Abstract
Background
Oesophageal adenocarcinoma is characterised by a strong male predominance. We aimed to test the hypothesis that menopausal hormonal therapy decreases the risk of oesophageal adenocarcinoma.
Methods
This population-based cohort study included all women who used systemic menopausal hormonal therapy (exposed) in Sweden between 2005 and 2018. For each exposed participant, five randomly selected female age-matched non-users of menopausal hormonal therapy (unexposed) were included. Cox regression provided hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, smoking-related diagnoses, Helicobacter pylori eradication, use of non-steroidal anti-inflammatory drugs/aspirin, use of statins and hysterectomy.
Results
The study included 296,964 users of menopausal hormonal therapy and 1,484,820 non-users. Ever-users of menopausal hormonal therapy had an overall decreased risk of oesophageal adenocarcinoma (HR 0.78, 95% CI 0.63–0.97), which remained unchanged after further adjustment for gastro-oesophageal reflux disease (HR 0.78, 95% CI 0.63–0.97) and obesity/diabetes (HR 0.79, 95% CI 0.63–0.98). Decreased HRs were indicated both in users of oestrogen only (HR 0.82, 95% CI 0.60–1.12) and oestrogen combined with progestogen (HR 0.75, 95% CI 0.56–1.00). The risk reduction was more pronounced in users younger than 60 years (HR 0.57, 95% CI 0.38–0.86).
Conclusions
Menopausal hormone therapy in women may decrease the risk of oesophageal adenocarcinoma.
Subject terms: Risk factors, Cancer epidemiology, Oesophageal cancer
Background
The past four decades have seen a rapid increase in the incidence of oesophageal adenocarcinoma (including cardia adenocarcinoma) in Western countries, while the incidence of the other main histological type of oesophageal cancer, oesophageal squamous cell carcinoma, has decreased in these countries [1–4]. The main established risk factors for oesophageal adenocarcinoma are gastro-oesophageal reflux disease, obesity and tobacco smoking, while infection with Helicobacter pylori decreases the risk [1, 5, 6]. Tobacco smoking and alcohol overconsumption are the main risk factors for oesophageal squamous cell carcinoma in Western populations [5, 6].
Oesophageal and cardia adenocarcinoma is characterised by a striking male predominance, with a male-to-female incidence ratio of up to 8-to-1 [7, 8]. This sex difference is not fully explained by the sex distribution of the main risk factors, whereas sex hormones may play a role [1, 8]. The 16-year delayed development of oesophageal adenocarcinoma in women compared with men supports the hypothesis that female sex hormones, mainly oestrogen, protect against this cancer [9]. Menopausal hormone therapy (MHT), also known as hormone replacement therapy, is a medication containing oestrogen only or oestrogen combined with progestogen in the treatment of postmenopausal symptoms in women. Some studies have suggested that MHT is associated with a reduced risk of oesophageal adenocarcinoma and also of squamous cell carcinoma [10, 11]. The largest study to date on the topic, our previous population-based cohort study conducted between 2005–2012 in Sweden, found that MHT was associated with a 38% reduced risk of oesophageal or cardia adenocarcinoma [12], but the follow-up of participants was relatively short (on average 7 years) and the power was limited. With an updated cohort, we aimed to re-test the hypothesis that MHT decreases the risk of oesophageal adenocarcinoma in a population-based study with a longer follow-up and better statistical power than existing studies.
