Background Prior systematic reviews indicate polycystic ovary syndrome (PCOS) is associated with cardiovascular diseases (CVDs), but their meta-analyses have very high statistical heterogeneity, likely because PCOS is a heterogenous syndrome diagnosed by having any two of the three symptoms: hyperandrogenism, oligo-amenorrhea/menstrual irregularity or polycystic ovaries. This limits the interpretation and clinical use of these results as the pooled estimate may not represent the CVD risk of any PCOS population. Furthermore, it is unclear whether observed associations can be entirely explained by PCOS-associated obesity. Several studies report higher risk of CVDs from individual PCOS symptoms, but a comprehensive assessment of how each symptom contributes to CVD risk is lacking. This study aims to assess CVD risk for women with one of the PCOS symptoms, and the influence of obesity.

Methods A systematic review and meta-analysis of observational studies was conducted. PubMed, Scopus, and Web of Science were searched without restrictions in July 2022. Studies meeting inclusion criteria examined the association between one of the three PCOS symptoms and risk of a CVD. Two reviewers independently assessed abstracts and full-text articles, and extracted data from eligible studies. Where appropriate, relative risk (RR) and 95%CI were estimated by random-effects meta-analysis in R. To examine the contribution of obesity to the CVD risk of PCOS women, results that adjusted for or did not adjust for obesity were pooled separately. Statistical heterogeneity was assessed using the I2 statistic.

Results Twenty-three studies, including 346,486 women, were identified. Oligo-amenorrhea/menstrual irregularity was associated with overall CVD (RR=1.29, 95%CI=1.09-1.53; I2=0.00%, p=0.379), coronary heart disease (RR=1.22, 95%CI=1.06-1.41; I2=51.06%, p=0.006) and myocardial infarction (RR=1.37, 95%CI=1.01-1.88; I2=6.47%, p=0.602) but not cerebrovascular disease (HR=0.85, 95%CI=0.49–1.47; 1 study). After further adjustment for obesity, results were broadly consistent, with PCOS still associated with overall CVD (RR=1.25, 95%CI=1.03-1.52; I2=51.69%, p=0.040), coronary heart disease (RR=1.25, 95%CI:1.03-1.51; I2=36.94%, p=0.044) and myocardial infarction (RR=1.31, 95%CI=1.11-1.55; I2=0.00%, p=0.567) but not cerebrovascular disease (RR=1.09, 95%CI:0.50-2.34; I2=32.22%, p=0.102). There was mixed evidence for the role of hyperandrogenism in CVDs. No studies examined polycystic ovaries as an independent exposure for CVD risk.

Conclusions Oligo-amenorrhea/menstrual irregularity is associated with greater risk of overall CVD, coronary heart disease and myocardial infarction, independent of obesity. This could inform how cardiometabolic screening and risk management may be tailored to specific PCOS phenotypes. More research is needed to assess the risks associated with hyperandrogenism or polycystic ovaries.

Conflict of Interest Nil