Abstract

Polycystic ovary syndrome (PCOS), affecting 5-10% of reproductive-aged women, is linked to metabolic disturbances such as insulin resistance, obesity, and lipid imbalance, which may elevate cardiovascular disease (CVD) risk. The relationship between PCOS and clinical cardiovascular events remains unclear. This meta-analysis evaluates the association between PCOS and cardiovascular and cerebrovascular events, including myocardial infarction (MI), stroke, ischemic heart disease (IHD), and overall CVD. We conducted a systematic review and meta-analysis of observational cohort studies published up to August 2024. Studies investigating the association between PCOS and cardiovascular or cerebrovascular events were included. Hazard ratios (HR) were used to assess mortality risk, while odds ratios (OR) evaluated CVD incidence. Statistical analyses were performed using STATA software, with publication bias assessed via funnel plots. Nineteen cohort studies, involving 1,222,912 participants, were analyzed. Women with PCOS had a significantly higher risk of stroke [OR: 1.89, 95% confidence interval (CI): 1.22-2.55]. However, no significant associations were found between PCOS and overall CVD (HR: 1.80, 95% CI: 5.43-9.04), MI (HR: 2.68, 95% CI: 0.69-4.82), or IHD (HR: 2.68, 95% CI: 0.69-4.67). Additionally, there was no significant increase in cardiovascular or all-cause mortality. This meta-analysis highlights that women with PCOS are at an increased risk of stroke, but no conclusive evidence links PCOS to other cardiovascular outcomes or mortality. Clinicians should prioritize stroke prevention in this population. Further large-scale, long-term studies are needed to clarify the cardiovascular risks associated with PCOS.

Keywords:

Polycystic ovary syndrome, cardiovascular diseases, cerebrovascular disorders, meta-analysis

PRECIS: Women with polycystic ovary syndrome (PCOS) have a significantly higher risk of stroke but no conclusive evidence links PCOS to other cardiovascular events or mortality.

Introduction

An endocrine condition, known as polycystic ovarian syndrome (PCOS), affects 5-10% of women who are of reproductive age and is characterized by common phenotypic and clinical symptoms^{(1, 2)}. It is brought on by insulin resistance (IR), follicular dysplasia, and hyperandrogenism, which collectively contribute to manifestations such as obesity, infertility, irregular menstruation, and hyperandrogenemia^{(3, 4)}. Metabolic disturbances are common in PCOS patients and are easily associated with other metabolic synthesis disorders, obesity, hypertension, diabetes, and disorders of lipid metabolism⁽⁵⁾. Therefore, there is a considerable rise in the risk of cardiovascular disease (CVD) in PCOS patients due to the increased risk of atherosclerosis, as indicated in citation⁽⁶⁾.

Since PCOS frequently exhibits IR, altered glucose regulation, dyslipidemia, high blood pressure (BP), and obesity as early as young adulthood or even childhood, women with PCOS are exposed to conventional cardiovascular risk factors over an extended period. Nevertheless, data regarding the relationship between the presence of numerous CVD risk factors and an increased risk of CVD events in PCOS-affected women are inconsistent^{(7, 8)}. These discrepancies may stem from variations in the diagnostic criteria for PCOS, differences in metabolic profiles, definitions of cardiovascular outcomes, or methodological limitations such as small sample sizes and study design differences. Notably, individuals meeting the National Institutes of Health (NIH) criteria for PCOS tend to exhibit more severe metabolic disturbances and may carry a greater cardiovascular risk than those diagnosed under the broader Rotterdam criteria. We also are not certain if women who have phenotypes C and D, which are non-NIH PCOS phenotypes, are more likely to experience CVD events⁽⁹⁾.

The correlation between PCOS and a higher long-term risk of CVD events is still up for debate, despite mounting data linking PCOS to CVD risk factors. It is unclear if established risk factors mitigate the relationship between PCOS and CVD, or if PCOS is a separate risk factor⁽¹⁰⁾. Notably, many participants in earlier studies were overweight or obese, highlighting the substantial impact of excess weight on conventional cardiovascular risk markers⁽¹¹⁾. Some previous meta-analyses have suggested an increased incidence of cardiovascular outcomes-such as coronary artery disease and cerebrovascular conditions-among women with PCOS⁽¹²⁾. Women from East Asian populations with PCOS tend to have a lower average body mass index (BMI) and milder signs of androgen excess than their Western counterparts⁽¹³⁾. It is unclear how East Asian women with PCOS, particularly those who are not obese, would fare in terms of long-term CVD risk. However, this meta-analysis aimed to assess the relationship between PCOS and the risks of CVD in women.

Materials and Methods

This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the identifier CRD42024625702.