Methods
Study design
This was a Swedish nationwide population-based cohort study, assessing the association between MHT and the risk of oesophageal cancer in women, during the period between 1 July 2005 to 31 December 2018. The source population consisted of all female Swedish residents aged 45 years or older who were included in the Swedish Prescribed Drugs and Health Cohort (SPREDH) [13]. In brief, SPREDH is a population-based cohort based on data from four national health data registries in Sweden: Prescribed Drug Registry, Patient Registry, Cancer Registry, and Cause of Death Registry. All of these registries had complete nationwide coverage during the study period. SPREDH includes 8.3 million adults (the vast majority of the Swedish population) with at least one record of selected commonly prescribed medications during the study period. The collected data include basic characteristics, prescribed and dispensed medications, healthcare utilisation, diagnoses and dates and causes of death. Linkage of individuals’ data between registries was enabled by the unique personal identity number assigned to each resident in Sweden. Individuals were excluded if they had any previous cancer of the oesophagus or cardia, breast or female genital organs at cohort entry, had at least two dispensed records of MHT before the age of 45 years, or had a second MHT dispensation before 2006. All participants were followed up until the date of any of the study outcomes, death or the end of the study period (31 December 2018), whichever occurred first. This study was approved by the Regional Ethical Review Board in Stockholm (reference number 2018/271–32).
Exposure
The exposure was at least two dispensed records (at an interval of 1 month or longer) of systemic MHT (oral, transdermal, or injection) during the study period. The MHT medications were identified from the Swedish Prescribed Drug Registry by their Anatomical Therapeutic Chemical (ATC) classification codes (Supplementary Table 1). The exposure started at the time of the second purchase of MHT. We did not define the exposure as starting at the first MHT prescription because we intended to avoid including short-term users who stopped the treatment because of side-effects or other reasons, where the influence of cancer risk would be negligible or absent. The exposure time is illustrated in detail in Supplementary Fig. 1.
For each exposed participant, five female non-users of MHT (unexposed) were randomly selected from SPREDH and matched by age (±1 year) at cohort entry, i.e. on the date of the user’s second MHT purchase. If less than 200 women were available for matching, the age range was increased by 1 year until at least 200 women were available for matching. The exposure was treated as a time-varying variable, i.e. non-users were shifted to the exposed group at any second dispensed record of MHT.
Outcome
The outcome was oesophageal or cardia adenocarcinoma, as identified from the Cancer Registry according to the diagnosis codes 150 and 151.1 in the International Classification of Diseases, 7th version (ICD-7) and histology code 096 in the WHO/HS/CANC/24 classification. Oesophageal squamous cell carcinoma was analysed for comparison purposes (ICD-7 code 150 and histology code 146). Censoring for death was ascertained through the Cause of Death Register.
Covariates
Nine covariates were considered in the analyses: age (continuous), gastro-oesophageal reflux disease (yes or no), obesity or diabetes (yes or no), smoking-related diagnoses (yes or no), alcohol-related diagnoses (yes or no), Helicobacter pylori eradication treatment (yes or no), use of non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin (yes or no), use of statins (yes or no) and hysterectomy (yes or no). Diagnoses and hysterectomy within 10 years before cohort entry were searched for in the Patient Registry. The Patient Registry covers all inpatient care since 1987 and all specialised outpatient care from both public and private sectors since 2001, and has almost 100% complete recording of all inpatient care and 80% completeness for specialised outpatient care [14]. Helicobacter pylori eradication treatment was defined as a record of a specific eradication package in the Prescribed Drug Registry during the study period and was treated as a time-varying variable. Use of other medications (NSAIDs, aspirin and statins) was defined as at least two dispensed records within 1 year before cohort entry in the Prescribed Drug Registry. The codes used to identify the covariates are provided in Supplementary Tables 2–4.
Statistical analysis
Cox proportional hazards regression was performed to estimate the relative risks of the study outcomes in MHT users compared with non-users, providing hazard ratios (HR) with 95% confidence intervals (CI). Both crude and multivariable models were applied. In the main multivariable model of oesophageal adenocarcinoma, adjustments were made for age, smoking-related diagnoses, use of non-steroidal anti-inflammatory drugs or aspirin and use of statins, hysterectomy and Helicobacter pylori eradication treatment. Further adjustments were made for reflux and obesity or diabetes separately in order to assess whether these covariates were involved in the mechanism behind potential associations between sex hormonal exposures and oesophageal adenocarcinoma. The analyses of oesophageal squamous cell carcinoma were adjusted for the covariates in the main model above, except for Helicobacter pylori eradication treatment, and additionally adjusted for alcohol-related diagnoses. The Cox models allowed baseline hazards to differ by year of birth, but the coefficients were constrained to be the same across strata. Subgroup analyses were conducted based on the regimen of MHT (oestrogen only, or oestrogen combined with progestogen). The proportionality hazards assumption was tested by computing the Schoenfeld residuals and was verified in the main models.
