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Jones T.H.,University of Sheffield | Jones T.H.,Robert Hague Center for Diabetes and Endocrinology
Journal of Diabetes | Year: 2010

Observations from clinical studies suggest that low serum levels of testosterone in men are often associated with obesity, insulin resistance, and metabolic compromise. Indeed, the clinical symptoms of late-onset hypogonadism are markedly similar to those of Type 2 diabetes mellitus (T2DM) and metabolic syndrome, and may share a similar pathophysiology. Observational and experimental data suggest that testosterone treatment improves a number of hallmark features of T2DM and metabolic syndrome, namely insulin resistance, obesity, dyslipidemia, and sexual dysfunction. Consequently, clinical studies have been undertaken to assess the impact of testosterone-replacement therapy in this patient group. The present article reviews the observational clinical data suggesting an association between low serum testosterone and metabolic impairment, the clinical data relating to the effects of testosterone treatment on components of the metabolic syndrome, and the randomized clinical trails that have formally investigated whether testosterone-replacement therapy provides clinical benefit to hypogonadal men with T2DM andor metabolic syndrome. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Zitzmann M.,Universitatsklinikum Munster | Mattern A.,Bayer AG | Hanisch J.,Bayer AG | Gooren L.,Medical Center | And 3 more authors.
Journal of Sexual Medicine | Year: 2013

Introduction. Morbidity/mortality is higher in men with below-normal serum testosterone. Restoring testosterone to normal is beneficial. Aim. Assessment of safety and effectiveness of injectable long-acting testosterone undecanoate (TU) in hypogonadal men in daily clinical practice. Methods. An international, multicenter, one-arm, prospective observational study in 23 countries. Main Outcome Measures. Parameters of erectile function, libido, vigor/vitality, mood, and ability to concentrate assessed by physician interview using items and five-point Likert scales. Physical and circulatory parameters as well as hematocrit, prostate-specific antigen (PSA) levels, glucose control, and lipid profiles. IPASS. An International, multicenter, Post-Authorisation (after authorized use in respective country) Surveillance Study on long-acting-intramuscular TU conducted at 155 centers in 23 countries in Europe, Asia, Latin America, and Australia. Patients received up to five TU injections during 9-12 months. Results. Of the 1,493 hypogonadal men enrolled, 1,438 (aged 49.2±13.9 years) having received 6,333 injections were analyzed. Scores of mental and psychosexual functions (libido, vigor, overall mood, and ability to concentrate) improved markedly, while mean waist circumference decreased from 100 to 96cm. Blood pressure and lipid parameters were altered in a favorable and significant manner. After four TU injection intervals, the percentage of patients with "low" or "very low" levels of sexual desire/libido decreased from 64% at baseline to 10%; moderate, severe, or extremely severe erectile dysfunction decreased from 67% to 19%. At the last observation, 89% of patients were "satisfied" or "very satisfied" with TU therapy. Adverse events and adverse drug reactions (ADRs) occurred in 12% and 6% of patients, respectively, mostly mild to moderate. The most common ADRs were increase in hematocrit, increase in PSA, and injection site pain (all <1%). No case of prostate cancer was observed. Conclusion. In this largest worldwide sample of hypogonadal men, injectable long-acting TU was effective and well tolerated. Zitzmann M, Mattern A, Hanisch J, Gooren L, Jones H, and Maggi M. IPASS: A study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. © 2012 International Society for Sexual Medicine.

Kelly D.M.,University of Sheffield | Jones T.H.,University of Sheffield | Jones T.H.,Robert Hague Center for Diabetes and Endocrinology
Journal of Endocrinology | Year: 2013

Coronary heart disease is a leading cause of premature death in men. Epidemiological studies have shown a high prevalence of low serum testosterone levels in men with cardiovascular disease (CVD). Furthermore, a low testosterone level is associated in some but not in all observational studies with an increase in cardiovascular events and mortality. Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation: key mediators of atherosclerosis. A bidirectional relationship between low endogenous testosterone levels and concurrent illness complicates attempts to validate causality in this association and potential mechanistic actions are complex. Testosterone is a vasoactive hormone that predominantly has vasodilatory actions on several vascular beds, although some studies have reported conflicting effects. In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure. Although the mechanism of the action of testosterone on vascular tone in vivo is not understood, laboratory research has found that testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells. Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis. The translational effects of testosterone between in vitro animal and human studies, some of which have conflicting effects, will be discussed in this review. We review the evidence for a role of testosterone in vascular health, its therapeutic potential and safety in hypogonadal men with CVD, and some of the possible underlying mechanisms. © 2013 Society for Endocrinology.

