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.

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Testosterone: a metabolic hormone in health and disease

Context: Lower circulating testosterone concentrations are associated with metabolic syndrome, type 2 diabetes, carotid intima-media thickness, and aortic and lower limb arterial disease in men. However, it is unclear whether lower testosterone levels predict major cardiovascular events. Objective: We examined whether lower serum testosterone was an independently significant risk factor for symptomatic cerebrovascular events in older men. Design: This was a prospective observational study with median follow-up of 3.5 yr. Setting: Community-dwelling, stroke-free older men were studied. Participants: A total of 3443 men at least 70 yr of age participated in the study. Main Outcome Measures: Baseline serum total testosterone, SHBG, and LH were assayed. Free testosterone was calculated using mass action equations. Incident stroke or transient ischemic attack (TIA) was recorded. Results: A first stroke or TIA occurred in 119 men (3.5%). Total and free testosterone concentrations in the lowest quartiles (<11.7 ...

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Lower Testosterone Levels Predict Incident Stroke and Transient Ischemic Attack in Older Men

http://www2.sahlgrenska.gu.se/pressimages/tivesten2.pdf

High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden.

Summary
Hypogonadism, erectile dysfunction (ED), visceral adiposity, insulin resistance and metabolic syndrome (MetS) often coexist in the same subjects. This cluster of abnormalities is associated with an increased risk of diabetes and cardiovascular diseases (CVD), affecting not only quality of life but also life expectancy. Longitudinal studies have also demonstrated that ED and male hypogonadism could be considered surrogate markers of incident CVD and MetS. However, how androgens signal fat depots and lessen them is still a matter of active research and whether or not low testosterone could play a pathogenetic role in CVD is still under debate. Hence, pathogenetic mechanisms linking hypogonadism with obesity and insulin resistance appear to be complex and often multi-directional. Visceral obesity can probably be considered a relevant cause of hypogonadism but at the same time, hypogonadism could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle. To provide a critical analysis of these issues, a comprehensive literary search was carried out to discuss the relationship between insulin resistance ED, visceral adiposity, MetS and hypogonadism focusing on their possible involvement in the development of CVD.

Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases.

In recent years, the interest in studying the impact of sex steroids and gender on the regulation of blood pressure and cardiovascular disease has been growing. Women are protected from most cardiovascular events compared with men until after menopause, and postmenopausal women are at increased risk of cardiovascular complications compared with premenopausal women. The pathophysiological mechanisms have not been elucidated, but are not likely to be as simple as the presence or absence of oestrogens, since hormone replacement therapy in elderly women in the Women's Health Initiative or HERS (Heart and Estrogen/progestin Replacement Study) did not provide primary or secondary prevention against cardiovascular events. Men are also thought to be at risk of cardiovascular disease at earlier ages than women, and these mechanisms too are not likely to be as simple as the presence of testosterone, since androgen levels fall in men with cardiovascular and other chronic diseases. In fact, many investigators now believe that it is the reduction in androgen levels that frequently accompanies chronic disease and may exacerbate cardiovascular disease in men. In the present review, the roles of sex steroids and gender in mediating or protecting against hypertension and cardiovascular disease will be discussed.

/pdf/sex-and-gender-differences-in-control-of-blood-pressure-3np3qd1bm4.pdf

Sex and gender differences in control of blood pressure

Background— The relation between endogenous testosterone concentrations and health in men is controversial Methods and Results— We examined the prospective relationship between endogenous testosterone concentrations and mortality due to all causes, cardiovascular disease, and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003 Among those without prevalent cancer or cardiovascular disease, 825 men who subsequently died were compared with a control group of 1489 men still alive, matched for age and date of baseline visit Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes (825 deaths), cardiovascular disease (369 deaths), and cancer (304 deaths) Odds ratios (95% confidence intervals) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 075 (055 to 100), 062 (045 to 084), and 059 (042 to 085), respectively (P<0001 fo

Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men

Background and Purpose— The purpose of this study was to investigate the association between occupational social class and stroke incidence and the extent to which classical, lifestyle, and psychosocial risk factors may explain such relationships. Methods— A prospective population study was conducted of 22488 men and women aged 39 to 79 years living in the general community in Norfolk, UK, recruited in 1993 to 1997 and followed up for stroke incidence to 2007. Results— An inverse relationship was observed between social class and stroke incidence with an age- and sex-adjusted hazard ratio for social Class V compared with I of 2.62 (95% CI, 1.63 to 4.22; P=0.001). Adjusting for classical (systolic blood pressure, total blood cholesterol, smoking, history of diabetes, and body mass index), lifestyle (plasma vitamin C levels, alcohol intake, and physical activity), and psychosocial (5-item version of the Mental Health Inventory) risk factors had little effect, and a socioeconomic differential was still appar...

NicholasWareham

Papers

Endogenous Testosterone and Mortality Due to All Causes, Cardiovascular Disease, and Cancer in Men

Social Class, Risk Factors, and Stroke Incidence in Men and Women