We performed subgroup analyses for oesophageal adenocarcinoma by age at cohort entry (<60 or ≥60 years), gastro-oesophageal reflux disease (yes or no), obesity or diabetes (yes or no), smoking-related diagnoses (yes or no), Helicobacter pylori eradication treatment (yes or no) and the duration of follow-up (<5 or ≥5 years). A sensitivity analysis excluded participants with any cancer diagnosis except for non-malignant melanoma (ICD-7 codes 140–209 excluding 191 in the Cancer Registry) before cohort entry. For benchmarking purposes, we analysed associations between MHT and risk of non-melanoma skin cancer (as comparison outcome); we selected non-melanoma skin cancer because of the lack of association with MHT in women [15].
An experienced biostatistician (GS) followed a detailed study protocol and used the statistical software Stata (Release 16, StataCorp, College Station, TX) when performing the data management and statistical analyses. All analyses were two-sided.
Results
Participants
The study comprised 296,964 users of MHT, including 128,208 (43.2%) users of oestrogen only and 168,756 (56.8%) users of oestrogen combined with progestogen, who were followed up for a total of 2,659,711 exposed person-years at risk. These exposed participants were compared with 1,484,820 age-matched non-users of MHT, who contributed to a total of 12,180,12 unexposed person-years at risk. The median duration of follow-up was 9.7 (interquartile range 4.0–12.9) years. The two groups had similar characteristics, except for a slightly lower prevalence of obesity or diabetes and use of statins, and a higher prevalence of hysterectomy among the MHT users (Table 1).
Table 1.
Characteristics of female study participants by exposure status, number (%).
| Characteristics | Users of MHT | Non-users of MHT |
|---|---|---|
| Total | 296,964 (100%) | 484,820 (100%)) |
| Person-years | 2,659,711 | 12,180,126 |
| Age at entry, years | ||
| ≤59 | 178,754 (60.2%) | 859,752 (57.9%) |
| ≥60 | 118,210 (39.8%) | 625,068 (42.1%) |
| Mean ± standard deviation | 60.7 ± 12.0 | 61.0 ± 12.2 |
| Gastro-oesophageal reflux disease | 12,283 (4.1%) | 58,037 (3.9%) |
| Obesity or diabetes | 14,397 (4.8%) | 100,641 (6.8%) |
| Smoking-related diagnoses | 5796 (1.9%) | 32,657 (2.2%) |
| Alcohol-related diagnoses | 3647 (1.2%) | 19,497 (1.3%) |
| Use of NSAIDS or aspirin | 64,907 (21.9%) | 334,889 (22.6%) |
| Use of statins | 21,597 (7.3%) | 162,507 (10.9%) |
| Helicobacter pylori eradication treatment | ||
| Before or at entry | 2672 (0.9%) | 12,079 (0.8%) |
| After entry | 6259 (2.1%) | 27,936 (1.9%) |
| Hysterectomy | 34,286 (11.6%) | 89,724 (6.0%) |
| Deaths during follow-up | 49,977 (16.8%) | 259,101 (17.4%) |
| Type of medication | ||
| Oestrogen only | 128,208 (43.2%) | |
| Oestrogen and progesterone | 168,756 (56.8%) | |
MHT menopausal hormone therapy, NSAIDs non-steroidal anti-inflammatory drugs.
