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In PCOS, unclear CV risk burden presents challenge for clinicians
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Polycystic ovary syndrome is the most common disorder in women of reproductive age, according to the CDC, with an estimated prevalence between 6% and 12% in the United States. 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. Several studies suggest PCOS raises the risk for developing type 2 diabetes by as much as fourfold.
“Considering the presence of metabolic risk factors already present in many women with PCOS at a young age, it is generally believed that the chances for developing cardiovascular disease in later life are significantly increased,” Marlise N. Gunning, MD, a physician researcher in the department of reproductive medicine and gynecology at University Medical Center Utrecht, the Netherlands, and colleagues wrote in the March 2017 issue of Climacteric. “Evidence generated so far, however, remains inconclusive. A large heterogeneity exists in women with PCOS, and therefore cardiovascular risk profiles may vary with PCOS phenotype, age, ethnicity and body mass index.”
In the absence of a definitive answer, experts continue to debate the level of CV risk in these women, when and how to intervene and what research is needed to paint a clearer picture for PCOS patients.
“We’re trying to unfold what that really, truly looks like,” Margo Minissian, PhD, ACNP, FAHA, a research scientist, clinical lipid specialist and cardiology nurse practitioner in the Barbra Streisand Women’s Heart Center at the Smidt Heart Institute at Cedars-Sinai, told Endocrine 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.”
But PCOS also often brings with it several unpleasant symptoms — namely, hirsutism, acne and amenorrhea —that can be more pressing, particularly for young patients, and demand immediate attention.
“I’m certainly against unduly inciting fear, and there is a lot out there on the internet, just from interacting with patients, that scares them,” Richard S. Legro, MD, FACOG, physician and professor of obstetrics and gynecology and public health services at Penn State College of Medicine, Milton S. Hershey Medical Center in Hershey, Pennsylvania, told Endocrine Today. “What I will focus on is, yes, there are acknowledged risk factors for cardiovascular disease in adolescents, and those tend to be overrepresented or clustered in adolescents with PCOS. I see PCOS as a window into those risk factors that might otherwise be missed.”
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 vs. women without the condition, with a potentially longer diabetes duration further raising CV risk.
“Having diabetes totally removes the protection that premenopausal women have against cardiovascular disease,” 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 and an Endocrine Today Editorial Board Member, said in an interview. “What is the risk for cardiovascular events? Unfortunately, we don’t know that because nobody has done the correct study where women are followed prospectively to an age where women start to experience cardiovascular events, which isn’t until they are in their 60s and 70s. The literature is chock full of studies trying to answer this question, but they are just inherently flawed because they’re not prospective studies to women of that age.”
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, Malgorzata Jacewicz-Swiecka, MD, of the department of endocrinology, diabetology and internal medicine at the Medical University of Bialystok, Poland, and colleagues 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 between 1992 and 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 and 4.5 in controls, which was statistically significant.
“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, 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 analyzed data from women with PCOS free of CVD or hypertension at baseline from PCOS OUH (n = 1,165), a university database of premenopausal women with PCOS, and PCOS Denmark (n = 18,112), a database of women with PCOS in the Danish National Patient Register. Researchers matched women with PCOS with three age-matched women without the condition (controls; n = 52,769). The cohort was followed for a mean of 11.1 years, and the median age was 29 years.
Glintborg and colleagues found that women with PCOS were nearly twice as likely to develop incident CVD, including hypertension, compared with 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 PCOS Denmark vs. 11.6 per 1,000 patient-years among controls (P < .001). Median age at diagnosis of CVD was 35 years in PCOS Denmark vs. age 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 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.”
“I do see the glucose intolerance as a prevalent feature among adolescents and adults with PCOS,” said Legro, also a co-author of the clinical review. “What I don’t see, when you look at studies that follow them over time, is a deterioration in the glucose intolerance over time. One of the questions that I have is, is this something that is present, but doesn’t necessarily progress? Is it an epiphenomenon of the PCOS? Is this a case where the glucose intolerance actually resolves as the reproductive sequelae of PCOS resolve? I can’t tell you that is the truth, but it is certainly the hypothesis.”
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 Endocrine Today.
Still, seemingly simple lifestyle interventions can sometimes be difficult changes to make, particularly for adolescent girls who are still understanding their PCOS diagnosis, according to Farrell-Turner. For teen girls, she said, it is key to involve the whole family in any changes.
