Testosterone Levels in Women: Implications for Fatty Liver and Beyond

Nonalcoholic fatty liver disease (NAFLD) affects one quarter of individuals globally, with a prevalence that continues to rise. ^1,2 Considered to be the hepatic manifestation of the metabolic syndrome, its emergence as the most common liver disease reflects the high prevalence of visceral adiposity, dyslipidemia, and insulin resistance in the population. NAFLD encompasses a spectrum of liver pathology from isolated fat in the liver, to more serious inflammation with or without liver scarring, known as nonalcoholic steatohepatitis (NASH). The public health impact of this condition is vast, as NASH is now a leading cause of cirrhosis and liver cancer. ³

Although the pathogenesis of NAFLD/NASH is multifactorial, there is a growing body of literature highlighting the important contribution of testosterone to hepatic steatosis in women. ⁴ To date, most studies linking testosterone and NAFLD are based in cohorts of women with polycystic ovary syndrome (PCOS), an endocrinopathy typically marked by metabolic comorbidities and high androgen levels, such as testosterone. Women with PCOS are a specific high-risk group for NAFLD, ³ and testosterone has been shown to increase their risk of NAFLD, independent of obesity and insulin resistance. ⁵ The study by Park et al. ⁶ expands upon existing data by highlighting the association of testosterone and NAFLD even among women without “high” testosterone levels. Within a large cohort of Korean women without androgen excess, these authors demonstrate a >2.5-fold higher odds of ultrasound-diagnosed NAFLD, per unit increase in log testosterone levels. Although free, or biologically active, testosterone levels were not evaluated, their findings do mirror previously published data within the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, in which increasing levels of free testosterone in premenopausal women were associated with prevalent NAFLD in midlife, including among women without androgen excess. ⁷

As testosterone promotes other metabolic derangements in women, it may come as no surprise that testosterone is associated with NAFLD. For example, diabetes is one of the strongest risk factors for NAFLD, and large-scale epidemiological data demonstrate increased risk of diabetes with higher testosterone levels in women. ⁸ Within postmenopausal women, administration of synthetic testosterone increases visceral adiposity. ⁹ In contrast to the current study, data from other cohorts have also identified an association between testosterone and NAFLD that extends to the postmenopausal population. ¹⁰ Testosterone has been further shown to directly regulate lipid metabolism within visceral and subcutaneous adipocytes in women. ¹¹ These findings align with clinical data from the CARDIA cohort in which visceral adiposity and, to a lesser degree, hypertriglyceridemia were identified as significant mediators of the association between testosterone and NAFLD in women, ⁷ supporting their potential role along the causal pathway.

Whether testosterone may represent a novel target for NAFLD therapeutics warrants consideration, particularly given the limited therapeutic options for this condition. Spironolactone, a competitive inhibitor of testosterone receptors, is commonly used to treat symptoms of high testosterone in women with PCOS. In hyperandrogenic women, insulin resistance has been shown to improve with spironolactone, ¹² and this agent improves glucose uptake in human adipocytes. ¹³ Short-course spironolactone trials have also demonstrated decreased visceral adiposity in patients with hyperaldosteronism ¹⁴ as well as decreased serum free fatty acids in women with PCOS. ¹⁵ In patients with biopsy-proven NAFLD, a recent randomized controlled trial found 52 weeks of vitamin E plus spironolactone to improve markers of hepatic steatosis and insulin resistance as compared with vitamin E alone. ¹⁶ Whether testosterone, or testosterone modulation, could affect NASH severity or progression remains to be studied.

In summary, testosterone must be considered in future studies of NAFLD, as well as broader research priorities addressing the long-term implications of metabolic disease in women. Androgens should be further considered in therapeutic studies in women, as testosterone modulation may have farther reaching metabolic effects on insulin resistance, dyslipidemia, and visceral adiposity with benefits that extend from liver health and beyond.