Main analyses
A total of 95 users and 598 non-users of MHT were diagnosed with oesophageal or cardia adenocarcinoma during the follow-up. MHT users had a decreased risk of oesophageal or cardia adenocarcinoma (adjusted HR 0.78, 95% CI 0.63–0.97). The risk remained unchanged after further adjustment for gastro-oesophageal reflux disease (HR 0.78 95% CI 0.63–0.97) and obesity or diabetes (HR 0.79, 95% CI 0.63–0.98). The point estimates for risk reduction were similar in users of oestrogen only (adjusted HR 0.82, 95% 0.60–1.12) and in those using oestrogen combined with progestogen (adjusted HR 0.75, 95% 0.56–1.00) (Table 2).
Table 2.
Risk of oesophageal or cardia adenocarcinoma and oesophageal squamous cell carcinoma associated with menopausal hormone therapy.
| Outcome and exposure | Number of cases | Crude hazard ratio (95% CI) | Adjusted hazard ratio (95% CI)a |
|---|---|---|---|
| Oesophageal or cardia adenocarcinoma | |||
| Non-users | 598 | 1.00 (Reference) | 1.00 (Reference) |
| Users | 95 | 0.72 (0.58–0.90) | 0.78 (0.63–0.97) |
| Oestrogen only | 44 | 0.85 (0.62–1.15) | 0.82 (0.60–1.12) |
| Oestrogen and progestin | 51 | 0.64 (0.48–0.85) | 0.75 (0.56–1.00) |
| Oesophageal squamous cell carcinoma | |||
| Non-users | 418 | 1.00 (Reference) | 1.00 (Reference) |
| Users | 68 | 0.74 (0.57–0.96) | 0.78 (0.60–1.01) |
| Oestrogen only | 31 | 0.85 (0.59–1.23) | 0.76 (0.52–1.10) |
| Oestrogen and progestin | 37 | 0.67 (0.48–0.93) | 0.80 (0.57–1.12) |
CI confidence interval.
aAdjusted for age, smoking-related diagnoses, use of non-steroidal anti-inflammatory drugs or aspirin, use of statins and hysterectomy, with additional adjustment for Helicobacter pylori eradication treatment for adenocarcinoma and additional adjustment for alcohol-related diagnoses for squamous cell carcinoma.
MHT use was also associated with a decreased risk of oesophageal squamous cell carcinoma (adjusted HR 0.78, 95% CI 0.60–1.01), with similar risk reductions for oestrogen only (adjusted HR 0.76, 95% CI 0.52–1.10) and oestrogen combined with progestogen (adjusted HR 0.80, 95% CI 0.57–1.12), although these associations were not statistically significant (Table 2).
Subgroup analyses
The association between MHT and the risk of oesophageal or cardia adenocarcinoma was particularly strong within 5 years of follow-up (HR 0.60, 95% CI 0.41–0.87) and in participants younger than 60 years (HR 0.57, 95% CI 0.38–0.86). No clear differences were found in risk estimates stratified by gastro-oesophageal reflux disease, obesity or diabetes, Helicobacter pylori eradication treatment or smoking-related diagnoses, although all point estimates were below 1 (Table 3). The HRs in the subgroup analyses remained unchanged after further adjustment for gastro-oesophageal reflux disease and obesity or diabetes diagnoses (Table 3).
Table 3.
Associations between use of menopausal hormone therapy and the risk of oesophageal or cardia adenocarcinoma stratified by covariates.
| Covariates | Number of cases in non-users/users | Hazard ratio (95% CI)a | Hazard ratio (95% CI)b |
|---|---|---|---|
| Age | |||
| <60 years | 208/27 | 0.57 (0.38–0.86) | 0.58 (0.39–0.86) |
| ≥60 years | 390/68 | 0.91 (0.70–1.18) | 0.92 (0.71–1.19) |
| Gastro-oesophageal reflux disease | |||
| No | 558/89 | 0.78 (0.63–0.98) | 0.79 (0.63–0.99) |
| Yes | 40/6 | 0.75 (0.32–1.78) | 0.76 (0.32–1.79) |
| Obesity or diabetes | |||
| No | 543/89 | 0.78 (0.62–0.98) | 0.78 (0.62–0.98) |
| Yes | 55/6 | 0.89 (0.38–2.07) | 0.88 (0.38–2.06) |
| Smoking-related diagnoses | |||
| No | 557/90 | 0.79 (0.63–0.99) | 0.79 (0.63–0.99) |
| Yes | 41/5 | 0.68 (0.27–1.74) | 0.69 (0.27–1.74) |
| Helicobacter pylori eradication treatment | |||
| No | 589/94 | 0.79 (0.63–0.98) | 0.79 (0.64–0.98) |
| Yes | 9/1 | 0.53 (0.07–4.16) | 0.53 (0.07–4.19) |
CI confidence interval.