Jones T.H.,Robert Hague Center for Diabetes and Endocrinology | Jones T.H.,University of Sheffield | Arver S.,Karolinska University Hospital | Behre H.M.,Martin Luther University of Halle Wittenberg | And 8 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - This study evaluated the effects of testosterone replacement therapy (TRT) on insulin resistance, cardiovascular risk factors, and symptoms in hypogonadal men with type 2 diabetes and/or metabolic syndrome (MetS). RESEARCH DESIGN AND METHODS - The efficacy, safety, and tolerability of a novel transdermal 2% testosterone gel was evaluated over 12 months in 220 hypogonadal men with type 2 diabetes and/or MetS in a multicenter, prospective, randomized, double-blind, placebo-controlled study. The primary outcome was mean change from baseline in homeostasis model assessment of insulin resistance (HOMA-IR). Secondary outcomes were measures of body composition, glycemic control, lipids, and sexual function. Efficacy results focused primarily on months 0-6 (phase 1; no changes in medication allowed). Medication changes were allowed in phase 2 (months 6-12). RESULTS - TRT reduced HOMA-IR in the overall population by 15.2% at 6 months (P = 0.018) and 16.4% at 12 months (P = 0.006). In type 2 diabetic patients, glycemic control was significantly better in the TRT group than the placebo group at month 9 (HbA1c: treatment difference, -0.446%; P = 0.035). Improvements in total and LDL cholesterol, lipoprotein a (Lpa), body composition, libido, and sexual function occurred in selected patient groups. There were no significant differences between groups in the frequencies of adverse events (AEs) or serious AEs. The majority of AEs (>95%) were mild or moderate. CONCLUSIONS - Over a 6-month period, transdermal TRT was associated with beneficial effects on insulin resistance, total and LDL-cholesterol, Lpa, and sexual health in hypogonadal men with type 2 diabetes and/or MetS. © 2011 by the American Diabetes Association.

Kelly D.M.,University of Sheffield | Jones T.H.,University of Sheffield | Jones T.H.,Robert Hague Center for Diabetes and Endocrinology
Journal of Endocrinology | Year: 2013

Testosterone is a hormone that plays a key role in carbohydrate, fat and protein metabolism. It has been known for some time that testosterone has a major influence on body fat composition and muscle mass in the male. Testosterone deficiency is associated with an increased fat mass (in particular central adiposity), reduced insulin sensitivity, impaired glucose tolerance, elevated triglycerides and cholesterol and low HDL-cholesterol. All these factors are found in the metabolic syndrome (MetS) and type 2 diabetes, contributing to cardiovascular risk. Clinical trials demonstrate that testosterone replacement therapy improves the insulin resistance found in these conditions as well as glycaemic control and also reduces body fat mass, in particular truncal adiposity, cholesterol and triglycerides. The mechanisms by which testosterone acts on pathways to control metabolism are not fully clear. There is, however, an increasing body of evidence from animal, cell and clinical studies that testosterone at the molecular level controls the expression of important regulatory proteins involved in glycolysis, glycogen synthesis and lipid and cholesterol metabolism. The effects of testosterone differ in the major tissues involved in insulin action, which include liver, muscle and fat, suggesting a complex regulatory influence on metabolism. The cumulative effects of testosterone on these biochemical pathways would account for the overall benefit on insulin sensitivity observed in clinical trials.This review discusses the current knowledge of the metabolic actions of testosterone and how testosterone deficiency contributes to the clinical disease states of obesity, MetS and type 2 diabetes and the role of testosterone replacement. © 2013 Society for Endocrinology Printed in Great Britain.

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