In the preliminary analysis, the search strategy yielded a total of 4,277 studies. After removing duplicates, 3886 studies remained for title and abstract screening. During this process, we excluded 3837 irrelevant citations, and 29 potentially relevant studies remained for full-text review. After excluding reviews, meta-analyses or studies that did not report outcome data, ten studies were found to be eligible for inclusion in this systematic review and dose‒response meta-analysis. Figure 1 shows the results of the study selection. Data from 10 studies were included in the final analysis, involving 480,628 participants32–41. One study was hospital-based, while the remaining nine were population-based studies. Seven of the included studies were from the United States, and three were from Sweden. The median follow-up period ranged from 5.4 to 13 years (two studies did not provide the median follow-up period). Details of the included studies are provided in Table 1. Ten of the included cohort studies were found to have a low risk of bias (NOS score ≥ 7). Detailed results of the risk of bias assessments for each study are provided in Appendix 2 in the supplement.
Associations between HRT use and the risk of CRC mortality
Ten cohort studies32–41 were included in our analysis of the association between HRT use and CRC mortality. The meta-analysis showed that HRT was associated with a 23% reduction in the risk for CRC mortality [HR = 0.77, 95% CI (0.68, 0.87), I2 = 69.5%, P < 0.05], Fig. 2. A dose‒response analysis showed strong evidence of a linear (P for nonlinearity = 0.34) association between HRT and CRC mortality based on five cohort studies, such that each additional year of HRT use was associated with a 3% reduction in the risk of CRC mortality; this decrease was statistically significant [HR = 0.97, 95% CI(0.94–0.99), P < 0.05], Fig. 3.
Subgroup analysis
Given the significant heterogeneity in the meta-analysis of all the included studies, we performed subgroup analyses to identify the sources of the heterogeneity. We conducted subgroup analyses based on study design, study region, research centre, study setting, use time, location, age and HRT type for CRC mortality in cohort studies. Seven cohort studies showed that HRT may reduce colon cancer mortality [HR = 0.79, 95% CI (0.68, 0.92), I2 = 69.1%, p < 0.05], and four cohort studies showed that HRT does not reduce rectal cancer mortality [HR = 0.78, 95% CI (0.55, 1.09), I2 = 58.1%, p = 0.15]. Compared with those with no HRT exposure, four cohort studies indicated that current HRT use [HR = 0.57, 95% CI (0.42,0.77), I2 = 39.5%, p < 0.05] has benefits for CRC mortality in women. The results are shown in Table 2. The decreased risk remained constant among other subgroups stratified by study design, study region, research centre, study setting, use time, location, age and HRT type. Moreover, the results of subgroup analyses showed significant between-group differences by study design, study region, research centre, study setting, use time, location and HRT type (P for between-group difference < 0.05).
Table 2
Subgroup analyses in a subset of included studies for risk of CRC mortality
Variables | | RR | 95% CI | I2(%) | P | No. of studies | P for interaction |
Overall | | 0.77 | 0.68 to 0.87 | 66.4 | < 0.001 | 10 | NA |
Study design | | | | | | | 0.001 |
| Prospective cohort | 0.75 | 0.68 to 0.81 | 0 | < 0.001 | 4 | |
| Retrospective cohort | 0.80 | 0.65 to 0.97 | 73.5 | 0.023 | 6 | |
Study region | | | | | | | 0.001 |
| USA | 0.77 | 0.66 to 0.90 | 69 | 0.01 | 8 | |
| Sweden | 0.73 | 0.63 to 0.85 | 0 | < 0.001 | 2 | |
Research centre | | | | | | 0.001 |
| Single | 0.72 | 0.62 to 0.84 | 0 | < 0.001 | 3 | |
| Multicentre | 0.78 | 0.67 to 0.91 | 76.5 | 0.015 | 7 | |
Study setting | | | | | | | 0.001 |
| Population-based | 0.78 | 0.68 to 0.89 | 70.6 | < 0.001 | 9 | |
| Hospital-based | 0.60 | 0.40 to 0.90 | 62.5 | 0.014 | 1 | |
HRT type | | | | | | | < 0.001 |
| Oestrogen | 0.78 | 0.60 to 1.02 | 77.6 | 0.066 | 5 | |
| Oestrogen + progestin | 0.78 | 0.46 to 1.33 | 90.1 | 0.359 | 3 | |
| Contraceptive | 0.92 | 0.74 to 1.14 | 0 | 0.432 | 2 | |
Location | | | | | | | 0.003 |
| Colon | 0.79 | 0.68 to 0.92 | 69.1 | 0.003 | 7 | |
| rectal | 0.78 | 0.55 to 1.09 | 58.2 | 0.148 | 4 | |
HRT use | | | | | | | 0.002 |
| former | 0.89 | 0.75 to 1.05 | 54.3 | 0.164 | 4 | |
| Current | 0.57 | 0.42 to 0.77 | 54.5 | < 0.001 | 4 | |
Years of use | | | | | | | 0.012 |
| ≤ 5 | 0.83 | 0.68 to 1.01 | 54 | 0.058 | 5 | |
| > 5 | 0.70 | 0.59 to 0.83 | 32.1 | < 0.001 | 5 | |
Age | | | | | | | 0.131 |
| < 50 | 0.74 | 0.56 to 0.98 | 42.2 | 0.039 | 2 | |
| 50–59 | 0.99 | 0.84 to 1.18 | 0 | 0.961 | 3 | |
| 60–69 | 0.85 | 0.74 to 0.98 | 69.4 | 0.028 | 3 | |
| > 70 | 1.01 | 0.88 to 1.36 | 0 | 0.394 | 2 | |
Note: HR: hazard ratio; HRT: hormone replacement therapy; CI: confidence interval.