aAdjusted for age, smoking-related diagnoses, Helicobacter pylori eradication treatment, use of non-steroidal anti-inflammatory drugs or aspirin, use of statins and hysterectomy, excluding the analysed variable.
bFurther adjusted for gastro-oesophageal reflux disease and obesity or diabetes, excluding the analysed variable.
Sensitivity analyses
The risk estimates for oesophageal or cardia adenocarcinoma remained virtually unchanged in the sensitivity analysis excluding individuals with any cancer before cohort entry (HR 0.78, 95% CI 0.62–0.98 for any MHT; HR 0.81, 95% CI 0.58–1.13 for oestrogen only; HR 0.76, 95% CI 0.57–1.03 for oestrogen and progestogen). MHT was associated with a slightly increased risk of non-melanoma skin cancer (HR 1.19, 95% CI 1.16–1.23).
Discussion
In this study, MHT use in women was associated with a decreased risk of oesophageal or cardia adenocarcinoma, particularly in those younger than 60 years. Use of MHT was also associated with a decreased risk of oesophageal squamous cell carcinoma.
Some methodological considerations deserve attention when interpreting the results of this study. Among strengths are the population-based design, large sample size, long and complete follow-up, and the use of high-quality and prospectively collected data from national health data registries. To reduce the risk of confounding, the analyses were adjusted for and stratified by all main risk factors for oesophageal adenocarcinoma. Because some of the covariates, particularly obesity, were underreported in the registries, residual confounding cannot be dismissed. To reduce this bias, we added diabetes diagnoses as a proxy for obesity because diabetes is closely associated with obesity. The lack of any risk reduction for non-melanoma skin cancer among MHT users in the cohort adds validity to the inverse associations identified in the present study. There was likely some level of misclassification of MHT status because dispensations before the study period were not recorded. However, such misclassification would be non-differential, i.e. not depending on the studied outcome, and thus would have diluted the associations between MHT and risk of oesophageal adenocarcinoma rather than explaining them. There was a lack of data on reproductive factors that may influence sex hormone levels. To our knowledge, this study was the largest cohort study to date that investigated the association between MHT use and the risk of oesophageal adenocarcinoma; however, due to the low incidence of this cancer in women, the statistical power was still limited, at least in the subgroup analyses. Due to the inherent time-related bias in observational pharmaco-epidemiological studies, particularly that the duration of use or accumulated exposure is closely correlated with that of follow-up, we did not assess the duration of MHT use in relation to the risk of oesophageal adenocarcinoma.
This study suggests that the use of MHT, both oestrogen only and combined with progestogen, decreases the risk of oesophageal adenocarcinoma. The magnitude of association in this study was weaker than that in our previous study (odds ratio 0.62, 95% CI 0.45–0.85) [12], but was similar to a meta-analysis of five studies (pooled odds ratio 0.75, 95% CI 0.58–0.98) [10]. The slightly weaker association in the present study compared to our previous study may be explained by the longer follow-up in the present study, because it seems that the risk reduction is greater within the initial follow-up period. We also observed a stronger association in women younger than 60 years than in those aged 60 years or older. When considered together, these observed heterogeneities by the duration of follow-up and age indicate that the perimenopause period might be particularly vulnerable to the potentially protective effect of MHT rather than a later period. Our recent Mendelian randomisation analysis, based on genetic factors regulating sex hormone levels, indicated that higher genetically predicted levels of oestradiol and progesterone may be associated with a decreased risk of oesophageal adenocarcinoma and its premalignant condition Barrett’s oesophagus in women [16]. A protective role of progestogen is also supported by the findings of a pooled analysis of three population-based case-control studies, which reported a dose-dependent risk reduction of oesophageal adenocarcinoma associated with breastfeeding [17]. However, a recent prospective cohort study from the UK Biobank found no association between serum oestradiol levels and risk of oesophageal adenocarcinoma, but that study only included 43 female patients with oesophageal adenocarcinoma [18].
