature associated with a complex clinical phenotype.

PURPOSE: Multiple factors influence intrauterine growth and lead to low birth sizes. The impact of genetic alterations on both pre- and post-natal growth is still largely unknown. The aim of this study was to investigate the prevalence of CNVs in an Italian cohort of SGA children with persistent short stature and complex clinical phenotype. rhGH treatment efficacy was evaluated according to the different genotypes. SUBJECTS AND METHODS: Twenty-four SGA children (10F/14M) with persistent short stature associated with dysmorphic features and/or developmental delay underwent CNV evaluation. RESULTS: CNVs were present in 14/24 (58%) SGA children. Six patients had a microdeletion involving the following regions: 3q24q25.1, 8p21.2p12, 15q26, 19q13.11, 20q11.21q12, 22q11.2. In three females, the same microdeletion involving 17p13.3 region was identified. In two different patients, two microduplications involving 10q21.3 and Xp11.3 region were observed. A further female patient showed both an 11q12.1 and an Xq27.1 microduplication, inherited from her mother and from her father, respectively. In a boy, the presence of a 12p13.33 microdeletion and a 19q13.43 microduplication was found. GH treatment efficacy, expressed by height gain and height velocity in the first 12 months of therapy, was similar in subjects with and without CNVs. CONCLUSIONS: These results show that pathogenic CNVs are common in SGA children with short stature associated with additional clinical features. Interestingly, the involvement of 17p13.3 region occurs with a relative high frequency, suggesting that genes located in this region could play a key role in pre- and post-natal growth. rhGH therapy has similar efficacy in the short term whether CNVs are present or not.

Growth hormone-releasing hormone promotes therapeutic effects of peripheral blood endothelial progenitor cells in ischemic repair.

PURPOSE: In peripheral artery disease, blockage of the blood supply to the limbs leads to blood flow attenuation and tissue ischemia. We investigated whether growth hormone-releasing hormone (GHRH) could enhance the biological functions and therapeutic effects of endothelial progenitor cells (EPCs) derived from adult human peripheral blood (PB). METHODS: EPCs were isolated from human PB (PB-EPCs) and cord blood and expanded in vitro. PB-EPCs incubated with or without GHRH were evaluated for proliferation, migration, and angiogenesis capacity and apoptosis rates under oxidative stress conditions. Activation of STAT3 and Akt pathways was evaluated using Western blot. A hind-limb ischemia (HLI) mouse model was used to study the efficacy of GHRH in improving EPC therapy in vivo. RESULTS: GHRH enhanced the proliferation, migration, and angiogenesis capacity of PB-EPCs and reduced apoptosis under H2O2 stimulation. These beneficial effects were GHRH receptor-dependent and were paralleled by increased phosphorylation of STAT3 and Akt. Transplantation of GHRH-preconditioned EPCs into HLI model mice enhanced blood flow recovery by increasing vascular formation density and enhanced tissue regeneration at the lesion site. CONCLUSION: Our studies demonstrate a novel role for GHRH in dramatically improving therapeutic angiogenesis in HLI by enhancing the biological functions of EPCs. These findings support additional studies to explore the full potential of GHRH in augmenting cell therapy for the management of ischemia.

Cardiovascular risk and dyslipidemia among persons living with HIV: a review.

BACKGROUND: Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles? DISCUSSION: Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice. CONCLUSIONS: Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.

Antagonist of GH-releasing hormone receptors alleviates experimental ocular inflammation.

