Unbiased Condition: Why Some Men Appear to Have Polycystic Ovary Syndrome

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It is believed that polycystic ovary syndrome (PCOS) can impact up to 10% of women but according to new genetic research presented in March at ENDO 2021, it can manifest in men as well. Endocrine News talks to the lead researcher, Jia Zhu, MD, about this somewhat surprising revelation as well as how this study could eventually lead to better treatment options for all patients with PCOS.

The Endocrine Society’s annual meetings always bring new, interesting, and even groundbreaking medical science to the endocrinology community and beyond, and while ENDO 2021 was all virtual due to the continued COVID-19 pandemic, this year’s annual meeting was no exception. But as with the best of science, answers often bring up more questions.

For instance, polycystic ovary syndrome (PCOS), a heterogenous condition that affects up to 10% of women of reproductive age, has been studied extensively, through physiological and genetic studies, yet the medical community still does not fully grasp what causes PCOS. Now, genetic research presented at ENDO 2021 suggests men can develop characteristics of PCOS as well. Since men obviously do not have ovaries, these findings point to the fact that PCOS may not depend on the ovaries at all. Again, more questions — and ones that need to be addressed if treatment options are to advance, since the disorder can lead to obesity, diabetes, and cardiovascular disease.

“We know ovarian-related factors and ovarian-independent factors both play a role, but we don’t know which are the inciting factors, which are the secondary consequences, or how they are connected or influence each other. As a result, the current treatment options for PCOS are limited to management of the symptoms without addressing the underlying causes. The sooner we understand what causes PCOS, the sooner we can develop targeted therapies for PCOS and its counterpart in men.” –  Jia Zhu, MD, attending physician, Division of Endocrinology, Boston Children’s Hospital, Boston, Mass.

“We know ovarian-related factors and ovarian-independent factors both play a role, but we don’t know which are the inciting factors, which are the secondary consequences, or how they are connected or influence each other,” says lead researcher Jia Zhu, MD, of Boston Children’s Hospital. “As a result, the current treatment options for PCOS are limited to management of the symptoms without addressing the underlying causes. The sooner we understand what causes PCOS, the sooner we can develop targeted therapies for PCOS and its counterpart in men.”

Typical and Surprising Comorbidities

For this study, Zhu and her team used genetic data from 176,360 men in the United Kingdom and used genetic data to calculate a polygenic risk score (PRS), which uses data from across the genome to estimate genetic susceptibility for PCOS . They tested for associations with metabolic disorders (obesity, diabetes, and cardiovascular disease) and male-pattern baldness.

The researchers found that men who had a high genetic risk score for PCOS had increased risk of obesity, diabetes, cardiovascular disease and male-pattern baldness. The authors write that the relationship between the PCOS PRS and cardiovascular disease appeared to be mediated by obesity, as assessed by body mass index (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,” they write.

Zhu explains that one strength of the study was its population size. According to Zhu, to get a better understand the genetics of complex and common disorders, such as PCOS, it is critical to have a large sample of individuals who can be assessed for even modest effects of genetic factors, as well as individuals who represent a general population so the findings can be applied to the population. “The UK Biobank is a tremendously valuable resource to the scientific community and provides a large, population-based cohort to conduct large-scale genomic studies, such as ours,” she says.

“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 features associated with PCOS,” Zhu says. “Thus, at least in some cases, the reproductive dysfunction of PCOS may be caused by biological mechanisms common to both men and women.”

Familial Traits

The concept of “male PCOS” was proposed 15 years ago, but it remains elusive, and there is no formal clinical definition. Male relatives of women with PCOS can also have features associated with PCOS, including obesity, type 2 diabetes, cardiovascular disease, and hyperandrogenism (high levels of androgen hormones such as testosterone). “We already knew from clinical observations that male relatives of women with PCOS had features associated with PCOS, likely because they shared genetic material with their female relatives,” Zhu says.

“Because men do not have ovaries yet can have these features associated with PCOS in women, our work reconceptualizes PCOS as more than a disorder of female reproductive function, but rather a cardiometabolic condition that affects both sexes. Future studies of the genetic risk factors for PCOS could help us to better understand the causes and potential treatment targets for PCOS.” – Jia Zhu, MD, attending physician, Division of Endocrinology, Boston Children’s Hospital, Boston, Mass.

In that case, Zhu says she and her team hypothesized and expected to find that genetic risk factors for PCOS would lead to increased risk for these disorders, which they confirmed. “What was particularly interesting to us was the fact that obesity had a major role in mediating these associations between polygenic risk for PCOS and all outcomes,” she says. “This finding really highlights the major role obesity has in PCOS and its associated comorbidities and provides additional validation that targeting obesity (and its biological pathways) is critical to the management and treatment of PCOS.”

Dissecting the Biology of PCOS

There is still much to learn about the genetics and underlying biology of PCOS. The ultimate goal is to improve the management and treatment of PCOS for women and the PCOS-like condition in men. Zhu says that clinicians are not quite to the point of being able to use genetic tools like polygenic risk scores in clinical practice to predict risk for the associated features of PCOS. “Until then, we can use these tools to dissect the biology of PCOS as a starting point for future clinical and genetic studies that will continue to pave the way for individualized care for patients with PCOS, including future genetic screening,” she says.

“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 features associated with PCOS. Thus, at least in some cases, the reproductive dysfunction of PCOS may be caused by biological mechanisms common to both men and women.” – Jia Zhu, MD, attending physician, Division of Endocrinology, Boston Children’s Hospital, Boston, Mass.

No doubt, more questions will follow and will likely open up more avenues to pursue. Questions like: In women, is there a subtype of PCOS that depends on the ovaries and another subtype that does not? How are the non-ovarian and ovarian pathways in PCOS connected, if at all? Is there a counterpart to the ovaries in men that contribute to the features of PCOS seen in men? How can we incorporate this information into clinical care? Should more interventions and therapeutics target cardiometabolic health for PCOS?

In the conclusion to their ENDO 2021 presentation abstract, the authors write, “Future dissection of these biological pathways will further inform efforts to identify pathological mechanisms underlying PCOS.”

For now, Zhu says she hopes this study will be a kind of lodestar for that work, since clinicians and scientists have expressed interest in this novel genetic approach to validating and characterizing the existence of a male counterpart to PCOS. “Because men do not have ovaries yet can have these features associated with PCOS in women, our work reconceptualizes PCOS as more than a disorder of female reproductive function, but rather a cardiometabolic condition that affects both sexes,” she says. “Future studies of the genetic risk factors for PCOS could help us to better understand the causes and potential treatment targets for PCOS.”

Bagley is the senior editor of Endocrine News. In the July issue, he wrote the CEU 2021 preview article about the session that details what endocrinologists need to know about fatty liver disease.

 

 

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