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- Material and Methods
There is an unexplained strong male predominance in the aetiology of oesophageal adenocarcinoma (OAC). The hypothesis that oestrogens are protective, deserves attention. A potential protective influence of exogenous oestrogen exposure, that is, hormone replacement therapy (HRT) and oral contraceptives (OC) has been addressed only in studies of limited statistical power, and the individual studies have not provided conclusive results. We conducted a systematic literature search and meta-analysis on HRT and OC and the risk of OAC. We used the databases PubMed and the Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by the Mantel–Haenszel random-effect method. A total of five studies were included. Compared to never users, ever users of HRT had a statistically significantly decreased risk of OAC (pooled OR = 0.75; 95% CI: 0.58–0.98), and ever users of OC had a borderline significantly decreased risk of this cancer (pooled OR = 0.76; 95% CI: 0.57–1.00). In conclusion, HRT and OC use seems to be associated with a decreased risk of OAC. However, further research is warranted.
Oesophageal adenocarcinoma (OAC) is up to nine times more common in men than women, yet the reasons behind this pattern remain unclear.[1, 2] Gastro-oesophageal reflux and high body mass index (BMI), the two main risk factors for OAC, seem to influence the risk of developing OAC similarly in both genders, and might not explain the male predominance.[3-6] The typical male fat distribution, with mainly abdominal adiposity, is a stronger risk factor for OAC than BMI alone, but it is uncertain if this exposure contributes the sex ratio of OAC. It has also been hypothesised that female sex hormones, mainly oestrogen, are protective. This oestrogen hypothesis is supported by a 20-year delay in the onset of OAC in women compared to men, and a particularly high male-to-female ratio during women's reproductive years. Individual investigations of the potential role of exogenous hormonal therapy in women, including hormone replacement therapy (HRT) and oral contraceptives (OC), in the aetiology of OAC have failed to provide conclusive results.[11-15] The low incidence of OAC in women has hampered the statistical precision in the available studies. HRT is used to mitigate discomfort caused by decreased levels of circulating oestrogen and progesterone after menopause. Combined HRT includes both oestrogens and progesterone, and is recommended to women with an intact uterus, as it counteracts endometrial hyperplasia associated with oestrogen therapy. Oestrogen only HRT is recommended to women who have undergone hysterectomy.[16, 17] The most commonly used OCs contain both oestrogen and progesterone. The often called ‘mini pill' contains progesterone only, and is recommended during breastfeeding as oestrogen reduces the amount of breast milk.
With the purpose of improving the knowledge of the relationship between HRT and OC exposure and risk of OAC, we conducted a systematic review and meta-analysis.
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- Material and Methods
This meta-analysis, based on five relevant studies, together including over 300 patients with OAC from five countries, found a 25 and 24% reduced risk of OAC among women using HRT and OC.
This is, to the best of our knowledge, the first study to show a statistically significantly reduced risk of OAC among HRT users. The association between OC and OAC was less robust in terms of the number of studies and the borderline statistical significance, but the available data indicate an association of similar strength to that found among HRT users.
This meta-analysis was limited by the low number of studies, and there were insufficient data to allow subgroup analysis of duration, type or dosage of HRT and OC use or adjust for potential confounding. The rough categorisation of HRT or OC use into ever or never use should, however, dilute true effects rather than enhance them, as the misclassification following such categorisation was likely to be similar among cases and controls. As with any meta-analysis, we cannot exclude the possibility that other studies may have been missed during our literature search, or that studies that observed null effects were absent from the literature altogether. Nevertheless, the funnel plot and Egger's regression asymmetry analysis found only little evidence of presence of small study effects and publication bias. Although the included studies differ in several aspects, including study design, the studies showed statistical homogeneity. The clinical heterogeneity, that is, the comparability in terms of study participants, exposure and outcome measures and other variables, is an inherent problem of meta-analyses, yet this should be limited by virtue of the strict inclusion criteria. In addition, potential confounding factors, that is, BMI and reflux, could not be taken into account due to the limited availability of data. However, it is unlikely that these factors would be strongly associated with use of HRT or OC, and thus, should not act as important confounders. Even though the included studies had similar exclusion and inclusion criteria as well as recruitment procedure, there was variability in the exposure and patient characteristics within and between the included studies. Due to the limited number of studies, we could not analyse the impact of the study design or design-specific biases, that is, recall bias and other information biases.
There is, to the best of our knowledge, no previous meta-analysis of exogenous oestrogen therapy and OAC. However, some meta-analyses indicate that HRT might decrease the risk of gastric adenocarcinoma,[27, 28] colorectal adenocarcinoma and oesophageal cancer of any histological type. However, regarding oesophageal cancer it is, crucial to separate adenocarcinoma and squamous cell carcinoma of the oesophagus in any aetiological research, as these histological types have very different patterns of incidence and aetiology, including a greater level of male predominance in OAC.
There are several mechanisms that might explain a possibly preventive effect of exogenous oestrogens in OAC development.[29-31] The serum oestradiol concentration is much higher in premenopausal women (produced mainly in the ovaries) than in men, but decreases substantially after menopause, and ultimately becomes lower than in elderly men. This pattern could explain the 20-year delay in OAC incidence among women. The presence of oestrogen receptors has repeatedly been shown in OAC[34-37] and in oesophageal tissue.[34, 35, 37, 38] Involvement of oestrogen signalling in regulation of adipose tissue metabolism indicates a possible link between the effects of oestrogen and abdominal adiposity (male obesity), one of the main risk factors for OAC.[32, 39, 40] Moreover, a recent study suggests that OAC and Barrett's oesophagus cells respond to treatment with selective oestrogen receptor ligands, resulting in decreased cell growth and apoptosis. Fat cells are a major source of endogenous oestrogen among postmenopausal women. If HRT protects against OAC, it might be expected that the association between body mass and OAC is weaker for women than men. The adverse effects of high fat levels in women might, to some extent, be offset by their higher oestrogen levels.
We restricted our meta-analysis to assess risk of invasive OAC. However, given the recognised multistep progression from gastro-oesophageal reflux, erosive oesophagitis, Barrett's oesophagus with and without dysplasia, to OAC, it would be valuable also to investigate if oestrogens influence these earlier steps in the carcinogenic pathway. Paradoxically, the risk of gastro-oesophageal reflux disease has been found to be increased among women using HRT,[41-43] despite the fact that such reflux is a main risk factor for OAC. However, it is possible that the increased risk of reflux and the decreased risk of OAC among HRT users are explained by different timing of HRT exposure. oestrogen might, for example, prevent OAC only at a later stage in the tumour progression.
There is a need for more research before any role of exogenous oestrogen exposure in the aetiology of OAC is established. However, if such research shows that HRT substantially reduces the risk of OAC, there is a potential for future research also addressing oestrogen therapy in highly selected risk groups of OAC, for example, patients with dysplastic Barrett's oesophagus, or as adjuvant therapy in patients with OAC, although side effects must be considered before such research is initiated. Our study showed a reduced risk of developing OAC of about 25% by HRT use in postmenopausal women, and the true risk estimates might well be lower considering the dilution of risk estimates typically followed by rough categorisation of the exposure.
In conclusion, this systematic review and meta-analysis suggest that use of HRT, and possibly also OC, decreases the risk of OAC, thus providing support for the hypothesis that exogenous oestrogen exposure counteracts OAC in women. These findings require more research before any association can be established.