Search Strategy

We followed the guidelines of Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA-P). We extracted eligible studies from PubMed, Scopus, and Google Scholar databases published in English up to August 2024. The searched keywords included “polycystic ovary syndrome,” “PCOS,” “sclerocystic ovarian degeneration,” “Stein-Leventhal syndrome,” “cardiovascular diseases,” “myocardial infarction,” “coronary heart disease,” “cardiovascular stroke,” “myocardial infarct,” “heart attack,” “ischemic heart disease,” “myocardial ischemia,” “stroke,” “cerebrovascular accident,” and “apoplexy.” Our search strategy is summarized in Table 1.

Inclusion and Exclusion Criteria

Observational studies investigating the association between PCOS and cardiovascular and cerebrovascular diseases were included. Editorials, conference abstracts, reviews, commentaries, and interventional studies were excluded. Animal studies, as well as non-English articles, were also excluded. Cardiovascular outcomes assessed encompassed both clinical and subclinical disease measures, including incidence, prevalence, and mortality. Cardiovascular-related deaths were defined as those caused by sudden cardiac arrest, acute myocardial infarction, advanced heart failure, peripheral arterial disease, or stroke (Table 2).

Data Collection and Quality Assessment

Two independent reviewers extracted the data using a consistent and standardized approach. Any disagreements were settled through discussion with a third reviewer. Extracted data included information such as the first author’s name, year of publication, study location, average participant age, sample size, follow-up period, type of study, diagnostic criteria for PCOS, and any confounding variables adjusted for. We also recorded outcomes such as cardiovascular and all-cause mortality, overall cardiovascular disease, ischemic heart disease, myocardial infarction, and stroke. The methodological quality of included studies was evaluated using the Joanna Briggs Institute critical appraisal checklist (available at https://jbi.global/critical-appraisal-tools), as summarized in Table 3.

Data Analysis

Hazard ratios (HR) with 95% confidence intervals (CI) were used to assess mortality risk, while odds ratios (OR) with 95% CI were applied to cardiovascular and cerebrovascular event rates, respectively. Heterogeneity across studies was evaluated using the I² statistic derived from chi-squared tests. Publication bias was visually assessed using funnel plots. All statistical analyses were conducted using STATA software, version 14.

Results

Study Selection

A total of 5,708 studies were found through PubMed and Scopus. After removing 3,433 duplicates, an additional 2,224 were excluded based on their titles and abstracts for not meeting the criteria. This left 51 studies for full-text review, and finally, 19 cohort studies with 1,222,912 participants were included (Figure 1).

Included Studies

Table 2 summarizes the characteristics of the included studies. The majority were conducted in in the United Kingdom (n=4)⁽⁷^,¹⁴^,¹⁵⁾, with additional studies from Sweden (n=3)⁽^16-18⁾, USA (n=3)⁽^19-21⁾, Denmark (n=2)⁽²²^,²³⁾, and single studies from Australia⁽²⁴⁾, Norway⁽²⁵⁾, the Netherlands⁽²⁶⁾, Taiwan⁽²⁷⁾, Iran⁽²⁸⁾, Finland⁽²⁹⁾, and Korea⁽³⁰⁾. Most studies followed a cohort design, including 12 prospective and 7 retrospective cohort studies. Assessment of study quality is detailed in Table 2. PCOS diagnosis varied, with the Rotterdam criteria (n=6)^{(9,17-19,22,28)}and International Classification of Diseases (ICD) codes (n=6)^{(7,22-24,27,29)} being the most frequently used methods. Other diagnostic approaches included the NIH criteria (n=2)⁽⁹^,²¹⁾, histopathological evaluation, laparoscopic criteria, self-reported characteristics, and androgen excess (n=2)⁽²⁰^,²⁶⁾.

Follow-up durations ranged from 3.83 years to 32 years, and the mean or median age at follow-up spanned from 25 to 81 years. Outcomes assessed included myocardial infarction (MI), cerebrovascular events (stroke or transient ischemic attack), composite CVD outcomes, ischemic heart disease, large-vessel disease, and major adverse cardiovascular events. Data collection methods included questionnaires, medical records, health insurance databases, clinical examinations, and registry records. Most studies adjusted for factors such as age, BMI, and metabolic conditions like diabetes and hypertension.

All-Cause Mortality

Seven studies evaluated the risk of all-cause mortality in PCOS versus non-PCOS groups. No significant difference in risk was observed between the two groups (HR: 0.98, 95% CI: 0.80-1.15, I²=0%) in a random-effects model (Figure 2).

Cardiovascular Death

Five studies assessed the risk of cardiovascular death. Similarly, there was no significant change in risk for the PCOS group compared to the non-PCOS group (HR: 1.75, 95% CI: -2.20-5.71, I²=38.4%) in a random-effects model (Figure 3).

Any CVD

Nineteen studies evaluated the risk of any CVD. Patients with PCOS did not have a significantly higher risk compared to those without PCOS (HR: 1.80, 95% CI: -5.43-9.04, I²=0%) in a random-effects model (Figure 4).

