Research Article: 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

Date Published: March 28, 2018

Publisher: Public Library of Science

Author(s): Balachandran Kumarendran, Michael W. O’Reilly, Konstantinos N. Manolopoulos, Konstantinos A. Toulis, Krishna M. Gokhale, Alice J. Sitch, Chandrika N. Wijeyaratne, Arri Coomarasamy, Wiebke Arlt, Krishnarajah Nirantharakumar, Jenny E Myers

Abstract: BackgroundAndrogen 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 findingsWe 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.ConclusionsWe 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.

Partial Text: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age, affecting 6%–10% of women worldwide [1]. Diagnostic criteria include the presence of androgen excess, oligomenorrhea, and evidence of polycystic ovaries (PCO) on ultrasound [2]. Though conventionally perceived as a reproductive disorder, PCOS is now emerging as a lifelong metabolic disorder, with evidence of increased prevalence of obesity, insulin resistance, and metabolic syndrome [3]. However, the metabolic disease burden in patients with PCOS exceeds that observed in simple obesity [4]. Androgen excess has been implicated as a distinct risk factor, with several studies showing circulating androgen burden to correlate closely with surrogate markers of metabolic risk, independent of body mass index (BMI) [5–7].

The study followed the preanalysis study plan (S1 Text) and is reported as per Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines (S2 Text).

The results of this study provide, to our knowledge, the most conclusive evidence to date that women with PCOS have an increased rate of NAFLD above that conferred by simple obesity. A previous meta-analysis of 7 studies with a combined sample size of less than 600 patients suggested an almost 4-fold increase in the risk of NAFLD in women with PCOS compared with matched controls [13]. A very recent meta-analysis that combined data of 2,700 patients from 17 studies found a 2.5-fold increased risk of NAFLD in women with PCOS compared with age- and BMI-matched controls [19]. To our knowledge, our population-based longitudinal cohort study is the first longitudinal and by far the largest study to examine the association between PCOS and NAFLD, analyzing over 63,000 women with PCOS against 121,000 matched controls. A diagnosis of PCOS was consistently associated with a 2.0–2.4-fold increase in rate of NAFLD in multiple adjusted analyses, and this increased hazard persisted even when restricting to patients with PCOS. Intriguingly, even women with PCOS with a normal BMI had a significantly increased rate of NAFLD.



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