Introduction

Hypertension is a major cause of morbidity and mortality worldwide and is an established risk factor for coronary heart disease and stroke1,2. Globally a high systolic blood pressure accounted for 10.4 million deaths and 208.1 million disability-adjusted life-years (DALYs) in 20133. Important risk factors for hypertension include overweight and obesity4, low physical activity5,6, high alcohol consumption7, dietary factors8,9,10,11, and use of non-narcotic analgesics12.

Endometrial cancer is the eighth most common type of cancer in women with approximately 320 000 cases recorded in 2012, accounting for about 4.8% of all cancers in women (2.3% overall)13. It is more common in high-income countries than in low-income countries, however, its incidence has been increasing in populations undergoing urbanization and economic growth, in parallel with increasing obesity rates and sedentary lifestyles14,15. Several risk factors for endometrial cancer have been established including excess body weight16, low physical activity17, diabetes history18, and use of unopposed hormone replacement therapy19. A history of hypertension has been evaluated as a risk factor for endometrial cancer in several case-control20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38 and cohort studies39,40,41,42,43,44, and many20,21,24,25,26,28,30,32,33,34,35,36,37,38,39,42,44, but not all22,23,27,29,31,39,42,44 of these found an increased endometrial cancer risk. Because obesity and diabetes are important risk factors for both hypertension45,46 and endometrial cancer16,18 it is not clear whether the association between hypertension and endometrial cancer could be due to confounding by these factors because some studies did not adjust for BMI20,21,25,33,35,38 or diabetes20,21,24,25,28,29,33,35,38. We conducted a systematic review and meta-analysis of case-control and cohort studies that had investigated the association between hypertension and endometrial cancer risk with an aim of clarifying the strength of the association, possible sources of heterogeneity and potential confounding by other risk factors.

Methods

Search strategy and inclusion criteria

We searched the PubMed and Embase databases up to 27th February 2016 for eligible studies. We used the following search terms in the PubMed search: (hypertension OR high blood pressure OR blood pressure OR risk factor) AND (endometrial cancer OR uterine cancer). We followed standard criteria for reporting meta-analyses47.

Study selection

We included published retrospective case-control studies and cohort studies that investigated the association between hypertension and the risk of endometrial cancer. Adjusted estimates of the relative risk (odds ratios and hazard ratios which were considered to be approximately equal given that endometrial cancer is a relatively uncommon cancer) had to be available with the 95% CIs in the publication. A list of excluded studies and exclusion reasons is provided in Supplementary Table 1. DA and AS conducted the study selection.

Data extraction

The following data were extracted from each study: The first author’s last name, publication year, country where the study was conducted, study period, sample size, number of cases/controls, exposure and subgroups of tumor characteristics (low, moderate or high aggressiveness) or cancer type (type 1 vs. type 2), relative risks and 95% confidence intervals for the association and variables adjusted for in the analysis. Data were extracted by one reviewer (DA) and checked for accuracy by a second reviewer (AS).

Statistical methods

We calculated summary relative risks of developing endometrial cancer by history of hypertension using the random-effects model by DerSimonian and Laird48 which takes into account both within and between study variation (heterogeneity). The average of the natural logarithm of the relative risks was estimated and the relative risk from each study was weighted by the inverse of its variance49.

Heterogeneity between studies was evaluated using Q and I2 statistics50. Cochran’s Q is calculated as the weighted sum of squared differences between individual study effects and the pooled effects across studies, with weights being those in the pooling method. I2 is a measure of how much of the heterogeneity that is due to between study variation rather than chance. I2-values of 25%, 50% and 75% indicates low, moderate and high heterogeneity respectively. We conducted main analyses (all studies combined) and stratified by study design (cohort studies, case-control studies) because of the greater potential for recall and selection bias in retrospective case-control studies and to investigate sources of potential heterogeneity. We also conducted subgroup analyses by other study characteristics such as sample size, number of cases, geographic location, and by adjustment for confounding factors. We also conducted a stratified analysis by whether the articles explicitly stated that participants with prevalent hysterectomies at baseline were excluded, and/or whether participants with incident hysterectomies were censored during follow-up in cohort studies, or excluded from the control group in case-control studies.