Disruptions in immunity and occurrence of inflammation cause many eye diseases. The growth hormone-releasing hormone-growth hormone-insulin-like growth factor-1 (GHRH-GH-IGF1) axis exerts regulatory effects on the immune system. Its involvement in ocular inflammation remains to be investigated. Here we studied this signaling in endotoxin-induced uveitis (EIU) generated by LPS. The increase in GHRH receptor (GHRH-R) protein levels was parallel to the increase in mRNA levels of pituitary-specific transcription factor-1, GHRH-R splice variant 1, GHRH, and GH following LPS insult. Elevation of GHRH-R and GH receptor was localized on the epithelium of the iris and ciliary body, and GHRH-R was confined to the infiltrating macrophages and leukocytes in aqueous humor but not to those in stroma. Treatment with GHRH-R antagonist decreased LPS-stimulated surges of GH and IGF1 in aqueous humor and alleviated inflammation by reducing the infiltration of macrophages and leukocytes and the production of TNF-α, IL-1ß, and monocyte chemotactic protein-1. Our results indicate that inflammation in the iris and ciliary body involves the activation of GHRH signaling, which affects the recruitment of immune cells and the production of proinflammatory mediators that contribute to EIU pathogenesis. Moreover, the results suggest that GHRH-R antagonists are potential therapeutic agents for the treatment of acute ocular inflammation.

Treatment of dyslipidemia in HIV.

Patients infected with HIV have a high risk of developing dyslipidemia. Effective therapeutic strategies can be challenging due to an increase risk of drug interactions and other comorbidities. Understanding the underlying pathophysiology and the principles of pharmacological and non-pharmacological therapeutic interventions can be of value in the appropriate management of dyslipidemia in the HIV-infected patient.

Population pharmacokinetic and pharmacodynamic analysis of tesamorelin in HIV-infected patients and healthy subjects.

The objective of this analysis was to characterize the time course of selected pharmacodynamic (PD) markers of tesamorelin: growth hormone (GH) and insulin-like growth factor (IGF-1) concentrations in HIV-infected patients and healthy volunteers. A total of 41 subjects in Phase I trials receiving subcutaneous daily doses of 1 or 2 mg of tesamorelin during 14 consecutive days were included in this analysis. A previous pharmacokinetic (PK) model of tesamorelin was used as the input function for the PD model of GH. Tesamorelin was hypothesized to stimulate the secretion of GH in an "episodic" manner, i.e., for a finite duration of time. The resulting PK/PD model of GH was used to describe the time course of IGF-1. The effect of age, body weight, body mass index, sex, race, and health status on the model parameters was evaluated. The model was qualified using predictive checks and non-parametric bootstrap. Within the range of the values evaluated no covariates were significantly associated with GH or IGF-1 model parameters. Model evaluation procedures indicated accurate prediction of the selected pharmacodynamic markers. The time course of GH and IGF-1 concentrations following multiple doses of tesamorelin were well predicted by the sequential PK/PD model developed using Phase I data.

Therapies for musculoskeletal disease: can we treat two birds with one stone?

Musculoskeletal diseases are highly prevalent with staggering annual health care costs across the globe. The combined wasting of muscle (sarcopenia) and bone (osteoporosis)-both in normal aging and pathologic states-can lead to vastly compounded risk for fracture in patients. Until now, our therapeutic approach to the prevention of such fractures has focused solely on bone, but our increasing understanding of the interconnected biology of muscle and bone has begun to shift our treatment paradigm for musculoskeletal disease. Targeting pathways that centrally regulate both bone and muscle (eg, GH/IGF-1, sex steroids, etc.) and newly emerging pathways that might facilitate communication between these 2 tissues (eg, activin/myostatin) might allow a greater therapeutic benefit and/or previously unanticipated means by which to treat these frail patients and prevent fracture. In this review, we will discuss a number of therapies currently under development that aim to treat musculoskeletal disease in precisely such a holistic fashion.

Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial.

IMPORTANCE: Among patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown. OBJECTIVE: To investigate the effect of tesamorelin on visceral and liver fat. DESIGN, SETTING, AND PATIENTS: Double-blind, randomized, placebo-controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013. INTERVENTIONS: Participants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months. MAIN OUTCOMES AND MEASURES: Primary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points. RESULTS: Forty-eight patients received treatment with study drug. Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, -6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage. Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, -16 to 29 mg/dL]; P = .53 overall across time points) were not significant. CONCLUSIONS AND RELEVANCE: In this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01263717.

Efficacy and safety of tesamorelin in people with HIV on integrase inhibitors.

