Worldwide cardiovascular disease (CVD) accounts for one of the highest proportions of non-communicable diseases, is a leading cause of morbidity and a major contributor to disability [1, 2, 3]. Cardio-metabolic disturbances, genetic, behavioral, environmental, and psycho-social risk factors are major drivers of CVD [1, 4, 5].

It is well documented that there are substantial differences between men and women in the prevalence and burden of different CVDs [6]. In this respect, there are a number of clinical conditions unique to women that have been described as female specific factors which increase CVD risks [7, 8, 9, 10]. Likewise, menopause has been related to an increased risk of CVDs in many studies [11, 12]. The exact underlying etiology is not fully understood, but it may be strongly attributed to estrogen deprivation [13]. This hormone, as the main sex steroid hormone, has some cardioprotective mechanisms such as increased angiogenesis, and vasodilatation and also may reduce fibroblast proliferation and antiapoptotic properties [14]. The average age at the onset of menopause is around 51 years [15], however, in 3–4% of all women, it occurs before the age of 40 years, which is called premature ovarian insufficiency (POI) [16]. The preliminary studies reported that POI could be an independent risk factor for cardiovascular mortality and morbidity [17, 18].

The aim of this systematic review and meta-analysis was to assess the risk of developing cardiovascular events among women with POI compared to women with age at menopausal 50–54 years.

This systematic review and meta-analysis was performed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [19], to achieve the following objectives: (i) to study the pooled risk of developing the composite outcome of all types of cardiovascular events, regardless of the type of events among women with POI defined as menopause 40 years compared to menopause aged 50–54 years; (ii) to study the pooled risk of developing specific cardiovascular events including coronary heart disease, stroke, heart failure, heart valve disease, pulmonary hypertension, chronic hypertension and death due to any cardiovascular events among women with POI compared to women with age at menopause of 50–54 years.

The review question was formulated using the PICO (population, intervention/index, control, and outcomes) statement as follows: population consisted of post-menopausal women (either natural or surgical); index was POI; control group included women with an age at menopause of 50–54 years; and the outcome of interest was composite and specific end-point of cardiovascular events.

Furthermore, the systematic review and meta-analysis was registered in the PROSPERO International Prospective Register of Systematic Reviews with the registration number CRD42022376480.

The present systematic review and meta-analysis of observational prospective studies with 4–20 years of follow up revealed that POI is an important risk factor for composite CV events, particularly for coronary heart disease after adjustment for hormone therapy. However, no difference was found regarding the risk of stroke and death due to CV events in POI and women experiencing menopause at 50–54 years. Subgroup analysis among those experienced natural POI confirmed these findings. We found no heterogeneity and publication bias among the included studies.

Cardiovascular disease is one of the leading causes of mortality among women [37]. There is substantial evidence indicating that the risk significantly rises following menopause [38, 39]. While the specific mechanisms behind the development of cardiovascular disease in menopausal women are not yet fully understood, several possibilities have been suggested. One potential mechanism is that the reduced exposure to endogenous estrogens — which have a protective effect on the cardiovascular system — may play a role. Menopause, characterized by estrogen deprivation, can lead to increased secretion of substances that contribute to oxidative stress and vasoconstriction, ultimately impairing endothelial function [40, 41]. Moreover, research has shown that menopausal transition is associated with negative changes in $\beta$-cell function and insulin sensitivity, serum lipid levels, basal metabolic rate, and body composition (including the deposition of fat around the heart) [42, 43]. These factors may represent early steps in the development of cardiovascular events in postmenopausal women.

POI is considered the most severe form of early menopause [16]. Although previous studies have demonstrated that early menopause is an independent risk factor for cardiovascular events [13, 44, 45] there is limited conclusive evidence regarding POI and its association with cardiovascular events. In agreement with our findings, Roeters van Lennep et al. [18] in a systematic review and meta-analysis of 10 observational studies published until 2012, reported that POI was significantly associated with an increased risk of developing overall cardiovascular disease (HR: 1.61, 95% CI 1.22–2.12) and ischemic heart disease (HR: 1.69, 95% CI 1.29–2.21). However, the results of that meta-analysis should be interpreted with caution since two of the ten studies with high weighting in the final pooled result [12, 46], did not strictly follow the definition of POI and included menopausal women aged 40 years as POI.

