Long-Term Testosterone Treatment Improves Fatty Liver and Kidney Function with Safe Outcomes on Cardio-, Metabolic and Prostate Health in Men with Hypogonadism. Prospective Controlled Studies

Long-Term Testosterone Treatment Improves Fatty and with Safe Men with Prospective Abstract Hypogonadism is receiving recognition for being a risk factor for fatty liver and impaired kidney function [1,2]. Emerging data, summarized here, suggest that long-term treatment with testosterone undecanoate injection may improve both liver and kidney function as well as metabolic deterioration with favorable safety profile on metabolism and prostate health [3,4].

An analysis of NHANES III data of a nationally representative sample of U.S. adults (n=4,758) found an association between low testosterone levels and an increased risk of NAFLD in men, even after adjustment for obesity and other metabolic risk factors [8].
Another study of 495 men found that the association between low testosterone and NAFLD persisted even after controlling for visceral abdominal fat (measured by computed tomography) and insulin resistance [9]. The 2012 Practice Guideline on the Diagnosis and Management of Non-alcoholic Fatty Liver Disease by the American Gastroenterological Association and American College of Gastroenterology acknowledged that hypogonadism is a risk factor for NAFLD.1 All NAFLD histological stages are associated with significantly increased overall mortality, and this risk increases progressively with worsening NAFLD histology [10,11].
Age-associated loss of kidney function has been recognized for decades [12] With aging, many people experience progressive decrease in glomerular filtration rate and kidney blood flow, with wide variability among individuals [12]. Overall, a decline in GFR of approximately 8 ml/min per 1.73 m 2 per decade, starting between the ages of 30 and 40 years can be considered an average kidney function decline [13]. Decreased kidney function, defined as eGFR less than 60 mL/min/1.73 m 2 and urine albumin-to-creatinine ratio 1.1 mg/mmol (10 mg/g) or more, is an independent predictor of mortality risk in the general population [14].
Population studies have found an association between lower testosterone levels and reduced kidney function among men in general population [2,15] as well as increased CKD stages, even in younger men and middle-aged men [16]. Importantly, the Diabetes Prevention Program (DPP) Outcomes Study found that in 889 men with overweight and glucose-intolerance who underwent a follow-up period of 11 years, low testosterone is a risk factor for abnormal kidney markers, even after adjustment for multiple other risk factors for kidney disease [2].
Despite evidence showing that low testosterone is a risk factor for both NAFLD and reduced kidney function, two medical conditions that are becoming more and more common due to the epidemic of obesity and type 2 diabetes, the effects of testosterone therapy in men with hypogonadism on liver and kidney function have not been adequately studied.

What this study adds
A real-world evidence study was conducted in 505 men (mean age: 61 ± 10 years) with testosterone levels ≤350ng/dL (≤12.1nmol/L) and symptoms of hypogonadism, of whom 321 men received treatment with testosterone undecanoate injection every 12 weeks (following an initial 6-week interval), for up to 12 years (3,4). The remaining 184 men opted against testosterone therapy and served as the control group.
Testosterone therapy was temporarily discontinued for 17 months in 147 men in the testosterone group after 5.5 years, due to reimbursement issues, and re-started upon resolution of reimbursement issues.
Kidney function was assessed by measuring serum creatinine, urea, uric acid and glomerular filtration rate (GFR), while hepatic steatosis was assessed with the fatty liver index, a predictor of NAFLD, which is calculated by inputting values for waist size, BMI, triglyceride and gamma-glutamyl transferase [17]. The fatty liver index score ranges from zero to 100. Fatty liver index < 30 rules out fatty liver (negative likelihood) while a score of ≥ 60 indicates a high likelihood that fatty liver is present.
Results showed that men receiving testosterone therapy had a decrease in serum creatinine (1.14 to 1.07 mg/dL), uric acid (6.8 to 5.5 mg/dL), urea (47.5 to 31.7 mg/dL) and an increase in GFR (86.6 to 98.5 mL/min/1.73m2) over the study period. The reduction in uric acid was mirrored for serum urea, which decreased from 48 to 32 mg/dL (serum urea data were only available for the testosterone group). In contrast, men not receiving testosterone therapy had an increase in serum creatinine (0.99 to 1.13 mg/dL) and a decrease in GFR (90.8 to 87.0 mL/min/1.73m 2 ). There was a slight reduction in uric acid (5.7±1.5 to 5.2±1.5 mg/dL).
Men in the testosterone group had decreased fatty liver index (84 to 59), gamma-glutamyl transferase (39 to 25 U/L), bilirubin (1.64 to 1.21 mg/dL) and triglycerides (252 to 175 mg/dL) over 12 years. In contrast, men not receiving testosterone therapy had an increase in fatty liver index (69 to 81) gamma-glutamyl transferase (38 to 40 U/L), bilirubin (1.04 to 1.12 mg/dL) and triglycerides (196 to 244 mg/dL). ALT levels declined slightly in both groups. Between group difference in AST was at year 1 (p<0.0001), year 2 (p<0.005) and year 4 (p<0.005), with the testosterone group having lower levels.
Waist size and BMI decreased in the testosterone group (107 to 94 cm and 31 to 28 kg/m 2 ) and increased in the control group (100 to 105 cm and 29 to 31 kg/m 2 ).

