High Testosterone Levels Linked to Risk of NAFLD in Women

Study findings suggest that elevated levels of androgens even in younger women may offer a clue to patients at increased risk of developing nonalcoholic fatty liver disease.

with Jae-Min Park, MD, and Monika Sarkar, MD

The prevalence of nonalcoholic fatty liver disease (NAFLD) is estimated to climb to 63% between 2015 and 2030, rising in conjunction with the increase in obesity rates.1,2

There may be another reason for the rise in NAFLD specific to women. Results reported by researchers from Seoul, South Korea, suggest that elevated testosterone may be associated with increased risk of NAFLD in premenopausal women. In this study,3 high or even high-normal levels of serum testosterone indicated an elevated risk for NAFLD in women who had not yet gone through menopause.

Young women are at increased risk of NAFLD too.

Data Support NAFLD Development Among the Nonobese 

Jae-Min Park, MD, and colleagues from Yonsei University College of Medicine retrospectively reviewed medical records from 716 women who were 20 years and older. The investigators believed that the association between higher testosterone and NAFLD would vary by menopausal status, since testosterone levels decline in postmenopausal women. Thus, they sought to compare serum testosterone/NAFLD rates in pre- and postmenopausal women.3

Their results indicated a 28.1% overall prevalence of NAFLD in this cohort; in particular:  19.2% among premenopausal women and 33.3% among postmenopausal women. As anticipated, serum testosterone levels were significantly lower among the older, postmenopausal women (P < 0.001).3

After adjusting for factors such as age, exercise habits, type 2 diabetes, body mass index, and lipid levels including triglycerides, the odds ratio (OR) for NAFLD for each 1 nmol/L increment in serum testosterone level was 2.79 (1.11–7.08) for premenopausal women, conferring a positive association between higher testosterone and NAFLD risk. This association was not seen in the postmenopausal women after adjusting for the same covariables.3

Role of Testosterone as Risk Factor for NAFLD in Women

There is growing evidence of a relationship between androgen hormones and NAFLD risk, but this appears to differ according to sex. Among men, testosterone deficiency is associated with higher rates of NAFLD.4-6 In women, the data have been more conflicted but recent evidence suggests that elevated testosterone in younger, premenopausal women may portend higher NAFLD risk later in life.7

Results of the prospective population-based Coronary Artery Risk Development in Young Adults (CARDIA) Cohort trial,7 published in American Journal of Gastroenterology, support those of the Korean study. The findings, reported by Monika Sarkar, MD, associate professor of medicine at the University of California at San Francisco, and colleagues from centers across the US, reflected data analyzed from 1,052 women. The aim of this study was to assess whether free testosterone levels measured at year two (1987–1988) would be associated with more prevalence of NAFLD in patients 25 years later. 7

Increased free testosterone was associated with more prevalent NAFLD later in life, according to the findings, even after adjusting for covariables similar to those in the Park study (e.g., insulin resistance, body mass index).

The CARDIA authors concluded that "Increasing free testosterone is associated with prevalent NAFLD in middle age, even in women without androgen excess," adding that visceral adiposity appears to play an important role in this relationship.7

The study by Park et al differed in design as it was looking at the association of testosterone levels to current NAFLD diagnosis, rather than future onset of liver disease, said Dr. Sarkar.

"Our study measured testosterone levels in reproductive-aged women and evaluated the association of higher testosterone levels with a later, midlife diagnosis of NAFLD," she said. "It is unlikely that NAFLD was present at the time participants’ hormone measurements were taken. These women were otherwise healthy, without metabolic risk factors, and during a time period that predated the US obesity epidemic."

Although the CARDIA study was limited to free testosterone levels in premenopausal women, other studies have identified a "strong and independent association of increasing quartiles of testosterone with hepatic steatosis in postmenopausal women,"Dr. Sarkar told EndocrineWeb. "Testosterone is likely an important risk factor for NAFLD among women regardless of reproductive age."

Examining the Sex Differences of Visceral Obesity in NAFLD 

The mechanisms behind the way androgens promote hepatic steatosis in women is not clearly elucidated. One key factor may be the location of visceral adipose tissue (VAT), for example, its accumulation in the abdomen and around internal organs, which tends to be higher in middle-aged women and known to be a risk factor for NAFLD.9

"We don't know yet whether testosterone in women is associated with NAFLD independent of other metabolic derangements," Dr. Sarkar stated in an editorial in Journal of Women's Health that accompanied the Park paper.10

However, the Korean data support the theory that obesity is not the only factor raising the risk of NAFLD in women who have high testosterone. South Korea actually has one of the lowest global obesity rates, with only 4.7% of the population ranked as obese, in contrast to the US with 36.2% of the population considered having obese.11

"I think the strength of the study by Park et al is that—despite women being thinner in South Korea than in the US NAFLD cohorts—the finding of increased rates of NAFLD persist, highlighting the broader role that testosterone may play across metabolic phenotypes," Dr. Sarkar told EndocrineWeb.

"Testosterone may play a role in NAFLD development among a broader population of women, not just in those without an androgen excess," she said. "The additional contribution of the South Korean study is really to identify consistency in findings among Asian women, supporting the association of testosterone with NAFLD in women across racial groups."

Role of Androgens in Nonalcoholic Fatty Liver Disease 

So, what is the connection? Are androgen hormones a marker of metabolic dysfunction in women with visceral adiposity, or is testosterone an independent risk factor for NAFLD in young women? "I suspect it's a combination of both," Dr. Sarkar explained. "In the CARDIA cohort, we adjusted for comprehensive metabolic parameters such as insulin resistance, lipids, and visceral adiposity, as well as change in these metabolic parameters over time.7Thus, these data do support an independent role of testosterone on NAFLD risk in women.3

"However, we also identified an important 'mediating' effect of visceral fat," she added. "About 40% of the observed association between testosterone and NAFLD seems to be explained by higher levels of visceral fat. Thus, abdominal adiposity is an undeniable piece of the puzzle, yet does not entirely explain testosterone's role in the pathophysiology of NAFLD in women."

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Intensifying Clinical Imperative to Address NAFLD Risk Factors

There is a growing urgency to understand the risks associated with NAFLD progression and driving the development in women. Compared with men, women with NAFLD have higher rates of complications such as nonalcoholic steatohepatitis (NASH), soon to become the number one cause of liver-related deaths globally and a leading indication for liver transplant in the US.2,12,13

"In future studies, we should consider the impact that testosterone modulation may have on insulin resistance, dyslipidemia, and visceral adiposity. This may have far-reaching metabolic effects extending beyond the liver," Dr. Sarkar said.

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