Myocardial Infarction

Twelve studies investigated the risk of MI. There was no significant difference between the PCOS and non-PCOS groups (HR: 2.68, 95% CI: 0.69-4.82, p=0.003; I²=82%, p<0.00001) in a random-effects model (Figure 5).

Ischemic Heart Disease

Seven studies evaluated ischemic heart disease outcomes. The analysis showed no significant increase in risk for patients with PCOS compared to controls (HR: 2.68, 95% CI: 0.69-4.67, I²=99.8%) in a random-effects model, Figure 6).

Stroke

Eleven studies assessed the risk of stroke. Unlike other outcomes, PCOS was associated with a significantly increased risk of stroke (OR: 1.89, 95% CI: 1.22-2.55, I²=97.7%) in a random-effects model (Figure 7).

Publication Bias

Publication bias for CVD death risk was assessed using Egger’s regression test, Begg’s test, and funnel plot analysis. While Begg’s test indicated no bias (p=1.00), Egger’s regression test and the funnel plot (Figure 8) revealed evidence of publication bias (p=0.01).

Discussion

This meta-analysis investigated the relationship between PCOS and cardiovascular outcomes, including all-cause mortality, cardiovascular mortality, MI, IHD, stroke, and overall CVD. Our findings indicate that while women with PCOS are at an increased risk for stroke, no significant association was observed for other cardiovascular outcomes, underscoring the need for further investigation into the specific pathways underlying these risks.

The current body of evidence on the impact of PCOS on CVD risk remains inconsistent. Although multiple studies have linked PCOS with various cardiometabolic abnormalities such as diabetes⁽³⁰⁾, dyslipidemia⁽³¹^,³²⁾, hypertension⁽³¹⁾, and metabolic syndrome⁽³⁰⁾, the direct connection to clinical cardiovascular events is not yet clear. IR and hyperinsulinemia, both of which are common in PCOS, contribute to oxidative stress, vascular dysfunction, and reduced vascular compliance, all of which increase the risk of CVD⁽³³⁾. Furthermore, PCOS leads to dysregulation of lipid metabolism, resulting in elevated levels of low-density lipoprotein and triglycerides and reduced high-density lipoprotein, which exacerbate the risk of atherosclerosis and dyslipidemia⁽³⁴⁾. The presence of excess adipose tissue in women with PCOS also raises levels of inflammatory cytokines and leptin, further worsening IR and promoting hypertension⁽³⁵⁾.

Previous systematic reviews have presented mixed findings regarding the association between PCOS and cardiovascular outcomes. For instance, De Groot et al.⁽³⁶⁾ reported that women with PCOS had approximately twice the risk of developing coronary heart disease and experiencing strokes. A review by Millán-de-Meer et al.⁽³²⁾ showed the prevalence of cardiovascular outcomes in both premenopausal and postmenopausal women, displaying a notable increase in OR for MI and stroke, though no remarkable increase was observed for overall CVD or coronary artery disease. A 2020 meta-analysis by Ramezani Tehrani et al.⁽³⁷⁾ found that reproductive-aged women with PCOS had a significantly higher HR for clinical cardiovascular events. More recently, studies by Tay et al.⁽³⁸⁾ and Zhang et al.⁽³⁹⁾ have indicated an elevated risk of myocardial infarction, ischemic heart disease, and stroke in women with polycystic ovary syndrome. Despite these findings, neither study reported a significant association between PCOS and either all-cause or cardiovascular-specific mortality, highlighting the complexity of this relationship.

Several methodological limitations must be considered when interpreting these findings. Many of the studies included in this analysis had small sample sizes, short follow-up periods, and primarily focused on younger women, which may limit the generalizability of the results. Additionally, there was inconsistency in the diagnostic criteria for PCOS across studies, and the inclusion of different PCOS phenotypes introduced heterogeneity. Importantly, the cardiovascular impact of different PCOS phenotypes is not uniform. Women with oligo-amenorrhea or menstrual irregularities appear to be at a higher risk for CVD, likely due to the effects of hyperinsulinemia and IR. On the other hand, the evidence linking hyperandrogenism to cardiovascular outcomes remains mixed⁽⁴⁰⁾.

Age also appears to be an important factor influencing cardiovascular risk in women with PCOS⁽³⁷⁾. Younger women tend to have higher cardiovascular risk due to factors such as central obesity, IR, and unfavorable lipid profiles⁽⁴¹^,⁴²⁾. However, these risks often decrease with age⁽⁴³⁾, as androgen excess and metabolic abnormalities tend to improve over time⁽⁴⁴^,⁴⁵⁾. The wide age range of participants in many cohort studies could have obscured significant associations between PCOS and cardiovascular outcomes, especially among older women.