Publication bias was assessed using Egger’s test51 and Begg-Mazumdar’s test52 and by inspection of funnel plots. Study quality was assessed using the Newcastle-Ottawa scale which ranks the studies on a scale from 0 to 9 based on the selection of the study population, comparability between cases and non-cases and the assessment of the outcome53. The statistical analyses were conducted using the software package Stata, version 13.0 software (StataCorp, Texas, US).

Results

Out of a total 7879 records identified by the search we included 25 studies with 28385 cases and 300598 participants in the meta-analysis of hypertension and endometrial cancer risk, including six cohort studies39,40,41,42,43,44 and nineteen case-control studies20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37 (Fig. 1 and Tables 1 and 2). Fourteen of the studies were from North-America, seven were from Europe, and four were from Asia (Tables 1 and 2).

Figure 1
figure 1

Flow-chart of study selection.

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Table 1 Prospective studies of hypertension and endometrial cancer.
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Table 2 Case-control studies of hypertension and endometrial cancer.
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The summary RR for all studies was 1.61 (95% CI: 1.41–1.85, I2 = 86%), and it was 1.73 (95% CI: 1.45–2.06, I2 = 89%) for case-control studies and 1.32 (95% CI: 1.12–1.56, I2 = 47%) for cohort studies (Fig. 2), however, the test for heterogeneity by study design was not significant, p = 0.19. In sensitivity analyses excluding one study at a time the summary RR ranged from 1.49 (95% CI: 1.34–1.65) when excluding the study by Zhang et al.33 to 1.65 (95% CI: 1.41–1.94) when excluding the study by Trabert et al.36. There was evidence of publication bias with Egger’s test, p = 0.005 (Fig. 3), however, when stratified by study design this was observed among case-control studies, p = 0.007, but not among cohort studies, p = 0.78.

Figure 2
figure 2

Hypertension and endometrial cancer, forest plot.

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Figure 3
figure 3

Hypertension and endometrial cancer, funnel plot.

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Subgroup and sensitivity analyses, study quality assessment

There were positive associations in almost all subgroup analyses (Table 3), and although there was no heterogeneity when stratified by study design, geographic location or number of cases, there was indication of heterogeneity when studies were stratified by confounding factors including smoking (p = 0.02), BMI (p = 0.003), oral contraceptive use (p = 0.02), hormone replacement therapy (p = 0.08), parity (p = 0.03), and age at menopause (p = 0.07), with weaker, but still significant associations among studies with such adjustments. When we conducted sensitivity analyses removing one study at a time, the size of the summary estimate persisted and did not vary substantially (Supplementary Table 2).

Table 3 Subgroup analyses of hypertension and endometrial cancer.
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In a further sensitivity analysis we also conducted a subgroup analysis by whether the studies explicitly stated that they excluded participants with prevalent hysterectomies at baseline and/or stated that they censored participants at the time of incident hysterectomy (cohort studies) or excluded participants who had undergone hysterectomy from the control group (case-control studies). The summary RR was 1.51 (95% CI: 1.28–1.78, I2 = 88.5%) for studies with such exclusions or censoring and 1.81 (95% CI: 1.49–2.20, I2 = 56.5%) for studies without such exclusions or censoring.

In a sensitivity analysis we also included a pooled analysis which assessed the association between quintiles of systolic blood pressure and endometrial cancer risk54, using the relative risk for the highest vs. the lowest quintile of systolic blood pressure. The results were not materially altered, summary RR = 1.61 (95% CI: 1.42–1.83, I2 = 38%) for all studies and 1.33 (95% CI: 1.16–1.52, I2 = 86%) for cohort studies. Further including another cohort study55 which reported on elevated blood pressure (≥130/≥85 vs. <130/<85 mm/Hg) or self-reported hypertension, not only hypertension, did also not substantially alter the results, summary RR = 1.57 (95% CI: 1.38–1.78, I2 = 85%) for all studies and summary RR = 1.28 (95% CI: 1.12–1.48, I2 = 46%) for cohort studies. Mean (median) study quality scores were 7.3 (7.0) for all studies combined, 7.3 (7.0) for case-control studies, and 7.3 (7.0) for cohort studies).

