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.

Testosterone is a key hormone in the pathology of metabolic diseases such as obesity. Low testosterone levels are associated with increased fat mass (particularly central adiposity) and reduced lean mass in males. These morphological features are linked to metabolic dysfunction, and testosterone deficiency is associated with energy imbalance, impaired glucose control, reduced insulin sensitivity and dyslipidaemia. A bidirectional relationship between testosterone and obesity underpins this association indicated by the hypogonadal-obesity cycle and evidence weight loss can lead to increased testosterone levels. Androgenic effects on enzymatic pathways of fatty acid metabolism, glucose control and energy utilization are apparent and often tissue specific with differential effects noted in different regional fat depots, muscle and liver to potentially explain the mechanisms of testosterone action. Testosterone replacement therapy demonstrates beneficial effects on measures of obesity that are partially explained by both direct metabolic actions on adipose and muscle and also potentially by increasing motivation, vigour and energy allowing obese individuals to engage in more active lifestyles. The degree of these beneficial effects may be dependent on the treatment modality with longer term administration often achieving greater improvements. Testosterone replacement may therefore potentially be an effective adjunctive treatment for weight management in obese men with concomitant hypogonadism.

Obesity, type 2 diabetes mellitus and the metabolic syndrome are major risk factors for cardiovascular disease. Studies have demonstrated an association between low levels of testosterone and the above insulin-resistant states, with a prevalence of hypogonadism of up to 50% in men with type 2 diabetes mellitus. Low levels of testosterone are also associated with an increased risk of all-cause and cardiovascular mortality. Hypogonadism and obesity share a bidirectional relationship as a result of the complex interplay between adipocytokines, proinflammatory cytokines and hypothalamic hormones that control the pituitary-testicular axis. Interventional studies have shown beneficial effects of testosterone on components of the metabolic syndrome, type 2 diabetes mellitus and other cardiovascular risk factors, including insulin resistance and high levels of cholesterol. Biochemical evidence indicates that testosterone is involved in promoting glucose utilization by stimulating glucose uptake, glycolysis and mitochondrial oxidative phosphorylation. Testosterone is also involved in lipid homeostasis in major insulin-responsive target tissues, such as liver, adipose tissue and skeletal muscle.

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.

Summary The current coronavirus disease (COVID‐19) pandemic caused by novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has a male bias in severity and mortality. This is consistent with previous coronavirus pandemics such as SARS‐CoV and MERS‐CoV, and viral infections in general. Here, we discuss the sex‐disaggregated epidemiological data for COVID‐19 and highlight underlying differences that may explain the sexual dimorphism to help inform risk stratification strategies and therapeutic options.

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ObjectiveTo evaluate the evidence on the transition process from child to adult services for young people with palliative care needs.DesignSystematic review.SettingChild and adult services and interface between healthcare providers.PatientsYoung people aged 13–24 years with palliative care conditions in the process of transition.Main outcome measuresYoung people and their families' experiences of transition, the process of transition between services and its impact on continuity of care and models of good practice.Results92 studies included. Papers on transition services were of variable quality when applied to palliative care contexts. Most focussed on common life-threatening and life-limiting conditions. No standardised transition program identified and most guidelines used to develop transition services were not evidence-based. Most studies on transition programs were predominantly condition-specific (eg, cystic fibrosis (CF), cancer) services. CF services offered high-quality transition with the most robust empirical evaluation. There were differing condition-dependent viewpoints on when transition should occur but agreement on major principles guiding transition planning and probable barriers. There was evidence of poor continuity between child and adult providers with most originating from within child settings.ConclusionsPalliative care was not, in itself, a useful concept for locating transition-related evidence. It is not possible to evaluate the merits of the various transition models for palliative care contexts, or their effects on continuity of care, as there are no long-term outcome data to measure their effectiveness. Use of validated outcome measures would facilitate research and service development.

BACKGROUNDAs the population ages, sicker patients often with multiple comorbidities are presenting in renal clinics. Some are deciding not to embark on dialysis. The objective of this study was to gain an understanding of the decision that some patients make not to embark on dialysis.METHODSNaturally occurring qualitative interviews were conducted with 30 patients and 17 caregivers managed within a Renal Supportive Care Service in an acute NHS Trust in London.RESULTSSeveral patients believed they had made an informed and autonomous decision, either on or against the advice of their doctor (n 5 17); some felt that they had no option but to refuse dialysis treatment, as it would not have been of benefit and might ultimately cause their death (n 5 7); some stated they had decided to opt for medication rather than dialysis 3 times a week and seemed to believe that either option would lead to the same outcome (n 5 2), and some felt there had been no decision to be made (n 5 4).CONCLUSIONSPrior to this study, little was known about those who decide not to embark on dialysis and how they make this decision. It cannot be presumed that decisions made by patients are fully understood and free from inappropriate professional or family influence, and the decision needs to be regularly revisited to check patients' and caregivers' understanding and to allow for reversal of the decision if fitting. There is a need to understand how service providers can help to ensure that such decisions are informed and supported by the best available supportive care thereafter.