Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men

Abstract

Purpose In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. Methods Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. Results In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. Conclusions The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014

Associations of Sex Steroids and Sex Hormone-Binding Globulin with Non-Alcoholic Fatty Liver Disease: A Population-Based Study and Meta-Analysis

“…Some studies have shown that men with simple steatosis or advanced NAFLD had lower testosterone levels than healthy controls of the same age [ 12 , 54 ]. Moreover, a recent study found that testosterone treatment is associated with reduced adipose tissue dysfunction and NAFLD in obese hypogonadal men, which suggests that testosterone may play a protective role in the progression of NAFLD and improves NAFLD by reducing intrahepatic triglycerides content [ 55 ]. While testosterone formulations are approved for men, they are not recommended for women [ 56 ].…”

Perspectives on Precision Medicine Approaches to NAFLD Diagnosis and Management

“…Male patients with hypogonadism and NAFLD could possibly benefit from testosterone administration [150,151]. However, the longterm safety profile of this therapy, including cardiovascular outcomes, remains unclear.…”

The role of the androgen receptor in the pathogenesis of obesity and its utility as a target for obesity treatments

“…[110][111][112][113] While these data provide evidence for a role of testosterone in the inhibition of adipogenesis in pre-adipocytes, they do not explain the action of testosterone to reduce the mass of preexisting fat depots in humans and rodents. Other mechanisms by which testosterone may regulate fat mass include modulation of lipid metabolism, 114,115 alteration of muscle metabolism 116 and alteration of mitochondrial function 117 ; with these actions being extensively reviewed elsewhere 118 therapies exhibited an increase in whole body fat mass of 11.2% for leuprolide and 6.4% for bicalutamide. 119 Similar increases in fat mass following bicalutamide 120 and enzalutamide 121,122 monotherapy have also been reported supporting a role for testosterone acting via the AR to regulate fat mass.…”