OBJECTIVE: Tesamorelin is the only FDA-approved therapy to treat abdominal fat accumulation in people with HIV (PWH). Phase III clinical trials were conducted prior to the introduction of integrase inhibitors (INSTIs), which are now a mainstay of HIV antiretroviral therapy. DESIGN: We leveraged a randomized double-blind trial of 61 PWH and metabolic dysfunction-associated steatotic liver disease to evaluate the efficacy and safety of tesamorelin 2 mg once daily vs. identical placebo among participants on INSTI-based regimens at baseline. METHODS: In the parent clinical trial, visceral fat cross-sectional area, hepatic fat fraction, and trunk-to-appendicular fat ratio were quantified using magnetic resonance imaging, proton magnetic resonance spectroscopy, and dual-energy x-ray absorptiometry, respectively, at baseline and 12 months. Metabolic and safety outcomes were compared between treatment arms. RESULTS: Among 38 participants on INSTI-based regimens at baseline, 15 individuals on tesamorelin and 16 individuals on placebo completed the 12-month study. Tesamorelin led to significant declines in visceral fat (median [interquartile range]: -25 [-93, -2] vs. 14 [3, 41] cm 2 , P  = 0.001), hepatic fat (-4.2% [-12.3%, -2.7%] vs. -0.5% [-3.9%, 2.7%], P  = 0.01), and trunk-to-appendicular fat ratio (-0.1 [-0.3, 0.0] vs. 0.0 [-0.1, 0.1], P  = 0.03). Tesamorelin was well tolerated with a similar frequency of adverse events, including hyperglycemia, between groups. CONCLUSIONS: The current analysis provides the first dedicated data on the efficacy and safety of tesamorelin among PWH on INSTI-based regimens. Despite the association of INSTI use with weight gain and adipose tissue dysfunction, tesamorelin had beneficial effects on body composition with no exacerbation of glycemic control.

Tesamorelin: a growth hormone-releasing factor analogue for HIV-associated lipodystrophy.

OBJECTIVE: To evaluate the efficacy and safety of tesamorelin, a growth hormone releasing factor analogue approved by the Food and Drug Administration in November 2010 for the treatment of lipodystrophy associated with HIV infection. DATA SOURCES: Literature was obtained through MEDLINE (1948-November 2011) and International Pharmaceutical Abstracts (1970-October 2011) using the search terms tesamorelin, TH9507, growth hormone releasing factor, and HIV-associated lipodystrophy syndrome. Additional publications were obtained through review of references within primary literature publications as well as pertinent Web sites. STUDY SELECTION AND DATA EXTRACTION: All articles published in English identified from the data sources were evaluated and all pertinent information was included. All studies relevant to the evaluation of efficacy and safety of tesamorelin in the management of HIV-associated lipodystrophy were included, with a focus on trials completed in humans. DATA SYNTHESIS: In 2 Phase 3 clinical trials and their pooled analyses, tesamorelin was proven to significantly decrease waist circumference and visceral adipose tissue (VAT) following 26 weeks of treatment. Both trials also demonstrated significant improvements in some subjective body image parameters. Both studies had 26-week extension phases that confirmed maintenance of VAT improvements on treatment without adverse impact on blood glucose and lipid parameters. Limited data support off-label uses of tesamorelin at this time. CONCLUSIONS: Tesamorelin is effective in improving visceral adiposity and body image in patients with HIV-associated lipodystrophy over 26-52 weeks of treatment. Potential limitations for its use include high cost and lack of long-term safety and adherence data. Tesamorelin provides a useful treatment option for management of patients with significant lipodystrophy related to HIV infection.

Growth hormone axis treatments for HIV-associated lipodystrophy: a systematic review of placebo-controlled trials.

