PCOS in men? Genetic study uncovers disease pathways common to both sexes

Genetic risk factors of polycystic ovary syndrome (PCOS) also induce a similar condition in men, suggesting that PCOS is not always and necessarily a disorder of women’s reproductive systems, according to a new study presented at the recently concluded ENDO 2021 virtual conference by the Endocrine Society.

“By demonstrating that genetic risk factors for PCOS are associated with obesity, diabetes and cardiovascular disease, and male-pattern baldness in men, we show that these genetic risk factors do not require ovaries to result in the characteristics of PCOS,” said Jia Zhu, MD, of the Boston Children’s Hospital and lead researcher of the present study.

Using genetic data from 206,851 unrelated women from the UK Biobank, the research team optimized a polygenic risk score (PRS) algorithm for predicting PCOS, and subsequently tested it on 176,360 men, also from the UK Biobank, controlling for potential confounders.

In addition, researchers also tested for associations with male-pattern baldness and metabolic disorders, such as obesity, diabetes, and cardiovascular diseases.

They found that genetic susceptibility for PCOS correlated significantly with metabolic dysfunction in men. Those who were in the top 20 percent of PCOS PRS, for example, were 17 percent more likely to have obesity, defined as body mass index (BMI) ≥30 kg/m² (odds ratio [OR], 1.17, 95 percent confidence interval [CI], 1.14–1.20; p=1.3×10^–30). [ENDO 2021, abstract OR17-3]

Similarly, high PCOS PRS increased the risk of type 2 diabetes in men by 15 percent (OR, 1.15, 95 percent CI, 1.09–1.20; p=5.3×10^–8), and of coronary artery disease by 5 percent (OR, 1.05, 95 percent CI, 1.01–1.09; p=0.03). Androgenic alopecia was also 5-percent more likely to develop in men who were genetically predisposed to PCOS (OR, 1.05, 95 percent CI, 1.01–1.08; p=0.01).

BMI appeared to mediate the association between PCOS PRS and coronary artery disease; on the other hand, controlling for BMI did not attenuate the link between PCOS PRS and type 2 diabetes mellitus and haemoglobin A1c, indicating that their interactions were through independent mechanisms.

The researchers also saw that BMI, free androgen index, as well as levels of triglycerides and haemoglobin A1c increased across deciles of PCOS PRS, while concentrations high-density lipoprotein cholesterol and sex hormone binding globulin decreased (p<0.001 for all).

“The treatment of PCOS is limited by our incomplete understanding of the disorder,” said Zhu. “Identifying the different causes for PCOS provides insights into the mechanisms of disease and is the first step in identifying future targets for treatment of the disorder.”

Commonly presenting as irregular menstruation, hyperandrogenism, and cardiometabolic dysfunction, PCOS affects up to 10 percent of women of reproductive age. PCOS can lead to life-long conditions such as obesity, diabetes, and cardiometabolic disease.

Both ovarian-dependent and -independent factors have been implicated in the condition, and there is a need to determine the inciting events and the secondary events. The present study suggests that PCOS may be primarily a disorder of cardiometabolic dysregulation and hyperandrogenism, and that ovarian dysfunction may be a secondary manifestation.

“Thus, at least in some cases, the reproductive dysfunction of PCOS may be caused by biological mechanisms common to both men and women. Future studies of the genetic risk factors for PCOS could help us to better understand the causes and potential treatment targets for PCOS,” said Zhu.