Growth hormone replacement therapy regulates microRNA-29a and targets involved in insulin resistance

Replacement of growth hormone (GH) in patients suffering from GH deficiency (GHD) offers clinical benefits on body composition, exercise capacity, and skeletal integrity. However, GH replacement therapy (GHRT) is also associated with insulin resistance, but the mechanisms are incompletely understood. We demonstrate that in GH-deficient mice (growth hormone-releasing hormone receptor (Ghrhr)(lit/lit)), insulin resistance after GHRT involves the upregulation of the extracellular matrix (ECM) and the downregulation of microRNA miR-29a in skeletal muscle. Based on RNA deep sequencing of skeletal muscle from GH-treated Ghrhr(lit/lit) mice, we identified several upregulated genes as predicted miR-29a targets that are negative regulators of insulin signaling or profibrotic/proinflammatory components of the ECM. Using gain- and loss-of-function studies, five of these genes were confirmed as endogenous targets of miR-29a in human myotubes (PTEN, COL3A1, FSTL1, SERPINH1, SPARC). In addition, in human myotubes, IGF1, but not GH, downregulated miR-29a expression and upregulated COL3A1. These results were confirmed in a group of GH-deficient patients after 4 months of GHRT. Serum IGF1 increased, skeletal muscle miR-29a decreased, and miR-29a targets were upregulated in patients with a reduced insulin response (homeostatic model assessment of insulin resistance (HOMA-IR)) after GHRT. We conclude that miR-29a could contribute to the metabolic response of muscle tissue to GHRT by regulating ECM components and PTEN. miR-29a and its targets might be valuable biomarkers for muscle metabolism following GH replacement. KEY MESSAGES GHRT most significantly affects the ECM cluster in skeletal muscle from mice. GHRT downregulates miR-29a and upregulates miR-29a targets in skeletal muscle from mice. PTEN, COL3A1, FSTL1, SERPINH1, and SPARC are endogenous miR-29a targets in human myotubes. IGF1 decreases miR-29a levels in human myotubes. miR-29a and its targets are regulated during GHRT in skeletal muscle from humans.

EMAS position statement: Testosterone replacement therapy in the aging male‏.

INTRODUCTION Late-onset hypogonadism (LOH) represents a common clinical entity in aging males, characterized by the presence of symptoms (most usually of a sexual nature, such as decreased libido, decreased spontaneous erections and erectile dysfunction) and signs, in combination with low serum testosterone concentrations. Whether testosterone replacement therapy (TRT) should be offered to those individuals is still under extensive debate. AIMS The aim of this position statement is to provide and critically appraise evidence on TRT in the aging male, focusing on pathophysiology and characteristics of LOH, indications for TRT, available therapeutic agents, monitoring and treatment-associated risks. MATERIALS AND METHODS Literature review and consensus of expert opinion. RESULTS AND CONCLUSIONS Diagnosis and treatment of LOH is justified, if a combination of symptoms of testosterone deficiency and low testosterone is present. Patients receiving TRT could profit with regard to obesity, metabolic syndrome, type 2 diabetes mellitus, sexual function and osteoporosis and should undergo scheduled testing for adverse events regularly. Potential adverse effects of TRT on cardiovascular disease, prostate cancer and sleep apnea are as yet unclear and remain to be investigated in large-scale prospective studies. Management of aging men with LOH should include individual evaluation of co-morbidities and careful risk versus benefit assessment.