Another plausible explanation of the positive association between POI and CV events could be related to the fact that POI is associated with other cardio-metabolic disorders. Recently, Anagnostis et al. (2019) [42] in a meta-analysis of thirteen studies reported that both early menopause $>$45 years and POI are significantly associated with increased risk of type 2 diabetes (OR: 1.15, 95% CI: 1.04–1.26, p = 0.003; and OR: 1.50, 95% CI: 1.03–2.19, p = 0.033) respectively. In another meta-analysis of 21 individual studies, Cai et al. (2022) [47] demonstrated that POI patients presented significantly higher waist circumference, total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, and fasting glucose. We hypothesize that the co-existence of other cardio-metabolic risk factors may predispose women with POI to CV events.

However, since underlying reasons and mechanisms related to surgical menopause as a complete lack of ovarian activity due to surgical removal of the organs, could be different from those who experienced natural POI, we performed a subgroup analysis based on the type of POI, whether natural or surgical. The results were found to be similar to the overall outcomes. It is worth mentioning that a considerable proportion of the study participants in this meta-analysis experienced natural POI, it was reasonable to anticipate that the outcomes would not deviate significantly.

Additionally, could highlight the need for the lack of comprehensive long-term studies including RCTs on POI. An international registry for women with POI could be a valuable resource for understanding the natural history of the condition and the long-term health outcomes associated with POI. Such a registry could collect data on a large number of women with POI, including demographic and clinical characteristics, as well as information on treatment and health outcomes over time. The data collected from such a registry could potentially help to fill the gap in evidence regarding the long-term health outcomes of women with POI, as well as provide valuable information for future research studies. In addition, a registry could serve as a resource for clinicians and researchers to improve patient care, support guideline development, and identify research priorities.

The main clinical implication of the current meta-analysis is to identify women with POI as a high risk population for CV events. It needs to be clearly defined if earlier medical therapy such as exogenous estrogen or lifestyle interventions would be valuable compared with the general population [48, 49] as well.

In conclusion, POI is associated with an increased risk of CV events, particularly coronary heart disease. Our findings also extend prior work with data supporting POI as a risk-enhancing factor for CV events. Future studies are warranted to confirm these findings and to explore the potential underlying mechanism linking CV events and POI.

Our study had certain limitations, including a relatively small number of studies included in the meta-analysis. Additionally, due to the lack of information in individual included studies, our results did not adjust for potential confounders such as women’s lifestyle, obstetrics history, age, and lipid profile. Additionally, it is suggested that the type of menopause including natural and surgical menopause may affect cardiometabolic disturbances [50]. However, this factor was not evaluated in most included studies. Besides, the menopausal age was self-reported in included studies. But it was argued that self-report could be a valid data collection tool for age at menopause and suggested that women could provide data on their natural or surgical menopausal age with sufficient accuracy [51, 52]. Further, some included studies published more than 20 years ago, which need to be updated in future studies. Although narrow inclusion criteria for this study led to the adoption of a small number of studies to this meta-analysis, the findings of our meta-analysis comprehensively add new knowledge to the body of international literature and also help with the provision of updated evidence on this important topic. Besides, in our present meta-analysis, we adhered to the precise definition of POI which led to the adoption of high quality evidence and a present precise presentation of the results. Moreover, it is worth noting that all of the included studies in the current meta-analysis had a population-based design, as a representative of general population characteristics with minimizing the selection bias, therefore the finding of this study could be extrapolated to the general population.

CV, cardiovascular; POI, premature ovarian insufficiency; HR, hazard ratio; CI, confidence interval.

Data are available on requested.

SB-G and RB-Y contributed to the conception of the study. SB-G, ECA, BN and TH contributed to the acquisition and interpretation of data. RB-Y analyzed the data and co-wrote the manuscript with SB-G. ECA and BN contributed to editorial changes in the manuscript. ECA, BN and TH revised the final manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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Nord University covered the processing charge to this article.

The authors declare no conflict of interest.