Discussion
Our systematic review found several key findings: (1) MHT showed a heterogeneity in findings for CRC risk with a slight tendency to a neutral or protective effect;[41,61] (2) MHT effect was either neutral or protective on colorectal adenoma;[31,51] (3) MHT had no impact on tumour grade,[42,47,53] subsite[3,37] and histologic type;[42,47] (4) MHT was not associated with CRC mortality;[1,32] and (5) MHT showed heterogeneous effects on CRC stage[47,50,52] and invasiveness,[42,52] respectively.
Although no significant increase in risk was found, several studies reported a non-significant risk increase for colorectal and colon cancer, which needs to be considered for a balanced overview.
When results of section 3.2 to 3.8 were separately analysed by PC-RCTs only, findings remained congruent to the summary of results of all study types. Our findings regarding CRC mortality and risk for CRC are consistent with those of a Cochrane review from 2017 analysing the long-term hormone therapy for peri- and postmenopausal women. This systematic review did not show a difference for colorectal cancer mortality between the MHT and placebo group. Regarding risk for CRC, overall effect of the Cochrane review was neutral or protective, with no statistical difference for the incidence of CRC for combined MHT and a significantly lower incidence for oestrogen only. However, our review is updating the current knowledge on CRC in terms of additional differentiation of risk for colorectal adenoma, risk for colon and rectal cancer, tumour stage and invasiveness, tumour grade, molecular and histologic characteristics and colon cancer site.[35]
The interpretation of studies addressing the impact of MHT on CRC had various limitations. Firstly, the number of studies showing a significant risk reduction versus studies showing no association was mostly similar. Here, a meta-analysis would be helpful.
Secondly, studies were quite heterogeneous in respect to study design, sample size, average age, average BMI, MHT regimens, duration of treatment and follow-up, respectively. Differences in study design provide varying levels of evidence. For example, case-control studies are often suboptimal, because the cases and controls may not be similar enough to each other for adequate comparison, long-term follow-up is often lacking and recall bias can be present. In both case-control and cohort studies, it is not possible to test patients in a blinded fashion. Cohort studies have the potential for a prospective follow-up, but the duration of included studies varied (from 6 months[1] to 18 years[45]). Reproductive stage was mostly peri- or postmenopausal and therefore well comparable. Effects of treatment differences were hard to analyse, because complete and exact information about components, dosage, regimen and application were rarely given. In addition, different types of MHT were often not analysed separately. Progestogen and combined MHT use should be studied individually, as it is unclear what separate impact, if any, progestogen may have on CRC.[69]
CRC is influenced by various modifiable and unmodifiable confounders such as removal of precancerous lesions, diet, alcohol consumption, tobacco smoking, physical activity, family history and race, but not all of these aspects were always taken into account.[3,69] Analysed studies collected data from women of different countries, which implies different health standards and ethnic risk:[69] the USA (majority of studies),[62,63] Australia,[18,44] New Zealand and England,[44] Norway,[3] Denmark,[14,22] Sweden,[20] Canadian,[12] France,[25] Italy,[8] Germany,[16,17] undefined European Countries[39] and various countries.[57,61]
It needs to be taken into consideration that studies showing a protective effect are often biased, because women taking MHT differ from non-users by often being on higher socioeconomic levels and therefore able to conduct a healthier lifestyle and by 'surveillance bias' (MHT users visit doctors more frequently than non-users and tend to undergo screening more often).[70]
Several other issues remain to be elucidated in concern of MHTs effect on CRC, which should be investigated in further studies, for example biochemical mechanism of MHT effect on the colon and rectum, possibility for a threshold duration necessary for protection and differences on the CRC effect by type of MHT.
In this literature search, an interesting observation and possible subject of further research due to small quantity of studies was found, proclaiming a significant risk reduction of distal large bowel cancer by MHT use.[26]
The clinical implication of this review assists physicians to inform their patients that MHT, although results are heterogeneous, tends to show a neutral or protective effect for CRC risk and no effect for CRC mortality, while other harmful changes in risk for chronic conditions need to be evaluated carefully. MHT is not suitable for primary prevention as women taking hormone therapy experience several important harms such as higher risks for stroke, thromboembolic events, gallbladder disease and urine incontinence.[2] Suitability of MHT for primary intervention of chronic conditions in postmenopausal women was comprehensively analysed in a systematic review published 2017 in the JAMA.[2] A more current meta-analysis could help decide whether MHT could be considered for primary prevention.
Nevertheless, MHT is currently not recommended for primary CRC prevention by international guidelines (EMAS,[71] NAMS,[72] IMS[73]).
Clin Endocrinol. 2021;95(3):390-397. © 2021 Blackwell Publishing