BACKGROUND: HIV-associated lipodystrophy is a disorder of fat metabolism that occurs in patients with HIV infection. It can cause metabolic derangements and negative self-perceptions of body image, and result in noncompliance with highly active antiretroviral therapy (HAART). Growth hormone (GH) axis drugs have been evaluated for treatment of this disorder, but no systematic review has been conducted previously. OBJECTIVES: The aim of the review was to compare the effects of GH axis drugs vs. placebo in changing visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and lean body mass (LBM) in patients with HIV-associated lipodystrophy. SEARCH METHODS: We searched MEDLINE (1996-2009), CENTRAL (Issue 4, 2009), Web of Science, Summons, Google Scholar, the Food and Drug Administration (FDA) website, and Clinicaltrials.gov from 13 October 2009 to 7 June 2010. We excluded newspaper articles and book reviews from the Summons search; this was the only search limitation applied. We also manually reviewed references of included articles. SELECTION CRITERIA: Inclusion criteria were as follows: randomized placebo-controlled trial (RCT); study participants with HIV-associated lipodystrophy; intervention consisting of GH, growth hormone releasing hormone (GHRH), tesamorelin or insulin-like growth factor-1 (IGF-1); study including at least one primary outcome of interest: change in VAT, SAT or LBM. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data and assessed study quality using a standardized form. The authors of one study were contacted for missing information. The main effect was calculated as a summary of the mean differences in VAT, SAT and LBM between the intervention and placebo groups in the included studies. Subgroup analyses were performed to assess different GH axis drug classes. RESULTS: Ten RCTs including 1511 patients were included in the review. All had a low risk of bias and passed the test of heterogeneity for each primary outcome. Compared with placebo, GH axis treatments decreased VAT [weighted mean difference (WMD) -25.20 cm(2) ; 95% confidence interval (CI) -32.18 to -18.22 cm(2) ; P<0.001] and increased LBM (WMD 1.31 kg; 95% CI 1.00 to 1.61 kg; P<0.001], but had no significant effect on SAT mass (WMD -3.94 cm(2) ; 95% CI -10.88 to 3.00 cm(2) ; P=0.27]. Subgroup analyses showed that GH had the most significant effects on VAT and SAT, but none on LBM. The drugs were well tolerated but statistically significant side effects included arthralgias and oedema. CONCLUSIONS: Our review indicates that, based on the findings of the 10 included studies, GH axis treatments are effective in reducing VAT and increasing LBM in patients with HIV-associated lipodystrophy. However, clinicians must decide whether the attributed benefits are clinically significant, considering the costs and potential risks of GH axis treatments. A limitation of this study is the small number of studies available of each GH axis drug class.

HIV infection, body composition changes and related metabolic complications: contributing factors and evolving management strategies.

PURPOSE OF REVIEW: Metabolic toxicities in HIV patients are common and contribute to clinical status and long-term sequelae. Body fat mass alterations, of multifactorial causes, continue to occur, despite use of antiretroviral drugs associated with fewer metabolic side-effects. The role of HIV itself in the development of these changes is being better defined and a deeper understanding of perturbations in intermediary metabolic processes is emerging. Treatment options are also being identified. RECENT FINDINGS: HIV itself may be a direct causal factor in the accelerated atherosclerosis and decreased levels of high-density lipoprotein that occur and contribute to increased cardiovascular complications. Antiretroviral drug-related and inflammation-related effects can cause mitochondrial toxicity and are an emerging area of research. The association of increased visceral adipose tissue with both drug-related and chronic inflammation-related factors is now better understood. The role of accelerated aging as a paradigm is useful to understand long-term outcome risks for patients. The use of growth hormone-releasing factor as a viable treatment option for increased visceral abdominal tissue has recently been confirmed for selected patients. SUMMARY: Metabolic issues persist in HIV patients who are otherwise stable. Understanding the various inter-related contributing factors has allowed for rapid improvement in patients' clinical status, but long-term consequences are of concern and require ongoing investigation in order to prevent limiting the otherwise important clinical achievements that have recently occurred.

Management of fat accumulation in patients with HIV infection.

The use of antiretroviral therapies has improved survival in people living with HIV to nearly normal rates. However, ongoing low-level HIV replication and incomplete immune recovery are associated with a chronic inflammatory stimulus. This increases several non-typically AIDS-related complications, including fat mass changes and metabolic conditions. Abdominal adiposity occurs as a result of complex interactions involving HIV itself, antiretroviral drug-associated factors, and several intermediary metabolic alterations and abnormal hormone levels. Abdominal adiposity in turn can further the metabolic derangements, and increase the risk of diabetes and cardiovascular disease. Abnormal growth hormone secretion plays a role in development of the fat depot changes. Effective long-term interventions to decrease central adiposity are limited but studies using growth hormone and especially growth hormone-releasing factor have shown encouraging results. Other emerging therapeutic options have been variably successful in the short term and the continuing clinical and therapeutic challenges will require ongoing investigation.