Associations between HRT use and the risk of all-cause mortality
Meta-analyses for all-cause mortality included seven cohort studies33,36−41. The meta-analysis of seven cohort studies showed that HRT was associated with a 29% reduction in the risk for all-cause mortality [HR = 0.71, 95% CI (0.54, 0.92), I2 = 89.6%, p < 0.05], Fig. 4. A linear (P for nonlinearity = 0.88) dose‒response analysis of three cohort studies showed that each additional year of HRT use was associated with a 2% decrease in the risk of all-cause mortality; this finding was not statistically significant [HR = 0.98, 95% CI(0.97, 1.01), P = 0.08], Fig. 5.
Subgroup analysis
Given the significant heterogeneity in the meta-analysis of all the included studies, we performed subgroup analyses to better understand the heterogeneity. The decreased risk remained constant among other subgroups stratified by study design, study region, research centre, study setting, use time, age and HRT type. Moreover, the results of subgroup analyses showed significant between-group differences by study design, study region, research centre, study setting, use time, age and HRT type (P for between-group difference < 0.05). The results are shown in Table 3.
Table 3
Subgroup analyses in a subset of included studies for risk of all-cause mortality
Variables | | RR | 95% CI | I2(%) | P | No. of studies | P for interaction |
Overall | | 0.71 | 0.54 to 0.92 | 89.6 | 0.01 | 9 | NA |
Study design | | | | | | | < 0.001 |
| Prospective cohort | 0.46 | 0.21 to 1.06 | 92.5 | 0.067 | 2 | |
| Retrospective cohort | 0.83 | 0.68 to 1.02 | 79.4 | 0.082 | 5 | |
Study region | | | | | | | < 0.001 |
| USA | 0.71 | 0.51 to 0.99 | 90.1 | 0.041 | 7 | |
| Sweden | 0.70 | 0.60 to 0.82 | 0 | < 0.001 | 1 | |
Research centre | | | | | | < 0.001 |
| Single | 0.71 | 0.62 to 0.81 | 0 | < 0.001 | 2 | |
| Multicentre | 0.70 | 0.46 to 1.05 | 91.8 | 0.085 | 5 | |
Study setting | | | | | | | < 0.001 |
| Population-based | 0.71 | 0.53 to 0.96 | 91.1 | 0.024 | 6 | |
| Hospital-based | 0.70 | 0.52 to 0.94 | 0 | 0.525 | 1 | |
HRT type | | | | | | | 0.002 |
| Oestrogen | 0.86 | 0.66 to 1.11 | 84.6 | 0.25 | 3 | |
| Oestrogen + progestin | 1.03 | 0.90 to 1.18 | 0 | 0.607 | 2 | |
| contraceptive | 0.88 | 0.65 to 1.18 | 47.8 | 0.385 | 2 | |
HRT use | | | | | | | < 0.001 |
| former | 0.97 | 0.83 to 1.13 | 47.7 | 0.688 | 3 | |
| Current | 0.60 | 0.35 to 1.02 | 95.3 | 0.061 | 4 | |
Years of use | | | | | | | < 0.001 |
| ≤ 5 | 0.86 | 0.60 to 1.24 | 86 | 0.426 | 3 | |
| > 5 | 0.89 | 0.80 to 0.98 | 4.3 | 0.021 | 3 | |
Age | | | | | | | 0.001 |
| < 50 | 0.78 | 0.65 to 0.95 | 30.5 | 0.013 | 2 | |
| 50–59 | 0.95 | 0.83 to 1.09 | 0 | 0.456 | 3 | |
| 60–69 | 0.79 | 0.70 to 0.90 | 81.4 | < 0.001 | 2 | |
| > 70 | 1.12 | 0.99 to 1.26 | 0 | 0.071 | 2 | |
Note: CI: confidence interval; HRT: hormone replacement therapy; HR: hazard ratio;
Sensitivity analyses and publication bias
The results of sensitivity analyses for the outcomes of CRC mortality and all-cause mortality were consistent with those of primary analyses based on cohort studies (Fig. 6A, B). Sensitivity analyses were performed using the leave-one-out method to further examine the stability of the results. We found that no individual study significantly altered the summary HR [lowest RR = 0.75, 95% CI(0.69,0.80); highest RR = 0.78, 95% CI(0.68, 0.89)] ( Appendix 3 in the supplement).
Funnel plots for CRC mortality demonstrate specific evidence of publication bias as determined by Begg's test (p = 0.82) and Egger’s test (p = 0.38) (Fig. 7A). Funnel plots for all-cause mortality also demonstrate evidence of publication bias as determined by Begg's test (p = 0.92) and Egger's test (p = 0.25) (Fig. 7B). However, there was no evidence of significant publication bias according to Begg’s test and Egger’s test.