Could hyperandrogenism in PCOS be cardioprotective?
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No, women with higher androgens have increased CV risk.
The hyperandrogenic phenotype of polycystic ovary syndrome is the one most closely related to the things we think are “bad” for cardiovascular disease — obesity, insulin resistance — and those seem to be the driving factors of CVD risk. We also see examples of elevated CV risk in the setting of higher androgen levels in postmenopausal women and transgender men prescribed gender-affirming hormone therapy.
At the time of the menopause transition, there is the abrupt cessation of estradiol, but the postmenopausal ovary can still make testosterone for more than a decade out. We previously published research showing postmenopausal women with higher testosterone levels relative to their estradiol levels were more likely to have incident CV events over the next 12 years, even after we adjust for risk factors, including diabetes.
Additionally, postmenopausal women with higher androgens had more coronary artery calcium progression, more atherosclerosis, worse endothelial function and increased cardiac hypertrophy on serial MRIs. Higher androgen levels were associated with this worse CV phenotype. Many of these women are unidentified because we do not routinely measure sex hormones after menopause.
We also see this in the transgender community. If you give testosterone to transgender men, that can lead to insulin resistance and higher blood pressure. Transgender men receiving gender-affirming HT tend to have worse endothelial dysfunction and more of a metabolic syndrome pattern.
Studies also suggest women with PCOS with higher levels of androgens have more microvascular endothelial dysfunction. The problem is, for older women, we are identifying them by their traditional risk factors, so that is what is being captured.
Every woman benefits from lifestyle intervention as a foundational approach. Healthy diet, preventing weight gain or normalizing weight can mitigate risk. BMI may be a mediating factor between PCOS, diabetes and CVD risk. Certainly, assess a woman’s risk. If they already have elevated CV risk, treat with statins. If aged 40 years or older, get a coronary artery calcium score. If BP is elevated, treat based on BP guidelines. We need to make sure these women are screened. Measure their HbA1c, glucose, BP, lipids. We must focus our prevention on these cardiometabolic complications and prevention of type 2 diabetes.
Erin D. Michos, MD, MHS, is associate professor of medicine and director of women’s cardiovascular health at the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease.
It is possible something about PCOS is protective against CVD.
We know that in the premenopausal years, women with PCOS have increased levels of markers for inflammation, metabolic dysfunction and other factors suggesting increased risk for CV events, such as myocardial infarction. In the premenopausal years, these factors in PCOS are associated with increased risks for stroke, hypertension, diabetes and glucose intolerance. The question is, do we also observe an increased risk for CVD events? The data so far have been unclear.
Increased CVD risk in PCOS during premenopause is difficult to measure because events are low overall. As women with PCOS age, even if they have an increased risk for CVD events, it is possible this risk is obscured by the relatively much larger increased risk provided by age, especially if the risk provided by PCOS is modest. This does not mean there is no increased CVD risk in PCOS; rather, we may not be able to readily measure it in small studies.
Are there things that could protect the cardiovascular system against damage in PCOS? Possibly. We should note that the levels of inflammation, insulin resistance, hyperinsulinemia and other markers of metabolic challenge are quite high in PCOS. Yet, we do not see an excess number of CVD events in PCOS in early life, as we see with other conditions, such as diabetes and stroke. Even understanding that perhaps the risk for CVD events is obscured by age as women with PCOS get older, it is also possible that perhaps they are not as severely affected as we would expect. That may be because there is a factor that is protective of CVD in PCOS. Or it may be that because PCOS is a complex genetic trait, affected women do not always carry the same enabling genetic risk factors for CVD that individuals with atherosclerosis and other vessel disease exhibit.
We must study CV function and related risk in women with PCOS more intensely, including performing large, well phenotyped cross-sectional and longitudinal studies — efforts that will require the increased investment and interest of many of the institutes and centers of the NIH. We must also continue to educate policymakers and government elected officials on the complexity and pervasiveness of PCOS, as currently the NIH is underfunding PCOS research.
Ricardo Azziz, MD, MPH, MBA, is professor of obstetrics and gynecology, medicine, and health care organization and policy at the University of Alabama at Birmingham School of Medicine and School of Public Health and chief science and strategy officer and executive vice president of operations, strategy and scientific affairs at the Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center.
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