The National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI), Office of Research on Women’s Health (ORWH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Cancer Institute (NCI), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and Office of Disease Prevention (ODP) convened a two-day virtual workshop titled “Cardiovascular (CV) Risk Across the Lifespan for Polycystic Ovary Syndrome (PCOS)” on October 13 and 22, 2021.The leadership and members of the PCOS Challenge, a patient advocacy group, also participated and provided important stakeholder input.
The purpose of this workshop was to address critical research needs and highlight research questions at the interface between PCOS and cardiovascular disease (CVD) risk across the lifespan. Presenters discussed the following workshop objectives: (1) epidemiological and pathophysiological links between CVD risk factors and PCOS, and the lifespan relationship between CVD and PCOS; (2) current PCOS diagnostic and clinical care guidelines; (3) mechanisms underlying CV risk across lifespan of women with PCOS; and (4) knowledge gaps and opportunities in PCOS-related CVD research. They also discussed opportunities for a coordinated research plan relevant to CVD in PCOS over the next 5 years to address identified research gaps.
PCOS is one of the most common endocrine disorders affecting adolescents and women of reproductive age, with a prevalence of between 8% and 13% depending on the population studied and definitions used. Etiology and pathogenesis are not well understood, and clinical assessment, management, and recognition of long-term consequences are suboptimal. PCOS has been considered as a specific female risk factor for CVD, although there is controversy on CVD in women with PCOS across their lifespan. Thus, in some studies, when compared to women without PCOS, risk for CVD in women with PCOS may be increased during their reproductive years. Limited data suggest that this risk may become similar to that in women without PCOS in menopause, as unaffected women develop increasing prevalence rates of CV risk factors. In addition, while insulin resistance (IR), type 2 diabetes (T2D), dyslipidemia, obesity, hypertension, and sleep disordered breathing are prevalent in women with PCOS and likely contribute to increased CV risk, the evidence for an independent association of PCOS with CVD is inconclusive. This workshop brought together a multidisciplinary team of scientists and practitioners to address these important knowledge gaps through carefully crafted sessions focused on identification of research opportunities in PCOS-related CVD across the lifespan and on disease-specific prevention, intervention, and implementation strategies.
After brief introductions and charge, the workshop participants discussed the following:
- Complexity of PCOS: PCOS is a chronic complex, underdiagnosed disorder, and the long-term consequences are under-recognized. At the earliest stages of diagnosing and treating PCOS, physicians have mainly considered the disease to be a reproductive and gynecological disorder and failed to understand the metabolic changes that women with PCOS go through as they age. Patients with PCOS often do not receive comprehensive care and counselling because of differences of opinion about what is and is not related to the disease. Many primary care physicians (PCPs) are not aware of the diagnostic criteria and non-reproductive effects of PCOS. PCOS patients, when faced with CVD, feel unprepared and under-treated.
- Need for newer diagnostic tools and criteria: Current diagnostic criteria for PCOS may be replaced with newer genetic tools which can elucidate disease mechanisms and provide biologically relevant classification for women with PCOS. Omics phenotypic signatures can also be used to identify population-specific variants.
- Epidemiologic studies: Current research on PCOS phenotypes and epidemiology has focused on women who have higher levels of androgens or/and irregular menses, and their association with PCOS and CVD risk (independent of obesity). In women of reproductive age with PCOS, there is a two-fold higher risk of hypertension and coronary artery calcification. PCOS, and irregular menses as proxy for PCOS, are associated with wide range of incident CVD (~30% to 2-fold) and these associations appear stronger among women of reproductive age. While genetically-predicted PCOS is not significantly associated with CVD outcomes, there is significant sharing of genetic susceptibility between PCOS and CVD. PCOS is not currently listed as a risk-enhancing factor in 2019 American College of Cardiology/American Heart Association primary prevention guidelines. Although research findings have not been consistent, there are women with PCOS who die of CVD at young ages (less than 50 years old). It was suggested that menstrual period irregularities should be a primary vital sign for CVD outcomes in women with PCOS.