Geographic and socioeconomic disparities should also be considered when interpreting these findings. Recent evidence suggests that cardiovascular risks associated with PCOS may be more pronounced in East Asian and African populations, particularly in lower-income countries⁽⁴⁶⁾. Variations in healthcare access, lifestyle, and socioeconomic conditions likely contribute to these differences⁽¹⁴⁾.

Despite the high prevalence of metabolic abnormalities in women with PCOS, the risk of cardiovascular events is not uniformly elevated across all individuals. Several protective factors may contribute to a more favorable cardiovascular profile in some women with PCOS. For example, women with PCOS tend to experience delayed menopause, and earlier menarche, which may lead to an extended exposure to the cardio-protective effects of estrogen. Additionally, due to heightened awareness of PCOS, proactive management of cardiovascular risk factors may mitigate some of the cardiovascular risks⁽⁴⁷^,⁴⁸⁾.

Although the exact impact of PCOS on cardiovascular health remains unclear, existing guidelines recommend preventive measures due to the high prevalence of cardiometabolic issues among affected individuals. These guidelines suggest that weight should be tracked in a non-stigmatizing and supportive manner, and lipid profiles should be first assessed at diagnosis, and thereafter, periodically based on overall cardiovascular risk. BP should be measured once a year, and an oral glucose tolerance test should be conducted at the time of diagnosis, with follow-up tests up to three times per year or more frequently if there are elevated diabetes risk factors or if pregnancy is being planned or achieved⁽⁴⁹^,⁵⁰⁾.

In conclusion, while PCOS is associated with significant metabolic and vascular abnormalities, the clinical translation to cardiovascular events is complex and influenced by factors such as age, phenotype, geography, and proactive risk management. Future research should focus on phenotype-specific risks, long-term outcomes, and diverse populations to better clarify the cardiovascular implications of PCOS.

Strengths and Limitations

This meta-analysis has several strengths. It includes a large sample size of over one million women and examines a broad range of cardiovascular outcomes, providing a comprehensive view of the relationship between PCOS and cardiovascular health. The inclusion of longitudinal studies, many of which had follow-up periods of 10 years or more, adds reliability to the findings. However, several limitations need to be acknowledged. Despite searching multiple databases and reviewing reference lists of prior studies, some relevant studies may have been missed. There was significant variability in how cardiovascular outcomes and study designs were defined across the included studies. Many studies relied on ICD codes to classify cardiovascular events. While widely used, these codes can be inaccurate. Additionally, some studies used questionnaires or self-reported data to collect information, which may introduce bias. Another challenge was the inconsistency in diagnostic criteria for PCOS. Different studies used varying definitions, such as the Rotterdam criteria, and others, which capture a range of PCOS phenotypes. This lack of standardization makes it difficult to differentiate cardiovascular risks associated with different PCOS subtypes. Moreover, most studies focused on premenopausal women, providing limited insights into how cardiovascular risks may change in aging women with PCOS. Therefore, further research is needed to address these limitations and provide more definitive answers regarding the long-term cardiovascular risks associated with PCOS.

Implications for Practice

This meta-analysis highlights the need for proactive management of cardiovascular risks in women with PCOS, particularly given the increased risk of stroke. Regular monitoring of blood pressure, glucose, and lipid levels, along with lifestyle modification, should be promoted. Care should be personalized based on age and PCOS phenotype, with younger women requiring a focus on metabolic health and older women on long-term vascular risk reduction. Addressing geographic and socioeconomic disparities is also essential to improve access to preventive care. Educating patients about their risks and promoting healthy lifestyles can further reduce complications.

Conclusion

This meta-analysis demonstrates an elevated risk of stroke among women with PCOS, but the evidence linking PCOS to other cardiovascular outcomes, for instance, MI and overall cardiovascular mortality, remains unclear. Although PCOS is frequently linked to metabolic disturbances like IR, abnormal lipid profiles, and high blood pressure, the impact of these factors on clinical cardiovascular events is complex and influenced by age, phenotype, geography, and preventive management. Future research should focus on phenotype-specific risks and larger, long-term studies to better understand the cardiovascular implications of PCOS.

Acknowledgments

The authors appreciate the support and guidance provided by the Clinical Research Development Unit of Al-Zahra Hospital throughout the course of this study. Their expertise and resources have been instrumental in the success of this project.

Authorship Contributions

Concept: S.T.M., P.B.A., Design: S.T.M., P.B.A., Data Collection or Processing: A.A., H.P., R.K., Analysis or Interpretation: S.T.M., P.B.A., Literature Search: A.A., H.P., R.K., Y.J., Writing: S.T.M., A.A., R.K., Y.J.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study received no financial support.

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Risk of cardiovascular and cerebrovascular events in polycystic ovarian syndrome women: An updated meta-analysis of cohort studies