Hyperandrogenism Linked to Increased Risk of MASLD in PCOS

Alex Henney, MBChB

Credit: Alex Henney on LinkedIn

Patients with polycystic ovary syndrome (PCOS) may face an increased risk of metabolic and cardiovascular disease, according to findings from a recent study.¹

Results showed a previous PCOS diagnosis significantly increased the risk of type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and cardiovascular disease, additionally calling attention to a greater prevalence of hepatic steatosis and hepatic fibro-inflammation in patients with PCOS based on abdominal MRI. Of note, risk varied by PCOS phenotype.¹

According to the World Health Organization, PCOS affects an estimated 8–13% of reproductive-aged women and represents one of the most common hormonal disturbances impacting women in this age group. Known complications of PCOS include infertility, MASH, metabolic syndrome, type 2 diabetes, sleep apnea, and endometrial cancer, underscoring its effect on both physical and emotional well-being.^2,3

“To date, limited prospective studies in women with PCOS analyze longer-term health consequences, extending into the post-menopausal period, contributing to heterogeneity in study findings,” Alex Henney, MBChB, an academic foundation doctor at Liverpool University Hospitals NHS Foundation Trust, and colleagues wrote.¹ “Additionally, in an era of precision medicine, disease phenotyping can differentiate between PCOS phenotypes, but no large studies have explored disease associations whilst attempting to provide mechanistic insights."

To determine the risk of metabolic disease, cardiovascular disease, related cancers, and dementia in patients with PCOS and explore potential differences by phenotype, investigators examined UK Biobank data for patients with a previous PCOS diagnosis at baseline and compared the incidence of each condition to an age- and BMI-matched cohort of healthy controls. PCOS was defined using an ICD-9/10 code or a doctor-verified self-reported diagnosis, additionally including patients with clinical codes and/or biochemical features of both hyperandrogenism and secondary amenorrhoea/oligomenorrhoea without other coding for PCOS. The control group, not known to have PCOS, was matched for age and BMI in a 5:1 ratio with cases.¹

The baseline prevalence of metabolic disease, cardiovascular disease, cancer, and dementia was assessed. Investigators then analyzed follow-up data to determine the time to incident type 2 diabetes, cardiovascular disease, cancer, and dementia, with any participant who reported the outcome of interest at baseline excluded from prospective analysis. They also compared multi-organ MRI data and examined the impact of PCOS phenotype on these outcomes.¹

Of the 502,516 volunteers with UK Biobank data, 6025 participants were analyzed in the present study: 1008 with a diagnosis of PCOS and 5017 matched controls. Investigators observed a greater prevalence of type 2 diabetes (7.3 vs 4%), hypertension (26.6 vs 19.0 %), hepatocellular carcinoma (0.1 vs 0.0%), and depression/anxiety (16.2 vs 11.3%) in participants with PCOS compared with controls. However, the prevalence of hormone-dependent or pancreatic cancer, other cardiovascular diseases, and dementia did not differ between the groups.¹

Further analysis revealed participants with PCOS had greater incident type 2 diabetes (Hazard ratio [HR], 1.47; 95% CI, 1.11-1.95) and all-cause cardiovascular disease (HR, 1.76; 95% CI, 1.35-2.30). Although univariate analysis revealed a significant association between PCOS and incident all-cause hormone-dependent cancer (HR, 1.37; 95% CI, 1.03-1.82), it was no longer significant after full multivariable adjustment. Additionally, univariate analysis revealed no significant association between PCOS and all-cause dementia (HR, 1.16; 95% CI, 0.48-2.81), remaining insignificant after full multivariable adjustment (HR, 0.96; 95% CI, 0.32-2.89).¹

Liver MRI confirmed more participants with PCOS had hepatic steatosis, defined as proton density fat fraction >5.5% (35.9% vs 23.9%; P = .02), and greater fibro-inflammation (721.4 vs 701.5ms; P <.01), compared with controls. However, no between-group differences existed for cardiac (bi-ventricular/atrial structure and function) or brain (grey and white matter volumes) imaging.¹

Investigators then stratified participants with PCOS into 2 phenotypes based on androgen level: hyperandrogenic and normoandrogenic, with hyperandrogenism defined as a Free Androgen Index >5%; 100×[testosterone concentration (nmol/liter)/sex hormone binding globulin concentration (nmol/liter)].¹

Of the 6025 participants originally included, 142 were identified as having hyperandrogenic PCOS and 617 were identified as having normoandrogenic PCOS, with 3775 controls additionally included in the subgroup analysis. Findings showed participants with normoandrogenic PCOS had greater incident all-cause cardiovascular disease (HR, 1.82; 95% CI, 1.29-2.56) while participants with hyperandrogenic PCOS were more likely to have hepatic steatosis (8.96 vs 6.04 vs 5.23%; P = .03) with greater fibro-inflammation (776.3 vs 707.7 vs 701.9 ms; P <.01).¹

Investigators acknowledged multiple limitations to these findings, including the lack of transvaginal ultrasound imaging data; the potential for diagnostic misclassifications and residual confounding/reporting bias; and the underpowering of some study findings.¹

“In summary, we highlight that people with PCOS are at an increased risk of metabolic and cardiovascular disease, with a potential divergence of risk according to PCOS phenotype,” investigators concluded.¹ “We note hyperandrogenism may confer opposing metabolic and cardiovascular effects, with a potentially amplified risk of MASLD despite lower risk of cardiovascular disease. These results suggest more precise phenotype classification may benefit ongoing risk stratification for patients with PCOS.”

References

1. ^{Henney AE, Gillespie CS, Lai JYM, et al. Risk of type 2 diabetes, MASLD and cardiovascular disease in people living with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. https://doi.org/10.1210/clinem/dgae481}
2. ^{World Health Organization. Polycystic ovary syndrome. Newsroom. June 28, 2023. Accessed July 16, 2024. https://www.who.int/news-room/fact-sheets/detail/polycystic-ovary-syndrome}
3. ^{Mayo Clinic. Polycystic ovary syndrome (PCOS). Diseases & Conditions. September 8, 2022. Accessed July 16, 2024. https://www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439}