Is PCOS an equal opportunity pathology?

Men don’t have ovaries. Fact. So, they can’t be affected by polycystic ovary syndrome, right? Well, not necessarily. Oddly enough, this is more of a moot point than might be expected from the logic of the two sentences above! In fact, the concept of there being a male version of PCOS was first proposed more than 15 years ago¹. Now, a new study from Boston Children’s Hospital/Harvard Medical School, USA presented at the recent Endo 2021 virtual congress has substantiated the hypothesis².

The Boston researchers were able to demonstrate a high rate of cardiometabolic dysfunction associated with androgenic conditions in men with a high polygenic PCOS risk score. Professor Jia Zhu, a Fellow in Clinical Endocrinology and Lead Investigator at Boston Children’s Hospital said, “We have shown that these genetic risk factors can act independently of ovarian function.”

How?

PCOS affects about 10% of women. It is characterised by ovulatory dysfunction, hyperandrogenism, insulin resistance, obesity, and raised cardiovascular risk factors. Genetics seems to play an important part because familial clustering is evident. However, the relationship between metabolic and ovulatory dysfunction in PCOS isn’t completely understood.

Professor Zhu said, “Both ovarian-related and ovarian-independent factors have been implicated in the pathogenesis of PCOS. But it remains to be determined which are the inciting events and which are the secondary consequences.” In his study, a polygenic risk score algorithm developed to predict PCOS in women was applied to men. The risk score was developed through genetic testing in 206,851 unrelated women in the UK Biobank. The algorithm was then simply applied to stratify risk in 176,360 men from the same biobank.

The comparative data was stratified into quintiles and deciles, revealing that:

• Those at highest risk, relative to those at lower risk, had numerically modest but highly significant increased odds ratio for obesity as defined by Body Mass Index (BMI): OR, 1.17; P < 0.13 x 10^–29
• Highest risk men also had significantly increased odds ratio for type 2 diabetes: OR, 1.15; P = 0.53 x 10^–7)
• Those in the highest risk group were also more likely to have coronary artery disease: Hazard Ratio, 1.05; P = .01
• Androgenic alopecia was also more prevalent in these men: OR, 1.05; P = .03.

Likewise, a stepwise increase, in terms of deciles was observed for the spread of cardiovascular risk factors. These included hemoglobin A1c, triglycerides, BMI and free androgen.

Interestingly, the relationship between the risk scores and both coronary artery disease and several dyslipidemias appeared to be mediated by BMI, but the relationship between the PCOS polygenic risk score and type 2 diabetes persisted even after adjusting for BMI.

PCOS not necessarily derived from ovaries

The findings suggest PCOS is actually not an ovary-derived syndrome and paves the way for better research into what causes the condition. Professor Zhu concluded, “Although the name polycystic ovary syndrome implies that the ovaries play a central role in the disorder, PCOS may not always be primarily a disorder of the female reproductive system. Our findings shed light on the significant and often lifelong associated metabolic conditions such as obesity, type 2 diabetes, CVD that affect women long beyond the reproductive years and that can also affect men who carry genetic risk factors for PCOS. Future studies on the mechanisms and treatment targets of the metabolic dysfunction associated with PCOS may benefit both men and women.”