Polycystic ovary syndrome, androgen excess, and the risk of nonalcoholic fatty liver disease in women: A longitudinal study based on a United Kingdom primary care database

Abstract

Background: Androgen excess is a defining feature of polycystic ovary syndrome (PCOS), which affects 10% of women and represents a lifelong metabolic disorder, with increased risk of type 2 diabetes, hypertension, and cardiovascular events. Previous studies have suggested an increased risk of nonalcoholic fatty liver disease (NAFLD) in individuals with PCOS and implicated androgen excess as a potential driver.

Methods and findings: We carried out a retrospective longitudinal cohort study utilizing a large primary care database in the United Kingdom, evaluating NAFLD rates in 63,120 women with PCOS and 121,064 age-, body mass index (BMI)-, and location-matched control women registered from January 2000 to May 2016. In 2 independent cohorts, we also determined the rate of NAFLD in women with a measurement of serum testosterone (n = 71,061) and sex hormone-binding globulin (SHBG; n = 49,625). We used multivariate Cox models to estimate the hazard ratio (HR) for NAFLD and found that women with PCOS had an increased rate of NAFLD (HR = 2.23, 95% CI 1.86-2.66, p < 0.001), also after adjusting for BMI or dysglycemia. Serum testosterone >3.0 nmol/L was associated with an increase in NAFLD (HR = 2.30, 95% CI 1.16-4.53, p = 0.017 for 3-3.49 nmol/L and HR = 2.40, 95% CI 1.24-4.66, p = 0.009 for >3.5 nmol/L). Mirroring this finding, SHBG <30 nmol/L was associated with increased NAFLD hazard (HR = 4.75, 95% CI 2.44-9.25, p < 0.001 for 20-29.99 nmol/L and HR = 4.98, 95% CI 2.45-10.11, p < 0.001 for <20 nmol/L). Limitations of this study include its retrospective nature, absence of detailed information on criteria used to diagnosis PCOS and NAFLD, and absence of data on laboratory assays used to measure serum androgens.

Conclusions: We found that women with PCOS have an increased rate of NAFLD. In addition to increased BMI and dysglycemia, androgen excess contributes to the development of NAFLD in women with PCOS. In women with PCOS-related androgen excess, systematic NAFLD screening should be considered.

Fig 1. Selection of patients with polycystic ovary syndrome (PCOS) and controls.

A total of 694 general practices were eligible for inclusion in the study, with a total of 2,706,062 women for the study period 2000–2016. A total of 64,787 women were listed as having PCOS according to the criteria defined in the “Methods” section. Controls were randomly matched to women with PCOS at a ratio of 2:1 within each practice, generating a random control cohort of 123,928 women. Participants with a documented history of alcohol excess were excluded; therefore, the final cohort consisted of 63,120 women with PCOS and 121,064 controls.

Fig 2. Impact of BMI and polycystic ovary syndrome (PCOS) on the hazard of nonalcoholic fatty liver disease (NAFLD).

PCOS and control groups were subcategorized into lean, overweight, and obese groups according to BMI, with lean control women designated as the reference category (unexposed, BMI <25 kg/m²). The analysis is adjusted for age, Townsend score of social deprivation, diabetes or impaired glucose regulation, and hypothyroidism at baseline. The hazard of NAFLD increased with BMI in both control women and women with PCOS. Lean women with PCOS had an almost 2-fold higher hazard of NAFLD compared to lean controls. The highest hazard of developing NAFLD was observed in the obese PCOS cohort.

Fig 3. Hazard of nonalcoholic fatty liver disease (NAFLD) according to serum testosterone and sex hormone-binding globulin (SHBG) levels.

(A) Serum testosterone (nmol/L) was available in 71,061 unselected women. Using women with testosterone levels below 1.0 nmol/L as a reference cohort, the hazard of NAFLD was 2.4-fold higher in those with serum testosterone levels of >3 nmol/l. (B) Serum SHBG was available in 49,625 unselected women. Using a reference cohort with SHBG levels of ≥60 nmol/L, the hazard of NAFLD was almost 5-fold elevated in patients with serum levels of <30 nmol/L. Both analyses are adjusted for age, Townsend score, diabetes or impaired glucose regulation, and hypothyroidism at baseline.