Discussion

To our knowledge this is the first meta-analysis of published observational studies of hypertension and the risk of endometrial cancer and our results confirm that hypertension is a strong risk factor for endometrial cancer with a 61% increase in the relative risk, however, the association was weaker in cohort studies (RR = 1.32) than among case-control studies (RR = 1.73). These findings are consistent with a large cohort study of 290 000 women in Austria, Norway and Sweden which found an increased endometrial cancer risk with increasing levels of diastolic blood pressure and in particular, systolic blood pressure54. The results also persisted in a sensitivity analysis including the results from this cohort study54 as well as the EPIC study55, which reported on elevated blood pressure or hypertension.

The present meta-analysis has some limitations. As hypertension is a condition that is strongly related to lifestyle factors and some medical conditions including diet, BMI, physical activity, and diabetes we cannot entirely exclude the possibility that the observed association between hypertension and endometrial cancer risk at least partly could be due to confounding. We found that the association was weaker, but still statistically significant, among studies that adjusted for smoking, BMI, oral contraceptive use, hormone replacement use, parity and age at menopause (RR = 1.14–1.34 for studies with such adjustment vs. 1.74–2.10 for studies without such adjustment). However, because there was still a significant association in subgroups that adjusted for these factors it could indicate that there is an adverse effect of hypertension on endometrial cancer risk, but that it may be slightly weaker than what was suggested from the overall summary estimates. Because the original studies did not stratify for BMI or diabetes it was not possible for us to investigate whether the association was limited to specific weight classes or if it was modified by diabetes status.

We also found that the positive association between hypertension and endometrial cancer persisted when the studies were stratified by whether participants with prevalent hysterectomies at baseline were excluded and/or whether participants with incident hysterectomies were censored, or whether prevalent hysterectomies were excluded from the control group. Hypertension may also be related to hysterectomies56,57,58, and could potentially bias the risk estimates, however, any bias would most likely be toward the null. We cannot exclude the possibility of residual confounding from other risk factors such as use of intrauterine device59, polycystic ovarial syndrome60, or other potential risk factors that the original studies may not have adjusted for.

Case-control studies are more likely to be affected by certain biases, such as recall bias and selection bias. Because we included both case-control and cohort studies there is a possibility that recall or selection bias might have affected the results in the case-control studies and the overall summary estimate. Although the association appeared to be stronger in case-control studies than among cohort studies, there was still a significant association among cohort studies, which suggest that recall bias or selection biases does not entirely explain the observed association. In addition, there was some indication of publication bias with Egger’s test, but this appeared to be restricted to the analyses of case-control studies and all studies combined, and was not observed among the cohort studies.

The biological mechanism(s) that may explain an adverse effect of hypertension on endometrial cancer risk are unclear at present. It has been suggested that long-term hypertension may lead to cellular senescence and inhibition of apoptosis61. It has also been suggested that medications used for the treatment of hypertension could increase cancer risk, however, a meta-analysis found little evidence of an association with overall cancer62, and a cohort study found no relation with female genital cancers63, although few studies have specifically investigated endometrial cancer.

Strengths of the present meta-analysis include the comprehensive search strategy, the detailed subgroup and sensitivity analyses, and the large sample size providing a more robust estimate of the association between hypertension and endometrial cancer risk. To date relatively few studies have investigated the association between hypertensive disorders of pregnancy and endometrial cancer risk with one study suggesting an increased risk with hypertensive disorders overall64, while another study found no association with preeclampsia overall, although an increased risk was observed with early-onset preeclampsia65. Any further studies could better assess the causality of the observed association between hypertension and endometrial cancer by using genetic risk scores for hypertension66,67. In addition, clarification of potential effect modification by age at exposure, BMI and diabetes status, and further studies of the association with subtypes of endometrial cancer are needed.

In conclusion, the results from this systematic review and meta-analysis suggest that women with hypertension may have a 61% increase in the relative risk of developing endometrial cancer. Any further studies should clarify potential effect modification by age, BMI and diabetes status, and the causality of the observed association, as well as the potential underlying mechanism(s).

Additional Information

How to cite this article: Aune, D. et al. Hypertension and the risk of endometrial cancer: a systematic review and meta-analysis of case-control and cohort studies. Sci. Rep. 7, 44808; doi: 10.1038/srep44808 (2017).

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