Effects of Testosterone Undecanoate vs Placebo on Intrahepatic Fat Content in Overweight/Obese Men With T2DM or Prediabetes and Hypogonadism

Background The epidemics of obesity, metabolic syndrome, type 2 diabetes, and atherosclerosis are increasing worldwide. Non-alcoholic fatty liver disease (NAFLD), for a long time unnoted in the metabolic field, is becoming recognized as a condition possibly involved in the pathogenesis of these diseases. Support for this hypothesis emerges from studies revealing that NAFLD precedes the manifestation of the metabolic derangements. NAFLD includes the whole spectrum from non-evolutive simple steatosis to progressive non-alcoholic steatohepatitis (NASH) with/without cirrhosis and hepatocellular carcinoma in individuals without relevant alcohol consumption. NAFLD is a relevant issue in public health owing to its' epidemiologic burden. It represents the most common chronic liver disease in the general population and is expected to increase in the future as a result of an ageing population, the improving control of other major causes of chronic liver disease and the epidemics of obesity and diabetes. The prevalence of NAFLD varies according to age, gender and ethnicity. In the general population, the prevalence of NAFLD is about 25% and the incidence is of two new cases/100 people/year. 2-3% of individuals in the general population will suffer from NASH. Furthermore, up to 15-20% of patients with NASH may develop cirrhosis and 30-40%of these patients who develop cirrhosis may suffer from liver-related mortality. NAFLD is tightly associated with the metabolic syndrome. The metabolic syndrome is a condition characterized by a cluster of alterations including glucose intolerance/ insulin resistance, abdominal obesity, atherogenic dyslipidemia (low concentrations of high density lipoprotein- cholesterol and high concentrations of triglycerides), elevated blood pressure, a proinflammatory and a prothrombotic state. It increases morbidity and mortality, especially due to cardiovascular disease. The prevailing hypothesis for NAFLD pathogenesis is the 'two-hit' model, with insulin resistance and hyperinsulinemia playing essential roles. Insulin resistance and hyperinsulinemia have a plethora of effects on hepatic lipid metabolism and can lead to accumulation of excess triglycerides in hepatocytes. The progression to NASH entails a 'second hit', which is believed to be due to oxidative stress, upregulation of inflammatory mediators, and dysregulated apoptosis, resulting in inflammation (producing NASH) and fibrosis. Currently, the only accepted treatment for NAFLD regardless of stage is lifestyle modifications. These include weight loss by a combination of decreased caloric intake and increased physical activity.

Study rationale Many patients worldwide are suffering from type 2 diabetes with steeply rising numbers predicted for the next decades. Although much progress can be seen in the field of diabetic research and new treatment modalities, new approaches have to be found to cure the disease and underlying risk factors. As men and women show sex specific differences especially in risk factors of T2DM, a sex- and gender-sensitive approach might be considered. Sex hormones might play an important role in the development and possibly the treatment of T2DM. In women higher but in men lower than normal testosterone concentrations predispose for a higher diabetes risk making evident that sex hormones and sex hormone equilibrium are relevant in disease progression. Especially in men low testosterone levels have deteriorating effects on glucose levels, which is aggravated in obesity as aromatization of testosterone to estrogen is enhanced. Due to this mechanism changes in energy homeostasis are reported which lead to changes in lipid accumulation, as described for visceral obesity. Testosterone deficiency is related to increases of visceral fat accumulation. Furthermore testosterone deficiency is associated with the development of non alcoholic fatty liver disease (NAFLD), a well known risk factor for progression of metabolic syndrome (MEtSy), T2DM and cardiovascular disease. Thus, testosterone replacement might be a successful way in hypogonadal men to treat obesity and counteract the further progression of MEtSy, T2DM or cardiovascular disease mainly driven by visceral fat accumulation and NAFLD and are able to improve quality of life.