Clinical Impact of Sexual Dimorphism in Non-alcoholic Fatty Liver Disease (NAFLD) and Non-alcoholic Steatohepatitis (NASH)

Patrizia Burra; Debora Bizzaro; Anna Gonta; Sarah Shalaby; Martina Gambato; Maria Cristina Morelli; Silvia Trapani; Annarosa Floreani; Fabio Marra; Maurizia Rossana Brunetto; Gloria Taliani; Erica Villa


Liver International. 2021;41(8):1713-173. 

In This Article

Pharmacological Treatment for NASH

Despite the high prevalence of NAFLD worldwide, currently there is no effective pharmacological treatment for NAFLD/NASH. The current therapies mainly focus on metabolic disorders associated with NAFLD.[152]

Regardless the clear sexual dimorphism of NAFLD/NASH, very few studies on possible therapeutic strategies deal with sex differences or consider natural age-related hormone fluctuations as a disease-modifying factor. A recent Chinese study has found pioglitazone to be more efficient in reducing liver fat content in NAFLD female than in male diabetic patients.[153]

A phase 2b study on MK-3655 (an insulin sensitizer) in pre-cirrhotic NASH is currently recruiting men and post-menopausal women (NCT04583423). Whether this patient selection will lead to the evaluation of sex-specific outcomes is not reported.

Most of the sex-specific studies on NAFLD therapy are targeted at sex hormones supplementation or inhibition; meanwhile, data on sex- and age-specific response to drugs in phase 3 trials are lacking (Table 2).

Potential Sex-specific Therapy

Oestrogen. Experimental data suggest that oestrogen is involved in the pathogenesis of the disease.[38,41] Oestrogen therapy in liver disease, besides improving several clinical conditions associated with menopause,[154] has demonstrated a protective effect on NAFLD in patients with diabetes.[44,155,156] One of these studies demonstrated that post-menopausal women receiving oestrogen and medroxyprogesterone showed a lower risk of diabetes.[155] Oestrogen therapy reduced the serum levels of IL-6, ALT, AST and ALP in post-menopausal women with T2DM.[156] In a study by Hamaguchi et al, the incidence of NAFLD in women taking HRT was higher than in pre-menopausal women, but lower than in menopausal women. HRT was not associated with increased risk of incident NAFLD.[15]

Since diabetes is a well-known risk factor for NAFLD/NASH,[157] and clinical trials using oestrogen therapy in diabetes suggest that this treatment reduces the risk of NAFLD/NASH in post-menopausal women.[158]

The extension of oestrogen therapy to male NAFLD/NASH patients is still in preclinical phase.[159,160]

Testosterone. As far as can be deduced from the available data, testosterone seems to have opposite effect on liver steatosis in men and women.

Most data on the effects of testosterone on NASH in women derive from populations affected by polycystic ovary syndrome (PCOS), in whom high testosterone increases the risk of NAFLD independently of obesity and insulin resistance.[161]

Women with hyperandrogenic PCOS have more severe hepatic steatosis as compared to the less common PCOS phenotype marked by normal androgens.[162]

The influence of high testosterone on NAFLD seems to be true for adult females regardless of age. In general, testosterone peak is reached in late adolescence and declines gradually over the next two decades, but remains stable across menopause and beyond.[163]

Pre-menopausal Women. A recent study on 207 pre-menopausal women with biopsy-confirmed NAFLD has found a more than two-fold higher risk of NASH, as well as NASH fibrosis, with increasing quartiles of free testosterone in women aged 22–27.[164]

A study by Park JP et al have found a positive association between serum testosterone level and US-diagnosed NAFLD in pre-menopausal, but not in post-menopausal women.[165]

CARDIA cohort data on young women aged 18–30 years upon enrolment showed that increasing quintiles of free testosterone were associated with prevalent NAFLD at 25 years of follow-up. Of note, this association persisted among women without androgen excess. This study utilized a computed tomography (CT) quantification of hepatic steatosis.[166]

Post-menopausal Women. In a study on a small group of post-menopausal women with biopsy-proven NAFLD, the NAFLD group had higher values of calculated Free Testosterone (cFT), bioavailable testosterone and Free Androgen Index (FAI), despite exhibiting similar to control levels of serum total testosterone. Serum sex hormone-binding globulin levels, bioavailable testosterone and FAI, but not cFT, were associated with NAFLD independently of age, body mass index and waist circumference.[167]

On the basis of a cross-sectional analysis using data from the Multi-ethnic Study of Atherosclerosis, post-menopausal women with high levels of bioavailable testosterone are at greater risk for fatty liver.[168]

Androgen-blocking Drugs. A competitive inhibitor of testosterone receptors, Spironolactone has shown good safety profile and tolerability in the treatment of hyperandrogenism symptoms. A recent trial in patients with histologically proved NAFLD found spironolactone plus vitamin E to improve markers of hepatic steatosis and insulin resistance as compared to vitamin E alone.[169]

Spironolactone is being evaluated in a pilot study (NCT03576755) in women of childbearing age (18–45 years) with NASH, to better understand the role of androgens in NASH.

Testosterone in Men. In men, lower testosterone levels are associated with imaging-confirmed NAFLD.[170] In a recent biopsy-proven NASH/NAFLD study,[171] men with low testosterone were more likely to have NASH with advanced fibrosis versus NAFLD.

A currently recruiting phase 2 study in adult men with biopsy confirmed that NASH (NCT04134091) is aimed at evaluating efficacy and tolerability of LPCN 1144, an oral prodrug of bioidentical testosterone.