Commentary
This is the first study showing that long-term treatment with testosterone undecanoate injection in men with hypogonadism has beneficial effects of on hepatic steatosis, liver function and kidney function, and is associated with reduced mortality [34]. Importantly, men with hypogonadism who did not receive testosterone therapy had a significant increase in fatty liver index and worsening of GFR.
An important observation was the worsening in parameters of both fatty liver and kidney function in testosterone treated men who had an interruption in testosterone therapy due to reimbursement issues, which then resumed improving when testosterone therapy was re-started upon resolution of reimbursement issues. This confirms previous findings showing that continuous testosterone therapy is required for achievement and maintenance of health benefits of testosterone therapy, as benefits disappear after discontinuation of testosterone therapy [18-24]. As pointed out in the British Society for Sexual Medicine guidelines on Adult Testosterone Deficiency, cessation of testosterone therapy results in reappearance of symptoms and reversal of benefits within 6 months, hence, testosterone therapy is likely required lifelong for persistent symptom resolution and maintenance of health benefits [25].
Previous randomized controlled trials of testosterone therapy have shown conflicting results on fatty liver. This could be due to small study sample, short testosterone treatment duration, different liver fat measurements and of different testosterone preparations (long-acting testosterone undecanoate injection vs. short-acting testosterone injection vs. gels) [26-30].
Available randomized controlled trials which showed that testosterone therapy reduces fatty liver used testosterone undecanoate injection [26,27]. The study presented above was conducted in a larger number of men who received treatment with testosterone undecanoate injection for up to 12 years, which is the longest reported follow-up. The finding that treatment with testosterone undecanoate injection resulted in a significant reduction in fatty liver index from 84 to 59, while men with hypogonadism not receiving testosterone treatment had a worsening of fatty liver index from 69 to 81, and the large difference in mortality among groups, is notable and congruent with data from other studies. A large-scale population-based study including over 3 million people For more information, see: Testosterone therapy for prevention and reversal of type 2 diabetes in men enrolled in a lifestyle program Remission of type 2 diabetes during long-term treatment with testosterone undecanoate injections Testosterone therapy in men with hypogonadism prevents progression from prediabetes to type 2 diabetes Most studies that have investigated hypogonadism and testosterone therapy in the context of kidney function focused on its association with morbidity and mortality in men with chronic kidney disease and end-stage kidney disease. The primary aim of these studies was to examine the effects of testosterone therapy in these patient populations on restoration of sexual function and improvements in metabolic parameters, lean muscle mass and mortality, and not parameters of kidney function [36,37]. Hence, the effect of testosterone therapy on kidney function is an understudied area. A large population study of US veterans, including 48,461 men, found that testosterone therapy resulted in a significant delay in progression of chronic kidney disease to endstage kidney disease, and prolonged survival time, corresponding to 25% reduced risk of mortality [38].
The study presented above is the first long-term study investigating the effect of testosterone therapy on kidney function, evaluated by GFR. The rapid reduction in uric acid observed in men receiving treatment with testosterone undecanoate injection, accompanied with an increase in GFR, suggests a direct beneficial effect of testosterone therapy on kidney function.
The reduction in myocardial infarction, stroke and mortality in the testosterone group confirms findings from previous studies [34,35.39] For more information, see: "Survival and cardiovascular events in men treated with testosterone" The significant reduction in fatty liver index and mortality seen in testosterone treated men compared to untreated men is a highly important finding, as there currently are no approved medications available for treatment of fatty liver disease.