Testosterone and glucose metabolism in men: current concepts and controversies

Abstract

A wealth of observational studies show that low testosterone is associated with insulin resistance and with an increased risk of diabetes and the metabolic syndrome. Experimental studies have identified potential mechanisms by which low testosterone may lead to insulin resistance. Visceral adipose tissue is an important intermediate in this relationship. Actions of testosterone or its metabolite oestradiol on other tissues such as muscle, liver, bone or the brain, and body composition-independent effects may also play a role. However, definitive evidence from randomised controlled trials (RCTs) to clarify whether the association of low testosterone with disordered glucose metabolism is causative is currently lacking. It therefore remains possible that this association is due to reverse causation, or simply originates by association with common health and lifestyle factors. RCTs of testosterone therapy in men with or without diabetes consistently show modest metabolically favourable changes in body composition. Despite this, testosterone effects on glucose metabolism have been inconsistent. Recent evidence suggests that the hypothalamic-pituitary-testicular axis suppression in the majority of obese men with metabolic disorders is functional, and may be, at least in part, reversible with weight loss. Until further evidence is available, lifestyle measures with emphasis on weight reduction, treatment of comorbidities and optimisation of diabetic control should remain the first-line treatment in these men. Such measures, if successful, may be sufficient to normalise testosterone levels in men with metabolic disorders, who typically have only modest reductions in circulating testosterone levels.

The Effect of Testosterone and Fenofibrate, Administered Alone or in Combination, on Cardiometabolic Risk Factors in Men with Late‐Onset Hypogonadism and Atherogenic Dyslipidemia

“…Unfortunately, no previous study has investigated the effect of testosterone therapy on cardiovascular morbidity or mortality, and therefore, the causality of the relationship between low testosterone levels and cardiovascular disease is unclear. Although observational studies show a consistent association of low testosterone with adverse lipid profiles [12,13], the question whether testosterone therapy exerts a beneficial effect plasma lipids remains uncertain. Moreover, in some studies, testosterone decreased circulating levels of HDL [14][15][16], considered to have a protective effect against coronary heart disease [17].…”

Transient Decrease in Circulatory Testosterone and Homocysteine Precedes the Development of Metabolic Syndrome Features in Fructose-Fed Sprague Dawley Rats

“…In human subjects, circulatory testosterone levels were negatively correlated with visceral obesity, IR, and fatty liver [9–11]. Similar observations were also reported in animal models [43] and testosterone replacement ameliorated MS symptoms [9–11]. El Hafidi et al reported low levels of testosterone in sucrose-fed rats for 20 weeks and no other study has noticed that in high-fructose-fed rats [44].…”

“…Clinical and animal studies reported the possible role of testosterone in the development of MS components including dyslipidemia, IR, and visceral obesity [9–11]. In human subjects, circulatory testosterone levels were negatively correlated with visceral obesity, IR, and fatty liver [9–11].…”

“…Components of MS including hypertriglyceridemia, nonalcoholic fatty liver disease, IR, and visceral obesity are shown to be associated with low testosterone levels in human subjects [9–11]. Several studies showed that low testosterone levels are associated with MS and increase the risk of obesity, type 2 diabetes, and CVDs [9–11].…”

Reactive oxygen species: players in the cardiovascular effects of testosterone

“…Unfavorable changes in the lipid profile (88), procoagulatory effects, activation of the sympathetic nervous system, and renin-angiotensin-aldosterone system, and insulin resistance are some of the indirect actions of testosterone that can affect the vasculature (25,52,66,76,105,119). Among the direct effects of testosterone, stimulation of proinflammatory enzymes in the vasculature [e.g., thromboxane synthase, as well as cyclooxygenase-1 (COX-1) and COX-2 in rat thoracic aorta and mesenteric arteries (31,177)], reactive oxygen species (ROS) generation in vascular smooth muscle cells (33), which may decrease NO bioavailability and lead to increased blood pressure and renal dysfunction (36,95,155,159), activation of vasoconstrictor signaling pathways (PKC, MAPKs), and increased vasoconstriction have been reported (34,35,99).…”