Unclear CV risk burden of polycystic ovary syndrome presents challenges for cardiologists

Polycystic ovary syndrome, or PCOS, is a hormonal disorder in women of reproductive age that is typically associated with infertility, according to the Mayo Clinic. An estimated 6% to 12% of U.S. women have PCOS, according to data from the CDC. PCOS can cause excess male hormone levels and infrequent or prolonged menstrual periods. In addition, the ovaries may form follicles, which prevent the regular release of eggs. The condition, which is typically associated with infertility, is also linked to an increased prevalence of several metabolic derangements, including obesity, insulin resistance, dyslipidemia and hypertension, contributing to increased risk for CVD.

“Often, women with PCOS don’t realize they have increased cardiovascular risk,” Erin D. Michos, MD, MHS, FACC, FAHA, associate director of preventive cardiology at the Ciccarone Center for the Prevention of Heart Disease, associate professor of medicine in the division of cardiology at Johns Hopkins School of Medicine and a Cardiology Today Next Gen Innovator, said in an interview. “They’re living with PCOS and often are dealing with irregular menses, infertility, acne and more of the male hormones. Infertility and menstrual problems are their main concern because these are generally women in the reproductive age and they may not have an understanding of their cardiac risk.”

PCOS is also associated with other symptoms — namely, hirsutism, acne and amenorrhea — that can be more pressing for women, particularly those who are younger, and demand immediate attention.

“There’s the potential for development of cardiac risk factors and lifelong risk for cardiovascular disease. Women with PCOS need lifelong monitoring for cardiovascular disease,” Laxmi Mehta, MD, FACC, FAHA, section director of prevention and women’s cardiovascular health and professor of medicine at Ohio State University Wexner Medical Center, told Cardiology Today. “We don’t have enough data on whether there’s a difference in treating the PCOS more aggressively at this time, however we must be on the lookout for development of cardiovascular disease.”

In the absence of a definitive answer, experts continue to debate the level of CV risk in women with PCOS, when and how to intervene, and avenues for further research to paint a clearer picture of this association.

Defining the problem

Most health care professionals are aware of the association between PCOS and CVD, but much remains to be learned.

“The main problem with PCOS is the hormonal imbalance. These women have higher levels of insulin and insulin resistance. This can increase their risk for elevated triglycerides and blood pressure. It also increases their glucose intolerance and risk for diabetes,” Michos said.

Understanding which risk factors conferred by PCOS contribute the greatest to poor CV outcomes is crucial.

“We’re trying to unfold what that really, truly looks like,” Margo Minissian, PhD, ACNP, FAHA, research scientist, clinical lipid specialist and cardiology nurse practitioner in the Barbra Streisand Women’s Heart Center at Cedars-Sinai’s Smidt Heart Institute, told Cardiology Today. “We know that women who are insulin resistant or have dyslipidemia or hypertension are at higher risk for heart disease, and these are many of the characteristics that go along with a woman who has PCOS. They typically have some of these underlying disorders much earlier than other women without PCOS do. Fundamentally, we want to recognize what those risk factors are, and we want to follow them closely over time.”

Some experts caution that CV risk in PCOS is more acute than studies suggest, in part because women with PCOS develop metabolic abnormalities, and sometimes type 2 diabetes, at an earlier age compared with women without the condition, with a potentially longer diabetes duration further raising CV risk.

Mixed findings

Studies attempting to get to the bottom of the CV risk question in adolescents and women with PCOS have demonstrated mixed findings.

In a meta-analysis published in September in Diabetes/Metabolism Research and Reviews, researchers found that women with PCOS are at higher risk for obesity and elevated cholesterol vs. healthy women; however, the researchers observed no increased prevalence of CVD across 47 longitudinal studies published from 1992 to 2018.

In one large, retrospective study in the analysis, the researchers found that women with PCOS did not differ in overall CVD mortality vs. the U.K. national average. Moreover, prospective research with more than 20 years of follow-up showed no significant difference in the overall CVD mortality among women with PCOS who had undergone ovarian resection vs. controls. In a retrospective, observational study, the RR of all-cause mortality and large vessel disease was not significantly different in women with PCOS vs. controls. However, another study found a twofold increase in reports of CVD in women with diagnosed metabolic syndrome vs. those without metabolic syndrome (9.5% vs. 4%).