“The child is not going to be likely to make changes if the parent is not,” Farrell-Turner said.
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. That is, while long-term goals are worthwhile to keep in mind, teenagers’ immediate concern, such as their appearance, self-image or self-esteem, and relationships with peers may be more likely than more distant concerns to incentivize development of a healthy lifestyle.”
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 don’t realize that they need to exercise and reduce their insulin resistance and they ought to start young,” Warren, who is an Endocrine Today Editorial Board Member, said in an interview. “If it doesn’t start young, particularly in postmenopause, what happens is a lot of physicians don’t realize the woman has PCOS, and they don’t realize their compounded risk. Even endocrinologists are not always familiar with the syndrome.
“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.
Screenings are key
When a woman or adolescent receives a PCOS diagnosis, experts agree that screenings are key to reduce a woman’s overall risk burden.
“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,” Dunaif said. “For assessing glucose tolerance, an HbA1c is not an adequate screening measure. Most of these women have impaired glucose tolerance after a glucose load, which is what you see in insulin resistance. The HbA1c does not accurately reflect that and can frequently be normal, as can the fasting glucose measurement. What keeps happening is somebody writes a poorly done paper that says the HbA1c measurement is enough [in PCOS] and everyone reverts back to that.”
Minissian said women diagnosed with PCOS should also undergo a CV risk assessment.
“With PCOS, we often identify these women when they are teenagers,” Minissian 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 new guidelines, the 2018 ACC/AHA Multisociety Guideline on the Management of Blood Cholesterol, which were recently presented at the American Heart Association Scientific Sessions. These women are going to typically be considered low risk on the atherosclerotic cardiovascular disease (ASCVD) 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 heart disease —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,” Minissian said.
Warren agreed.
“Besides looking at the evolution of heart disease as these patients get older, I would like to look at using the modalities that we have for heart disease — taking an appropriate history and trying to determine if these patients are at risk, such as a coronary calcium score,” Warren said. “That’s a very noninvasive test that has become inexpensive. We should be looking at those parameters earlier.”
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, wrote of the 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.
Legro said a long-term, prospective study — one that follows a cohort of women with a PCOS diagnosis before they develop CV risk factors or events and follows them for 25 or 30 years — is what is needed to accurately measure the CV risk burden. Such a study, he added, would be difficult to undertake.
“There is often an association with cardiovascular disease when we do superficial, big data-type research and look at PCOS from ICD-9 or ICD-10 codes, and then see if those same people also went on to develop cardiovascular events or hospitalization for cardiovascular events,” Legro said. “When you look at the prospective studies, the data tend to be weaker, in my opinion. To me, that suggests a selection bias.
“It’s so drummed into our heads that women with PCOS have cardiovascular risk factors, that, often, a woman will get that diagnosis because she is obese, for instance, and has no other signs and symptoms,” Legro said. “Yet obesity is not even a diagnostic criterion for PCOS. It’s often assumed to be a PCOS equivalent, which it is not.”
Warren said a better understanding of PCOS, in general, is needed to appropriately assess CV risk in patients.
“It’s a tricky thing,” Warren said. “You have to make a diagnosis of PCOS, and physicians are not attuned to asking about irregular menses and other clinically presenting symptoms, like hirsutism or acne. That’s something that should be plugged into the evaluation of cardiovascular disease, but isn’t. We haven’t done any extensive studies on women with PCOS as they age.”
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.”
In the meantime, the true level of CV risk will continue to be a matter of debate.
“The jury is out, but we know that diabetes is such a powerful risk factor that I don’t think we can be complacent in women with PCOS,” Dunaif said. “They need to have aggressive attention paid to modifiable CV risk factors.” – by Regina Schaffer
- References:
- 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.
- Gunning MN, et al. Climacteric. 2017;doi:10.1080/13697137.2017.1316256.
- 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.
- 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.
- Richard Legro, MD, can be reached at Penn State College of Medicine, 500 University Drive, Hershey, PA 17033; email: rsl1@psu.edu.
- Margo Minissian, PhD, 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.
- 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.
Disclosures: Legro reports he has received consultant fees from AbbVie, Baring, Bayer, Fractyl and the NIH. Dunaif, Farrell-Turner, Minissian and Warren report no relevant financial disclosures.
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