A photopolymerized composite hydrogel and surgical implanting tool for a nucleus pulposus replacement

Nucleus pulposus replacements have been subjected to highly controversial discussions over the last 40 years. Their use has not yet resulted in a positive outcome to treat herniated disc or degenerated disc disease. The main reason is that not a single implant or tissue replacement was able to withstand the loads within an intervertebral disc. Here, we report on the development of a photo-polymerizable poly(ethylene glycol)dimethacrylate nano-fibrillated cellulose composite hydrogel which was tuned according to native tissue properties. Using a customized minimally-invasive medical device to inject and photopolymerize the hydrogel insitu, samples were implanted through an incision of 1 mm into an intervertebral disc of a bovine organ model to evaluate their long-term performance. When implanted into the bovine disc model, the composite hydrogel implant was able to significantly re-establish disc height after surgery (p < 0.0025). The height was maintained after 0.5 million loading cycles (p < 0.025). The mechanical resistance of the novel composite hydrogel material combined with the minimally invasive implantation procedure into a bovine disc resulted in a promising functional orthopedic implant for the replacement of the nucleus pulposus.

Effects of aerobic exercise on ectopic lipids in patients with growth hormone deficiency before and after growth hormone replacement therapy

Growth hormone replacement therapy (GHRT) increases exercise capacity and insulin resistance while it decreases fat mass in growth hormone-deficient patients (GHD). Ectopic lipids (intramyocellular (IMCL) and intrahepatocellular lipids (IHCL) are related to insulin resistance. The effect of GHRT on ectopic lipids is unknown. It is hypothesized that exercise-induced utilization of ectopic lipids is significantly decreased in GHD patients and normalized by GHRT. GHD (4 females, 6 males) and age/gender/waist-matched control subjects (CS) were studied. VO2max was assessed on a treadmill and insulin sensitivity determined by a two-step hyperinsulinaemic-euglycaemic clamp. Visceral (VAT) and subcutaneous (SAT) fat were quantified by MR-imaging. IHCL and IMCL were measured before and after a 2 h exercise at 50-60% of VO2max using MR-spectroscopy (∆IMCL, ∆IHCL). Identical investigations were performed after 6 months of GHRT. VO2max was similar in GHD and CS and significantly increased after GHRT; GHRT significantly decreased SAT and VAT. 2 h-exercise resulted in a decrease in IMCL (significant in CS and GHRT) and a significant increase in IHCL in CS and GHD pre and post GHRT. GHRT didn't significantly impact on ∆IMCL and ∆IHCL. We conclude that aerobic exercise affects ectopic lipids in patients and controls. GHRT increases exercise capacity without influencing ectopic lipids.

Cerebral Microembolization During Aortic Valve Replacement Using Minimally Invasive or Conventional Extracorporeal Circulation: A Randomized Trial.

To compare intraoperative cerebral microembolic load between minimally invasive extracorporeal circulation (MiECC) and conventional extracorporeal circulation (CECC) during isolated surgical aortic valve replacement (SAVR), we conducted a randomized trial in patients undergoing primary elective SAVR at a tertiary referral hospital. The primary outcome was the procedural phase-related rate of high-intensity transient signals (HITS) on transcranial Doppler ultrasound. HITS rate was used as a surrogate of cerebral microembolism in pre-defined procedural phases in SAVR using MiECC or CECC with (+F) or without (-F) an oxygenator with integrated arterial filter. Forty-eight patients were randomized in a 1:1 ratio to MiECC or CECC. Due to intraprocedural Doppler signal loss (n = 3), 45 patients were included in final analysis. MiECC perfusion regimen showed a significantly increased HITS rate compared to CECC (by a factor of 1.75; 95% confidence interval, 1.19-2.56). This was due to different HITS rates in procedural phases from aortic cross-clamping until declamping [phase 4] (P = 0.01), and from aortic declamping until stop of extracorporeal perfusion [phase 5] (P = 0.05). Post hoc analysis revealed that MiECC-F generated a higher HITS rate than CECC+F (P = 0.005), CECC-F (P = 0.05) in phase 4, and CECC-F (P = 0.03) in phase 5, respectively. In open-heart surgery, MiECC is not superior to CECC with regard to gaseous cerebral microembolism. When using MiECC for SAVR, the use of oxygenators with integrated arterial line filter appears highly advisable. Only with this precaution, MiECC confers a cerebral microembolic load comparable to CECC during this type of open heart surgery.