In one analysis, which excluded arterial hypertension and dyslipidemia, the estimated incidence of CVD was 6.4 per 1,000 person-years in the PCOS group vs. 4.5 in controls, which was statistically significant.

In addition, in a paper published in the Journal of Women’s Health in 2016, researchers found that the prevalence of PCOS was similar to the general population in women who were postmenopausal. These women who had clinical features of PCOS did not have an increased risk for CAD or mortality.

“It appears that the PCOS women have increased tendency of obesity, abdominal fat distribution, dyslipidemia and deterioration of glucose metabolism compared to the healthy women,” the researchers wrote. “However, data about higher prevalence of [arterial hypertension] in PCOS seem to be unconvincing. Furthermore, although CV risk is clearly increased in young patients with PCOS, authors of most of the cited publications did not find significant excess of CVD prevalence, meaning both CHD and [cerebrovascular disease] morbidity or mortality in PCOS women.”

However, in findings presented in May at the European Congress of Endocrinology annual meeting then published in Cardiovascular Diabetology, researchers came to a different conclusion. In a national, register-based study, Dorte Glintborg, MD, PhD, clinical associate professor of endocrinology at the University of Southern Denmark and consultant at Odense University Hospital, and colleagues found that women with PCOS were nearly twice as likely to develop incident CVD or hypertension vs. women without PCOS (HR = 1.7; 95% CI, 1.6-1.8). The total event rate for CVD was 19.2 per 1,000 patient-years in the PCOS Denmark cohort vs. 11.6 per 1,000 patient-years among controls (P < .001). Median age at diagnosis was 35 years in PCOS Denmark vs. 36 years among controls (P = .02).

In a PCOS Disease State Clinical Review issued in 2015 by the American Association of Clinical Endocrinologists and the American College of Endocrinology, researchers noted that the prevalence of metabolic syndrome in adolescents with PCOS “appears to be very high.” The researchers cited a U.S. study, using Androgen Excess and PCOS Society criteria to define PCOS, that reported a higher proportion of metabolic abnormalities in adolescents with PCOS compared with adolescents without, even after excluding BMI. The review states that “insulin resistance and the components of metabolic syndrome are, therefore, important targets of therapy in adolescent girls with PCOS.”

There are currently no established guidelines regarding optimal CV treatment in women with PCOS. In fact, in the 2018 Guideline on the Management of Blood Cholesterol from 12 societies, PCOS itself was not included as a risk enhancer, although other factors such as metabolic syndrome, premature menopause, hypertensive disorders of pregnancy and other adverse pregnancy outcomes were included, Janet Wei, MD, FACC, cardiologist and assistant professor of medicine at Barbra Streisand Women’s Heart Center, Smidt Heart Institute at Cedars-Sinai, said in an interview.

Wei added, “[The guideline] did not include PCOS, likely due to insufficient data to support that PCOS is associated with increasing CV mortality independent of the known CV risk factors.”

Reaching patients early

Early intervention in PCOS can help a woman to, ideally, set up a healthier lifestyle, including regular physical activity, a healthy diet and minimal weight gain, when they can reap the most benefit, according to Kristen Farrell-Turner, PhD, assistant professor of psychology at Carlos Albizu University, Miami Campus.

“Several studies have shown that, even in the absence of significant weight loss, just exercising more often can decrease a lot of the clinical signs of PCOS, including infertility,” Farrell-Turner told Cardiology Today.

Particularly when discussing potential CV complications and other long-term concerns that could accompany a PCOS diagnosis, she said, a clinician must be careful when discussing risk burden.

“You don’t want to induce fear in a teenager that she might have cardiovascular disease 30 years from now, or that she might not be able to get pregnant 2 decades from now,” Farrell-Turner said. “It’s a long way away, and so far in the distance, that it may not be something important to them. I’m not sure it should be important to teenagers.”

Many patients with PCOS are unaware of the steps they need to take to improve their health, according to Michelle Warren, MD, medical director of the Center for Menopause, Hormonal Disorders and Women’s Health in New York.