Evidence of insulin-like growth factor binding protein-3 proteolysis during growth hormone stimulation testing.

OBJECTIVES: The ternary complex is composed of insulin-like growth factor (IGF)-I, IGF binding protein (IGFBP)-3 and acid labile subunit (ALS). Growth hormone (GH) promotes IGFBP-3 proteolysis to release free IGF-I, ALS, and IGFBP-3 fragments. Our aim was to determine whether elevated GH levels during GH stimulation testing would trigger IGFBP-3 proteolysis. DESIGN: This prospective study of 10 short prepubertal children (height standard deviation score -2.37 +/- 0.31) used arginine and GH releasing hormone stimulation to study dynamic changes in the ternary complex moieties. IGFBP-3 was measured in two assays: a radioimmunoassay (RIA) that detects both cleaved and intact IGFBP-3; and an immunochemiluminescence assay (ICMA) that detects only intact IGFBP-3. RESULTS: IGFBP-3 measured by RIA increased by 19% (p < 0.05), while IGFBP-3 measured by ICMA did not significantly increase (6.1%). CONCLUSION: The significant increase in IGFBP-3 measured by RIA, but not ICMA, provides evidence of IGFBP-3 proteolysis during acute GH stimulation.

Relationship of IGF-1 and IGF-Binding Proteins to Disease Severity and Glycemia in Nonalcoholic Fatty Liver Disease.

CONTEXT: Growth hormone (GH) and IGF-1 help regulate hepatic glucose and lipid metabolism, and reductions in these hormones may contribute to development of nonalcoholic fatty liver disease (NAFLD). OBJECTIVE: To assess relationships between hepatic expression of IGF1 and IGF-binding proteins (IGFBPs) and measures of glycemia and liver disease in adults with NAFLD. Secondarily to assess effects of GH-releasing hormone (GHRH) on circulating IGFBPs. DESIGN: Analysis of data from a randomized clinical trial of GHRH. SETTING: Two US academic medical centers. PARTICIPANTS: Participants were 61 men and women 18 to 70 years of age with HIV-infection, ≥5% hepatic fat fraction, including 39 with RNA-Seq data from liver biopsy. MAIN OUTCOME MEASURES: Hepatic steatosis, inflammation, and fibrosis by histopathology and measures of glucose homeostasis. RESULTS: Hepatic IGF1 mRNA was significantly lower in individuals with higher steatosis and NAFLD Activity Score (NAS) and was inversely related to glucose parameters, independent of circulating IGF-1. Among the IGFBPs, IGFBP2 and IGFBP4 were lower and IGFBP6 and IGFBP7 (also known as IGFBP-related protein 1) were higher with increasing steatosis. Hepatic IGFBP6 and IGFBP7 mRNA levels were positively associated with NAS. IGFBP7 mRNA increased with increasing fibrosis. Hepatic IGFBP1 mRNA was inversely associated with glycemia and insulin resistance, with opposite relationships present for IGFBP3 and IGFBP7. GHRH increased circulating IGFBP-1 and IGFBP-3, but decreased IGFBP-2 and IGFBP-6. CONCLUSIONS: These data demonstrate novel relationships of IGF-1 and IGFBPs with NAFLD severity and glucose control, with divergent roles seen for different IGFBPs. Moreover, the data provide new information on the complex effects of GHRH on IGFBPs.

A super-agonist of growth hormone-releasing hormone causes rapid improvement of nutritional status in patients with chronic kidney disease.