- Mechanisms underlying PCOS-related CVD risk: Women with PCOS have profound peripheral IR, independent of obesity. Furthermore, obesity is frequently associated with PCOS and substantially worsens IR and the risk for metabolic syndrome, CVD, and T2D. However, more data are needed to show that PCOS poses as a CVD risk factor independent of obesity. There is an interrelationship between androgens and cardiometabolic/vascular risk factors in PCOS, but data are inconclusive as to whether androgen levels are independently associated with CVD. Recent data suggests that 11-oxygenated androgens, which do not decline with age or menopause and increase with body mass index (BMI), may also contribute to the circulating androgen pool. Androgen excess-PCOS is associated with mild hypertension and endothelial dysfunction, a relationship that can be independent of IR and body fat. Coagulation abnormalities related to increased thrombin generation and decreased fibrinolysis have been shown in PCOS; this is related to BMI, IR, and inflammation.
- Co-morbidities linked to CVD: Sleep disordered breathing is prevalent in women with PCOS and likely contributes to increased CV risk through autonomic dysfunction and systemic inflammation. There is a well-documented increase in prevalence of mood disorders in PCOS, with depression clearly linked to increased CVD, but need to determine phenotypic and ethnic variation as well as degree of benefit of lifestyle and pharmacological intervention. Suggestion of increased COVID-19 risk in women with PCOS was observed in one study likely due to associated risk factors (obesity, diabetes, hypertension, CVD, high androgen levels). The relationship between cancer, PCOS, and CVD is still being defined as endometrial and ovarian cancer associations may share mechanisms with CVD.
Research opportunities addressing CVD in PCOS were discussed and are summarized below:
- Determine biological underpinnings of PCOS (including genetics) and identify underlying mechanisms for any differences in cardiometabolic risks for women with PCOS.
- Investigate PCOS across the research continuum from mechanistic discovery research to clinical trials, health services research on models of holistic care to epidemiology, and cohort natural history studies.
- Conduct studies that evaluate long-term hormonal and metabolic changes with reproductive aging and menopause in women with PCOS, their influence on PCOS phenotype and their CV consequences.
- Consider social determinants of health (SDoH) and include representation of diverse racial/ethnic (African American, American Indian/Alaska Native, Hispanic, Asian), geographic, and age groups (longitudinal cohorts, including children at risk and women aging with PCOS) and global populations, in order to understand the full spectrum of PCOS. Carefully characterize differences in cardiometabolic risks across the lifespan, biologic variations, and SDoH in women with PCOS to help resolve conflicting evidence.
- Determine the role of underlying environmental or racial/ethnic factors in the prevalence, phenotype, and economic burden of PCOS by expanding the number, comparability, consistency, and harmonization of epidemiologic studies of PCOS, globally and by region.
- Develop strategies to determine contributing factors which may increase or decrease risk in aging and premenopausal women to address CVD, dyslipidemia, metabolic syndrome, and hypertension (e.g., androgen levels, sex hormone binding globulin, birth control pills, etc.).
- Conduct studies aiming to better understand preconception PCOS risk and adverse pregnancy outcomes and associated CVD later in life.
- Develop strategies for prevention/treatment of CVD in patients with PCOS of different ages (offspring of mothers with PCOS, adolescents, women of reproductive age and postmenopausal women).
- Synchronize and coordinate collection of biosamples from ongoing and future studies as they play a critical role for defining PCOS retrospectively and for CVD intermediates.
- Increase use of Electronic Health Records (EHR) to increase sample size and diversity and expand the outcomes of interest, taking into consideration that there are caveats, such as diagnostic biases, validation of search criteria, improvements in natural language processing, and keyword algorithms. Require an inclusion of menstrual and reproductive history as mandatory elements in the EHR.
- Use data science and system biology approaches for disease subtyping and validation and developing of risk prediction models for CVD in PCOS women.