“A lot of people with PCOS do not realize that they need to exercise and reduce their insulin resistance and they ought to start young,” Warren said in an interview. “If it does not start young, particularly in postmenopause, what happens is a lot of physicians do not realize the woman has PCOS, and they don’t realize their compounded risk. Even endocrinologists are not always familiar with the syndrome.”

Cardiologists are often not asking women about risk factors that are unique to them such as PCOS, Michos said.

“Many cardiologists do not ask these because they are not thinking about [PCOS] as major risk factors of cardiovascular disease,” she said.

“We tend to focus on the other diseases that they have — the hypertension, the diabetes, the obesity — rather than the underlying problem that they have had since they were very young,” Warren said.

Screening is key

When a woman or adolescent receives a PCOS diagnosis, experts agree that screenings are key to reduce a woman’s overall risk burden, including CV risk assessment.

“It’s doing the comprehensive risk assessment as soon as they are diagnosed, including lipid profiles and assessment of glucose tolerance, particularly if they are overweight or obese,” Andrea Dunaif, MD, chief of the Hilda and J. Lester Gabrilove division of endocrinology, diabetes and bone disease at the Icahn School of Medicine at Mount Sinai, said in an interview.

“With PCOS, we often identify these women when they are teenagers,” Minissian, a Cardiology Today Editorial Board Member, said. “If that is the case, then we’re able to further risk stratify them for future cardiovascular disease risk by screening for genetic cholesterol disorders, such as familial hyperlipidemia, early-onset hypertension and diabetes or insulin resistance. In addition, implementing lifestyle changes is at the center of the 2018 cholesterol guideline. These women are going to typically be considered low risk on the atherosclerotic cardiovascular disease risk calculator, even when having these risk factors. With that being said, it’s in the lap of the clinician to be able to further evaluate that woman, based on her lifetime risk.”

For example, Minissian said, if a woman with PCOS has a family history of CVD — something that is not factored into an ASCVD risk calculation — a provider may want to measure that patient’s level of C-reactive protein or assess her coronary calcium score.

“Especially in older women with PCOS, these additional tests can serve as tie breakers to further risk stratify them,” she said.

Michos agreed that measuring coronary calcium scores can be helpful in these women.

“I ask my female patients about a history of PCOS, but we do not really have established guidelines of what is the optimal cardiovascular treatment to do in these women beyond just treating the individual risk factors,” Michos told Cardiology Today. “There is a lot more work we can do to understand at what point we should intervene and what is the best intervention to lower their risk beyond more aggressive lifestyle changes. For women over the age of 40 with a history of PCOS, measuring a coronary calcium score is what I do in my clinical practice to further refine these women’s risk.”

Another challenge is that not all phenotypes of PCOS are associated with increased CV risk.

“Not all phenotypes [using the Rotterdam criteria] convey the same risk for cardiovascular risk factors,” Wei, a Cardiology Today Next Gen Innovator, said. “Not all PCOS is equal and doctors caring for these patients need to pay attention to clinical features, as the combined oligo-ovulation and hyperandrogenism phenotype is associated with the highest risk of metabolic syndrome and insulin resistance.”

More research, education needed

In an analysis published in The Journal of Clinical Endocrinology & Metabolism in March 2015, Roger Hart, MD, and Dorota A. Doherty, PhD, both of the School of Women’s and Infants’ Health at the University of Western Australia, described challenges in assessing the implications of a PCOS diagnosis on a woman’s long-term health.

“Because the definition of PCOS has only recently been clarified, it is impossible to accurately derive the health-related, longer-term associations of this medical condition,” Hart and Doherty wrote, adding that most of the previous studies addressing long-term consequences of PCOS relied on “small, self-selected populations that have mainly focused on cardiometabolic endpoints.” Many studies have used presumed diagnosis, by measuring midlife androgens, to study CVD risk in women with PCOS.

More data are also needed on the development of risk factors from when a woman is diagnosed with PCOS.

“There’s research on the associations of PCOS and cardiovascular disease, but it is mostly retrospective,” Mehta told Cardiology Today. “We need more prospective long-term data examining PCOS women from the onset of diagnosis of PCOS to when they develop these cardiac risk factors. Does altering their risk factors earlier substantially affect their outcomes? To what effect does PCOS have on microvascular dysfunction?”

