A condition thought only to affect women may cause male-pattern baldness

Polycystic ovary syndrome — as the name suggests — is a disease typically associated only with women, but it is time to think again.

The syndrome, also known as the acronym PCOS, affects women’s menstrual cycles, plays havoc with hormone levels, and can make the metabolism go awry. PCOS symptoms can include irregular periods, oily skin, erroneous facial hair, and difficulty getting pregnant, as well as weight problems, diabetes, and even cardiovascular issues. It affects as many as 10 percent of women during their reproductive years, and although the symptoms can be treated, there is no cure and scientists know little about what drives the syndrome.

So little, in fact, that they may have got one critical aspect of PCOS entirely wrong: Despite the name, a version of the syndrome can affect men, too.

What’s new — For the first time, researchers show that the primary cause of polycystic ovary syndrome may not depend on the ovaries at all. That’s according to preliminary evidence presented on Tuesday at ENDO2021, the Endocrine Society's annual meeting.

By testing male relatives of women with the syndrome, scientists found a genetic component to the condition which, in men, can lead to male pattern baldness, risk of obesity, diabetes, and heart problems. The lead researcher on the study Jia Zhu, who is a doctor at Boston Children's Hospital, tells Inverse the new evidence prompts a rethink about everything scientists thought they knew about this “women’s disease.”

“This tells us that men can have a PCOS-like condition that we still need to better understand and define,” she says.

Why it matters — The findings suggest PCOS is actually not an ovary-derived syndrome. In turn, they pave the way for better research into what causes the condition, and may enable scientists to develop a wider array of treatments — and maybe even find a cure.

“Our study really provides genetic evidence that PCOS is more than a disorder of female reproduction and has long-term health implications beyond the reproductive years for both women and men,” Zhu says.

These findings help better define PCOS, demonstrating that it may not be a disorder of female reproduction after all, but rather a cardiometabolic condition, caused by the disruption of biological pathways common to both women and men, independently of the reproductive organs.

How they did it — Zhu and her team used genetic data gleaned from the UK Biobank, a British biomedical database replete with the genetic information of half a million people. From these data, they analyzed 176,360 men’s genetic susceptibility for PCOS. Then, the researchers drilled down into the 20 percent of men with the highest genetic risk for PCOS and found their risk correlated with increased genetic risk for obesity, diabetes, cardiovascular disease, and male-pattern baldness.

“When it comes to the metabolic — type-2 diabetes, obesity, and cardiovascular disease — and hyperandrogenic — male-pattern baldness — complications of PCOS, women and men may have more in common than we thought,” Zhu says.

“Hyperandrogenic” here refers to a defining feature of PCOS, “hyperandrogenism,” which means atypically high levels of androgen hormones, which play important roles in the development and maintenance of “male” characteristics. Testosterone, for example, is an androgen hormone. In females with PCOS, atypically high androgen-hormone levels most often manifest as excessive body hair (think facial hair, back hair, chest hair, and leg hair), or, conversely, thinning or even balding hair on the head.

This mirrors the effects of high androgen levels in men: High levels of testosterone, for example, are associated with head hair loss and “male-pattern baldness.”

“That’s why we considered male-pattern baldness as a hyperandrogenic feature of PCOS associated with genetic risk factors for PCOS in men,” Zhu explains.

What’s next — The findings are preliminary, which means they need to be confirmed in further research and peer-reviewed. But they hint there may be multiple different causes for PCOS, and that there may be many different biological mechanisms involved, according to Zhu. Further genetic studies could help tease out the individual differences and how different genes play into risk for PCOS, both in men and in women.

“Genetic susceptibility of PCOS had been described in both men and women. The pathology of the syndrome includes insulin and/or gonadotropin-androgen pathways,” Anis Rehman, who is a researcher at Southern Illinois University, explains to Inverse. Rehman was not involved in the new study.

“It is still too early to change the general public health screening guidelines to identify cardiovascular and metabolic diseases based on this study. However, the study does point out the importance of PCOS in female family members on male family members’ health,” Rehman says. In other words, if you are a bald man, and have female family members who have PCOS, the two conditions may be more related than you think.

Polycystic ovary syndrome is an endocrinopathy that two researchers named Stein and Leventhal initially described in 1935, Rehman says. In light of these new findings, it could prompt a rethink on whether we should rename PCOS the “Stein-Leventhal syndrome.”

Broadly, Zhu says, the new work offers a hint at the discoveries awaiting scientists who seek genetic explanations for health conditions. By investigating what causes PCOS in women, scientists could unlock the biology behind how hormones shape our physiology — whether we are male or female.

“We hope our findings provide additional support for focusing and targeting the metabolic complications of PCOS in clinical practice and research in both women and men on the long term,” Zhu says.

Abstract:

Background: Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects 6-10% of women of reproductive age. PCOS is often characterized by a triad of ovulatory dysfunction, hyperandrogenism, and cardiometabolic dysfunction. 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. Studies of male relatives of women with PCOS have proposed a male counterpart of PCOS, which suggests that PCOS is not always a primary disorder of female reproduction, but rather can be, at least in part, a condition of cardiometabolic dysregulation and hyperandrogenism, with ovarian dysfunction as a secondary consequence.

Methods: To investigate a genetically defined male counterpart of PCOS, we optimized a polygenic risk score (PRS) algorithm for predicting PCOS based on 206,851 unrelated women of European ancestry in the UK Biobank, then used this algorithm to calculate PCOS PRS for 176,360 men in the UK Biobank. We used logistic regression to calculate odds ratios for dichotomous outcomes by comparing men with high and low PRS (testing a variety of percentile cutoffs) and ANCOVA to compare continuous outcomes across deciles of PRS. All analyses were adjusted for age, age², assessment center, genotyping array, and the first 10 principal genetic components to account for ancestry.

Results: Men who carried a high PCOS PRS (top 20%) had a 17% increased risk of obesity defined as BMI ≥30 kg/m² (OR 1.17, 95% confidence interval [CI] 1.14-1.20, p=1.3x10^-30), 15% increased risk of type 2 diabetes mellitus (OR 1.15, 95% CI 1.09-1.20, p=5.3x10^-8), 5% increased risk of coronary artery disease (OR 1.05, 95% CI 1.01-1.09, p=0.03), and 5% increased risk for androgenic alopecia (OR 1.05, 95% CI 1.01-1.08, p=0.01). BMI, hemoglobin A1c, triglycerides, and the free androgen index all increased across deciles of the PRS, while HDL and SHBG decreased across PRS deciles (p all <0.001). The relationship between the PCOS PRS and coronary artery disease, HDL, and triglycerides appeared to be mediated by BMI. In contrast, the associations between the PCOS PRS and type 2 diabetes mellitus and hemoglobin A1c remained significant after adjusting for BMI, suggesting independent mechanisms of pathogenesis.

Conclusions: By demonstrating associations between PCOS genetic risk factors and cardiometabolic dysfunction and androgenic conditions in men, we have shown that these genetic risk factors can act independently of ovarian function. Thus, at least in some cases, the reproductive dysfunction of PCOS in women may arise secondarily from disruption of biological pathways common to both men and women. Future dissection of these biological pathways will further inform efforts to identify pathological mechanisms underlying PCOS.