- Identify barriers to PCOS-related research. Strengthen the researcher/investigator pipeline and encourage more research on PCOS to be conducted. Emphasize need and opportunity for investigators in cardiovascular and metabolic sciences to engage in PCOS-related research.
- Engage stakeholders in research priority setting, core outcome determination, and in coproduction of research and implementation to generate meaningful outcomes for women with PCOS.
Immediate Research opportunities:
- Use existing cohorts to advance PCOS understanding through retrospective and prospective data collection.
- Current cohorts include All of Us, MESA, CARDIA, Dallas Heart study, nuMoM2b and nuMoM2b HHS, NHS2 and NHS3, SOL, Jackson Heart, SWAN, CHARMS, WHI, WISE, Icelandic Medical Records Cohort, and ECHO.
- Leverage mobile Health (mHealth) technology, simple screening with validated tools, and EHRs to capture CV events; develop deeper phenotyping with mHealth questions.
- Develop new approach to combine transgenerational cohorts (use cohorts that examine different age groups).
- Advocate for the addition of menstrual and reproductive history to current clinical trials that include women. Encourage the inclusion of menstrual and reproductive history in future clinical trials. Recommend the use of validated questionnaires or apps to collect this information.
- Conduct studies that reevaluate CVD endpoints from existing or past primary prevention CVD trials where PCOS status can be determined (e.g., statin trial).
- Conduct new studies including the youngest age possible (potentially fetal environment). Include biological samples for omics characterization, use a validated questionnaire for PCOS diagnosis, menstrual cycling, include ethnic/racial diversity as well as range of PCOS phenotypes.
- Include intermediate endpoints (carotid intima- media thickness, coronary artery calcium, arterial stiffness, peripheral endothelial dysfunction) to help determine CV outcomes.
- Consider transgenerational cohorts and novel designs for merging existing cohorts with new cohorts.
- Characterize PCOS phenotypes, including multiple factors contributing to PCOS (for example, it would be helpful for the hyperandrogenic phenotype to perform detailed steroid profiling in clinical trials and cohorts).
- Develop guidelines for CVD risk factor screening and associated prevention and treatment strategies.
- Strategies for implementation of evidence-based practice supported by rigorous data and current knowledge.
- Increase awareness of PCOS; address all stakeholders including students, health professionals and patients, and develop specialty modules for primary and specialty clinicians and patient groups to help overcome the barriers of teaching about women’s health and reproductive disorders. Implement strategies to improve clinical practice and change knowledge of primary care physician and other specialists who are on the PCOS care team.
- Encourage multidisciplinary and interdisciplinary care collaboration to help with diagnosis and needs of patients managing their health. PCOS requires research expertise outside reproductive medicine and management of patients often requires coordination among OB/Gyn, cardiovascular, endocrine, oncology and primary care clinicians. Facilitate collaboration and shared resources.
- Develop and facilitate training of young investigators to conduct research on PCOS.
The working group plans to prepare a manuscript for publication in a peer-reviewed journal that highlights discussions on the knowledge gaps and the research and other opportunities explored at the workshop.
C. Noel Bairey Merz, M.D., Cedars-Sinai Medical Center
Anuja Dokras, M.D., Ph.D., University of Pennsylvania
Andrea Dunaif, M.D., Icahn School of Medicine and Mount Sinai Health System
NIH Planning Committee
Jasmina Varagic, M.D., Ph.D., NHLBI
Patrice Desvigne-Nickens, M.D., NHLBI
Charlotte A. Pratt, Ph.D., M.S., R.D., NHLBI
Koyeli Banerjee, Ph.D., NHLBI
Aaron Laposki, Ph.D., NHLBI
Esther Eisenberg, M.D., Ph.D., NICHD
Ashley Vargas, Ph.D., NICHD
Karen Winer, M.D., NICHD
Lisa Halvorson, M.D., NICHD
Pamela Stratton, M.D., ORWH
Melissa Green-Parker, Ph.D., ODP
Britton Trabert, Ph.D., NCI
Ellen Leschek, M.D., NIDDK