The biological effects of oestrogens depend on the binding to nuclear receptors, i.e. the oestrogen receptors alpha and beta. Expression of oestrogen receptor beta has been documented in oesophageal adenocarcinoma [19, 20]. Downstream mechanisms regarding how oestrogens may prevent oesophageal adenocarcinoma development remain unclear, but may include regulation of cell cycle and growth arrest, and promotion of apoptosis in tumour cells through ligation to oestrogen receptor beta [8, 21].
This study also found a decreased risk of oesophageal squamous cell carcinoma in women using MHT, of a magnitude similar to that for oesophageal adenocarcinoma. Oesophageal squamous cell carcinoma is also more common in men than in women, with an average male-to-female incidence ratio of 2–3-to-1 globally [22]. This sex difference is partially explained by sex differences in the exposure to the main risk factors, i.e. tobacco smoking and alcohol overconsumption [23, 24], but sex hormones may also play a role. A meta-analysis of four studies together with our previous cohort study also found a reduced risk of oesophageal squamous cell carcinoma in MHT users [11]. Studies have shown the expression of oestrogen receptors and inhibition of cell growth by oestrogen in oesophageal squamous cell carcinoma [20, 25].
The findings of this study, together with previous lines of evidence, highlight the need for further establishing any causal relation between MHT and prevention of oesophageal adenocarcinoma, assessing the possible vulnerable time period, and exploring the underlying biological mechanisms. Randomised controlled trials examining sex hormones in relation to the risk of developing oesophageal adenocarcinoma in the general population are not feasible due to the possible health risks associated with MHT and the low incidence of oesophageal adenocarcinoma in the general female population. However, if a preventive effect of sex hormones is confirmed in additional large-scale cohort studies, it may be worth assessing sex hormonal therapeutic targets in the prevention of oesophageal adenocarcinoma in selected high-risk individuals or as an adjuvant therapy in order to prevent tumour recurrence after curatively intended treatment.
In summary, this large and population-based cohort study suggests that women using MHT are at a decreased risk of oesophageal or cardia adenocarcinoma. This finding supports the hypothesis that female sex hormones contribute to the substantially lower incidence of this cancer in women compared with men.
Supplementary information
Acknowledgements
Not applicable.
Author contributions
SHX and JL jointly conceived and designed the study, and collected the data. GS contributed to the designing of study and performed data analysis. SHX prepared the first draft of the paper. GS and JL contributed to the interpretation of the results and critically reviewed the manuscript. All authors had full access to all of the data (including statistical reports and tables) in the study and SHX can take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding
This study was supported by the Swedish Cancer Society (grant number 190043) and the Swedish Research Council (grant number 2019–00209).
Data availability
The data that support the findings of this study are available from the corresponding author (SHX) upon reasonable request. The codes for the data analysis are archived by the biostatistician (GS).
Competing interests
The authors declare no competing interests.
Ethics approval and consent to participate
This study was approved by the Regional Ethical Review Board in Stockholm (reference number 2018/271–32). Informed consent is exempted for register-based research in Sweden. The study was performed in accordance with the Declaration of Helsinki.
Consent for publication
Not applicable.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
The online version contains supplementary material available at 10.1038/s41416-021-01575-8.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data that support the findings of this study are available from the corresponding author (SHX) upon reasonable request. The codes for the data analysis are archived by the biostatistician (GS).