Warren said a better understanding of PCOS, in general, is needed to appropriately assess CV risk in patients.

There are a lack of data about whether women with PCOS should see a cardiologist or whether the care would be superior than seeing a general internist or a primary care physician.

“As long as their primary care physician is checking and counseling about cardiovascular risk factors and is alert to the fact that these patients are at higher risk for subclinical atherosclerosis, it is unknown whether additional screening by a cardiologist is helpful,” Wei said.

More funding for appropriate research for PCOS is also needed, Dunaif said.

“The main problem is the fact that this is not a mainstream medical condition, and that is most likely due to its name, which is totally misleading,” Dunaif said. “Clearly, there needs to be funding for the appropriate kind of research for this condition.”

Besides funding, one of the most critical components to treating women with PCOS and women in general is collecting more information on their reproductive history.

“As cardiologists, especially those who are not part of a women’s heart center, it’s increasingly important to ask female patients about their reproductive health,” Wei told Cardiology Today. “Too often these reproductive health questions, whether it be about menstrual cycle, menopause or pregnancy history, are overlooked, and this is important information when we’re counseling female patients about their future cardiovascular risk.” – by Regina Schaffer and Darlene Dobkowski

References:

• Bairey Merz CN, et al. J Womens Health. 2016;doi:10.1089/jwh.2015.5441.
• CDC. PCOS and Diabetes, Heart Disease, Stroke. Available at: www.cdc.gov/diabetes/library/spotlights/pcos.html. Accessed Nov. 8, 2018.
• Dokras A. Steroids. 2013;doi:10.1016/j.steroids.2013.04.009.
• Dokras A. Steroids. 2013;doi:10.1016/j.steroids.2013.04.009.
• Glintborg D, et al. Cardiovasc Diabetol. 2018;doi:10.1186/s12933-018-0680-5.
• Hart R, et al. J Clin Endocrinol Metab. 2015;doi:10.1210/jc.2014-3886.
• Jacewicz-Swiecka M, et al. Diabetes Metab Res Rev. 2018;doi:10.1002/dmrr.3054.
• Mayo Clinic. Polycystic ovary syndrome (PCOS). Available at: www.mayoclinic.org/diseases-conditions/pcos/symptoms-causes/syc-20353439. Accessed Jan. 17, 2019.

• For more information:
• Andrea Dunaif, MD, can be reached at the Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1055, New York, NY 10029; email: andrea.dunaif@mssm.edu.
• Kristen Farrell-Turner, PhD, can be reached at Carlos Albizu University, Miami Campus, 2173 NW 99th Ave., Miami, FL 33171; email: kfarrell@albizu.edu.
• Laxmi Mehta, MD, FACC, FAHA, can be reached at Richard M. Ross Heart Hospital, 452 W. 10th Ave., Columbus, OH 43210; email: laxmi.mehta@osumc.edu; Twitter: @drlaxmimehta.
• Erin D. Michos, MD, MHS, FACC, FAHA, can be reached at The Johns Hopkins Hospital, Blalock 524, 600 North Wolfe St., Baltimore, MD 21287; email: edonnell@jhmi.edu; Twitter: @erinmichos.
• Margo Minissian, PhD, ACNP, FAHA, can be reached at the Barbra Streisand Women’s Heart Center at the Smidt Heart Institute at Cedars-Sinai, 127 S. San Vicente Blvd., Advanced Health Sciences Pavilion, Suite A9304, Los Angeles, CA 90048; email: margo.minissian@cshs.org; Twitter: @minissianm.
• Michelle Warren, MD, can be reached at the Center for Menopause, Hormonal Disorders and Women’s Health, 134 E. 73rd St., New York, NY 10021; email: mpw1@cumc.columbia.edu.
• Janet Wei, MD, FACC, can be reached at Barbra Streisand Women’s Heart Center at Cedars Sinai Heart Institute, 8631 W. Third St., Los Angeles, CA 90048; email: janet.wei@cshs.org; Twitter: @janetweimd.

Disclosures: Dunaif, Farrell-Turner, Mehta, Michos, Minissian, Warren and Wei report no relevant financial disclosures.