Long-term testosterone therapy may improve NAFLD symptoms in men
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Two-year therapy with testosterone undecanoate normalized serum testosterone levels and reduced nonalcoholic fatty liver disease grade among men with obesity, functional hypogonadism and type 2 diabetes, data show.
“Nonalcoholic fatty liver disease (NAFLD) is emerging as a public health issue worldwide, is highly prevalent in patients with type 2 diabetes, and is linked to obesity, insulin resistance and atherogenic dyslipidemia, and is also connected to functional hypogonadism,” Kristina Groti Antonic, MD, PhD, a specialist in internal medicine in the department of endocrinology, diabetes and metabolic disease at University Medical Centre Ljubljana, Slovenia, told Healio. “NAFLD increases cardiovascular risk and mortality in obese men with type 2 diabetes. Testosterone could potentially affect NAFLD due to its myogenic and anti-inflammatory effects, prompting us to include NAFLD as one of areas of our study. Furthermore, studies into effects of testosterone on NAFLD in patients with type 2 diabetes are rare, exacerbating the need for us to attempt to also address this interesting, yet often disregarded complication of type 2 diabetes.”
Groti Antonic and colleagues analyzed data from 55 men with obesity, functional hypogonadism and type 2 diabetes who participated in a 1-year double-blind, placebo-controlled study, and then 1 year of follow-up. Participants were randomly assigned to one of two groups: a testosterone group (n = 28) received 1,000 mg testosterone undecanoate for 2 years and a placebo group (n = 27) received placebo the first year and 1,000 mg testosterone undecanoate the second year.
Researchers measured total, calculated free and calculated bioavailable testosterone levels, fasting plasma glucose, HbA1c, lipid profile and prostate-specific antigen at baseline, 12 and 24 months. Liver ultrasounds for NAFLD grade assessments were performed at baseline and 2 years. Researchers used t tests and Wilcoxon signed-rank to detect changes from baseline. The findings were presented virtually at the European Congress of Endocrinology.
Liver assessment showed improvement in NAFLD grades (P < .001) after 2 years of testosterone replacement therapy.
Men in both groups experienced normalized testosterone levels with testosterone therapy, which stayed in the normal range during the second year of the study. There were no adverse events observed.
“We did not expect to see a statistically significant difference in the placebo group, which was only switched to testosterone therapy for the second year,” Groti Antonic told Healio. “Testosterone affects the body via different mechanisms and the mechanisms believed to be involved in any improvement in NAFLD — changes in body composition, such as increase of proportion of lean body mass at the expense of fat mass — take a relatively long time to manifest.”
Groti Antonic said the findings show long-term testosterone therapy is associated with significant improvements in metabolic parameters and the anti-inflammatory effects of testosterone in conjunction with reductions in body weight and waist circumference improve metabolic function and liver function.
“This is an important finding, which warrants further studies in this area, hopefully carried out on even larger scale,” Groti Antonic said.
Perspective
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Paresh Dandona, MD, PhD
The recent work on the beneficial effect of long-term testosterone treatment in hypogonadal men with type 2 diabetes with NAFLD is potentially a landmark study. Clearly, the previously demonstrated reduction in adiposity and increase in lean body mass in a study by Dhindsa and colleagues (Dhindsa S, et al. Diabetes Care. 2016; doi:10.2337/dc15-1518) after treatment with testosterone for 6 months has further benefits with prolonged treatment. NAFLD affects more than 100 million Americans, and there is no effective treatment available; however, this research suggests treatment of hypogonadism in such patients kills two birds with one stone. Furthermore, it is likely to prevent the progression of NAFLD to nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma.The mechanisms underlying the reduction in fat hepatic and other sites is not clear; however, insulin sensitizing and anti-inflammatory effects of testosterone may contribute to this effect. There is one study reporting that the incorporation of dietary fat into visceral adipose tissue is inhibited by testosterone (Marin P, et al. J Clin Endocrinol Metab. 1995; doi:10.1210/jcem.80.1.7829619). In this context, it is also worth mentioning that two long-term studies with testosterone have shown that testosterone causes marked weight loss, with loss of adiposity with a concomitant reversal in prediabetes (Yassin A, et al. Diabetes Care. 2019; doi:10.2337/dc18-2388) and diabetes (Haider KS, et al. Diabetes Obes Metab. 2020; doi:10.1111/dom.14122).
The entire spectrum of benefits with testosterone replacement is still to be unraveled.
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Groti Antonic K, et al. Abstract #481. Presented at: European Congress of Endocrinology; May 22-26, 2021 (virtual meeting).
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