The Association of Sex Steroid Hormone Concentrations With Non-alcoholic Fatty Liver Disease and Liver Enzymes in US Men

Hong Phan; Aline Richard; Mariana Lazo; William G. Nelson; Samuel R. Denmeade; John Groopman; Norma Kanarek; Elizabeth A. Platz; Sabine Rohrmann


Liver International. 2021;41(2):300-310. 

In This Article

Abstract and Introduction


Background & Aims: This study aimed to analyse the association of sex hormone levels with liver enzyme levels and non-alcoholic fatty liver disease (NAFLD) in a nationally representative sample of men.

Methods: A total of 919 men from the US National Health and Nutrition Examination Study (NHANES) III were included in this cross-sectional analysis of data from 1988 to 1991. We used existing data on serum total and free testosterone, total and free estradiol, androstanediol glucuronide (AAG) and sex steroid-binding globulin (SHBG), and estimated their associations with aspartate aminotransferase (AST), and alanine aminotransferase (ALT) and NAFLD, as determined using ultrasound, after adjusting for possible confounders including age, race, smoking, alcohol, physical activity, waist circumference and steroid hormones.

Results: Lower total testosterone (TT) and higher free estradiol were associated with higher odds of NAFLD after adjusting for confounders including the other sex hormones. Lower TT was associated with higher odds of elevated AST, but not ALT. Free testosterone, total estradiol, SHBG and AAG were not associated with NAFLD or liver enzymes.

Conclusions: This study supports an inverse association between TT concentration and NAFLD in men independent of other sex hormones (SHBG, AAG and estradiol) and known risk factors, such as obesity, age and lifestyle. Exploration of whether TT might be a non-invasive marker for NAFLD diagnosis is warranted.


Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide. It has a prevalence in the United States of at least 21%,[1] which is increasing in parallel with the obesity and type 2 diabetes mellitus pandemic.[2] NAFLD was first described by Ludwig in 1980 on examination of histopathological liver biopsy specimens,[3] and was divided into two categories; (a) non-alcoholic fatty liver (NAFL) with hepatic steatosis ≥5% and mild non-specific inflammation (70%-75% of cases) and (b) non-alcoholic steatohepatitis (NASH) with histopathological features of hepatocellular injury (20%-25% of cases). NASH is described as the progressive type of NAFLD, with a reported 20% of patients going on to develop cirrhosis.[4] Since liver biopsy is invasive and not readily available, NAFLD diagnosis is usually made based on clinical history and non-invasive imaging suggesting the presence of hepatic steatosis, or elevated liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]), once that other causes of hepatic steatosis including excessive alcohol intake or specific medications, are excluded.[5] Ultrasound scan is able to detect the presence of fatty infiltration with high sensitivity when steatosis is greater than 30%.[4]

Mechanisms leading to hepatic steatosis are multifactorial.[6] An alteration in the balance between influx or synthesis of hepatic lipids and their export or oxidation leads to hepatic triglyceride accumulation. This leaves the liver susceptible to secondary insults leading to hepatocellular inflammation and fibrosis. In particular, hyperinsulinaemia drives hepatic triglyceride production by increasing serum free fatty acid levels, and promotes de novo hepatic lipogenesis through up-regulation of lipogenic transcription factors.

Since insulin resistance is a major risk factor for NAFLD, it is considered to be the hepatic manifestation of the metabolic syndrome. Obesity, male gender, Hispanic ethnicity and type 2 diabetes mellitus are all independent risk factors for NAFLD.[1] In addition, patients with NAFLD have higher mortality compared with similarly aged persons without NAFLD, with the most common cause of death being cardiovascular disease even after controlling for other metabolic risk factors.[7]

NAFLD is more common in men than in women,[8] and gender-related differences in liver disease can depend on circulating levels of sex hormones and hepatic expression of sex hormone receptors.[9] In a meta-analysis of five trials (n = 4715 men), higher total testosterone (TT) in men was associated with reduced odds of NAFLD, whereas the opposite relationship was seen in women (three trials, n = 1581 most postmenopausal women). Furthermore, higher sex hormone-binding globulin (SHBG) was associated with reduced odds of NAFLD in both men and women.[10] The relationship between other sex hormones and NAFLD is less well explored.

Case Report

We present the case of a 68-year-old white man with and prostate cancer with rising PSA levels and who was receiving androgen deprivation therapy (ADT) for 5 years. He had a history of diabetes (metformin), normal baseline HDL and LDL cholesterol, elevated triglycerides and social alcohol use. Weight was 105.8 kg and BMI was 30.8 kg/m2. The patient was enrolled in a clinical trial (NCT01084759), in which he received cyclic treatment with FDA-approved, high-dose testosterone (testosterone cypionate 400 mg intramuscularly every 28 days). Baseline CT scan was performed prior to starting testosterone and showed signs of a fatty liver compatible with NAFLD. After 3 months of treatment, a CT scan showed complete resolution of the fatty liver disease. Weight was 104.2 kg with BMI 30.3 kg/m2. After cessation of testosterone, the patient resumed ADT and had a follow-up CT scan after 3 months to assess disease response which showed that fatty liver had returned. After 2 years on ADT, the patient was re-exposed to a high-dose testosterone therapy for 3 months. A CT scan performed to assess disease response demonstrated prompt disappearance of fatty liver immediately after the start of the therapy (Figure 1).

Based on the results of this case report, we aimed to evaluate the association between circulating sex hormone levels and hepatic steatosis and elevated liver enzymes, three manifestations of NAFLD, in a nationally representative sample of non-institutionalized men from the Third National Health and Nutrition Examination Survey (NHANES III).