Chronic kidney disease is frequently associated with protein-energy wasting related to chronic inflammation and a resistance to anabolic hormones such as insulin and growth hormone (GH). In this study, we determined whether a new GH-releasing hormone super-agonist (AKL-0707) improved the anabolism and nutritional status of nondialyzed patients with stage 4-5 chronic kidney disease randomized to twice daily injections of the super-agonist or placebo. After 28 days, this treatment significantly increased 24-h GH secretion by almost 400%, without altering the frequency or rhythmicity of secretory bursts or fractional pulsatile GH release, and doubled the serum insulin-like growth factor-1 level. There was a significant change in the Subjective Global Assessment from 'mildly to moderately malnourished' to 'well-nourished' in 6 of 9 patients receiving AKL-0707 but in none of 10 placebo-treated patients. By dual-energy X-ray absorptiometry, both the mean fat-free mass and the body mineral content increased, but fat mass decreased, all significantly. In the AKL-0707-treated group, both serum urea and normalized protein equivalent of nitrogen appearance significantly decreased with no change in dietary protein intake, indicating a protein anabolic effect of treatment. Thus, our study shows that stimulation of endogenous GH secretion by AKL-0707 overcomes uremic catabolism of patients with advanced chronic kidney disease.

Metabolic effects of a growth hormone-releasing factor in patients with HIV.

BACKGROUND: Visceral adipose tissue accumulates during antiretroviral therapy in many patients who are infected with the human immunodeficiency virus (HIV); this process is associated with an increased cardiovascular risk. We assessed the use of a growth hormone-releasing factor analogue, tesamorelin, to decrease visceral adiposity. METHODS: We randomly assigned 412 patients with HIV (86% of whom were men) who had an accumulation of abdominal fat to receive a daily subcutaneous injection of either 2 mg of tesamorelin or placebo for 26 weeks. The primary end point was the percent change from baseline in visceral adipose tissue as shown on computed tomography. Secondary end points included triglyceride levels, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol, the level of insulin-like growth factor I (IGF-I), and self-assessed body image. Glycemic measures included glucose and insulin levels. RESULTS: The measure of visceral adipose tissue decreased by 15.2% in the tesamorelin group and increased by 5.0% in the placebo group; the levels of triglycerides decreased by 50 mg per deciliter and increased by 9 mg per deciliter, respectively, and the ratio of total cholesterol to HDL cholesterol decreased by 0.31 and increased by 0.21, respectively (P<0.001 for all comparisons). Levels of total cholesterol and HDL cholesterol also improved significantly in the tesamorelin group. Levels of IGF-I increased by 81.0% in the tesamorelin group and decreased by 5.0% in the placebo group (P<0.001). Adverse events did not differ significantly between the two study groups, but more patients in the tesamorelin group withdrew from the study because of an adverse event. No significant differences were observed in glycemic measures. CONCLUSIONS: Daily tesamorelin for 26 weeks decreased visceral fat and improved lipid profiles, effects that might be useful in HIV-infected patients who have treatment-associated central fat accumulation. (ClinicalTrials.gov number, NCT00123253 [ClinicalTrials.gov] .).

Growth hormone for in vitro fertilization.

BACKGROUND: In an effort to improve outcomes of in-vitro fertilisation cycles the use of growth hormone has been considered. Improving the outcomes of in-vitro fertilisation is especially important for subfertile women who are considered 'poor responders'. OBJECTIVES: To assess the effectiveness of adjuvant growth hormone in in-vitro fertilisation protocols. SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Groups trials register (June 2009), the Cochrane Central Register of Controlled Trials (Cochrane Library Issue 2, 2009), MEDLINE (1966 to June 2009), EMBASE (1988 to June 2009) and Biological Abstracts (1969 to June 2009). SELECTION CRITERIA: All randomised controlled trials were included if they addressed the research question and provided outcome data for intervention and control participants. DATA COLLECTION AND ANALYSIS: Assessment of trial risk of bias and extraction of relevant data was performed independently by two reviewers. MAIN RESULTS: Ten studies (440 subfertile couples) were included. Results of the meta-analysis demonstrated no difference in outcome measures and adverse events in the routine use of adjuvant growth hormone in in-vitro fertilisation protocols. However, meta-analysis demonstrated a statistically significant difference in both live birth rates and pregnancy rates favouring the use of adjuvant growth hormone in in-vitro fertilisation protocols in women who are considered poor responders without increasing adverse events, OR 5.39, 95% CI 1.89 to 15.35 and OR 3.28, 95% CI 1.74 to 6.20 respectively. AUTHORS' CONCLUSIONS: Although the use of growth hormone in poor responders has been found to show a significant improvement in live birth rates, we were unable to identify which sub-group of poor responders would benefit the most from adjuvant growth hormone. The result needs to be interpreted with caution, the included trials were few in number and small sample size. Therefore, before recommending growth hormone adjuvant in in-vitro fertilisation further research is necessary to fully define its role.

Effects of ghrelin, GH-releasing peptide-6 (GHRP-6) and GHRH on GH, ACTH and cortisol release in hyperthyroidism before and after treatment.

In thyrotoxicosis GH responses to stimuli are diminished and the hypothalamic-pituitary-adrenal axis is hyperactive. There are no data on ghrelin or GHRP-6-induced GH, ACTH and cortisol release in treated hyperthyroidism. We, therefore, evaluated these responses in 10 thyrotoxic patients before treatment and in 7 of them after treatment. GHRH-induced GH release was also studied. Peak GH (µg/L; mean ± SE) values after ghrelin (22.6 ± 3.9), GHRP-6 (13.8 ± 2.3) and GHRH (4.9 ± 0.9) were lower in hyperthyroidism before treatment compared to controls (ghrelin: 67.6 ± 19.3; GHRP-6: 25.4 ± 2.7; GHRH: 12.2 ± 2.8) and did not change after 6 months of euthyroidism (ghrelin: 32.7 ± 4.7; GHRP-6: 15.6 ± 3.6; GHRH: 7.4 ± 2.3), although GH responses to all peptides increased in ~50% of the patients. In thyrotoxicosis before treatment ACTH response to ghrelin was two fold higher (107.4 ± 26.3) than those of controls (54.9 ± 10.3), although not significantly. ACTH response to GHRP-6 was similar in both groups (hyperthyroid: 44.7 ± 9.0; controls: 31.3 ± 7.9). There was a trend to a decreased ACTH response to ghrelin after 3 months of euthyroidism (35.6 ± 5.3; P = 0.052), but after 6 months this decrease was non-significant (50.7 ± 14.0). After 3 months ACTH response to GHRP-6 decreased significantly (20.4 ± 4.2), with no further changes. In hyperthyroidism before treatment, peak cortisol (µg/dL) responses to ghrelin (18.2 ± 1.2) and GHRP-6 (15.9 ± 1.4) were comparable to controls (ghrelin: 16.4 ± 1.6; GHRP-6: 13.5 ± 0.9) and no changes were seen after treatment. Our results suggest that the pathways of GH release after ghrelin/GHRP-6 and GHRH are similarly affected by thyroid hormone excess and hypothalamic mechanisms of ACTH release modulated by ghrelin/GHSs may be activated in this situation.

Anabolic and anticatabolic agents used in burn care: What is known and what is yet to be learned.

Major thermal injury induces profound metabolic derangements secondary to an inflammatory "stress-induced" hormonal environment. Several pharmacological interventions have been tested in an effort to halt the hypermetabolic response to severe burns. Insulin, insulin growth factor 1, insulin growth factor binding protein 3, metformin, human growth hormone, thyroid hormones, testosterone, oxandrolone, and propranolol, among others, have been proposed to have anabolic or anticatabolic effects. The aim of this broad analysis of pharmacological interventions was to raise awareness of treatment options and to help establishing directions for future clinical research efforts. A PubMed search was conducted on the anabolic and anticatabolic agents used in burn care. One hundred and thirty-five human studies published between 1999 and 2017 were included in this review. The pharmacological properties, rationale for the treatments, efficacy considerations and side effect profiles are summarized in the article. Many of the drugs tested for investigational purposes in the severely thermally injured are not yet gold-standard therapies in spite of their potential benefit. Propranolol and oxandrolone have shown great promise but further evidence is still needed to clarify their potential use for anabolic and anticatabolic purposes.