Interpretation
The impact of oestrogen-only and combined HRT on all-cause mortality was reported separately in only a few previous studies. The Women’s Health Initiative Trials19 found that combined or oestrogen only HRT for a median of 5.6 years was not associated with all-cause, cardiovascular, or cancer mortality, and Stram et al. (2011)23 found a reduced risk of death in younger users of combined HRT but not in older postmenopausal women.. Our results partly agree with these two studies but there were some major differences. WHI was a randomized control trial consisting of 13,816 postmenopausal HRT users versus placebo, and Stram et al. (2011) used survey data from California Teachers Cohort Study. The mean age of women in both studies was around 63 years, which is more than a decade away from menopausal transition age. WHI investigated only one single dose of oral HRT, whereas the participants in this study took various doses and preparations of oral and transdermal HRT, and were followed up for longer.
Pooled analysis of 26,708 women from 30 trials by Salpeter et al.(2004)42 showed that HRT reduced total mortality by 39% in women of mean age 54 years at baseline, but not in older women (mean age 66 years). Our results on combined HRT agree with Ettinger et al.(1996),15 Hunt et al.(1987),16Grodstein et al.(1997)17, and Salpeter et al.(2009)18 who also reported a reduced risk of all-cause death in HRT users with a variation from 27% to 46%. However, this study found a lower reduction of hazards of death than the above-mentioned studies. Several factors may have caused the difference. Firstly, this study estimated hazards using big health data from primary care while most other studies used survey or register data. Secondly, we analyzed combined and oestrogen-only HRT separately, while most other studies did not. Other possible causes of lower reduction of hazards in this study in comparison to others is that the majority of observational studies did not have age- matched controls, and some of them were criticized for healthy users selection bias.17 In this study, both cases and controls have the same age and similar health characteristics at study entry. In addition, this study estimated hazards of mortality by adjusting for a wide range of important confounders while most other studies adjusted for demographical and/or lifestyle variables only. However, in unadjusted analysis, we found greater reduction of hazards of all-cause mortality in both oestrogen-only and combined HRT users.
This study found no significant interactions of HRT type or age at initiation with other morbidities or lifestyle factors such as hypertension or smoking, which means that the effect of HRT on the hazards of all-cause mortality were the same across different patient subgroups. This study found that a history of both oophorectomy and hysterectomy was associated with significantly improved survival. In addition, our result agrees with the findings of Drever et al.(1995)43 in respect to significant survival variation due to deprivation. Finally, this study found significant heterogeneity in patients’ survival between GP practices.
Current NICE clinical guidelines44 in the UK recommend offering combined HRT to symptomatic women with a uterus, and oestrogen-only HRT to women without a uterus after discussing the benefits and risks. According to the NICE, benefits of HRT include prevention of osteoporotic fractures, colorectal cancer, and cardiovascular disease if the therapy starts before the age of 60 years, and the risks include slight increase of CHD, stroke, and thromboembolic events. All-cause mortality studies were not reviewed by NICE yet. In this study, combined HRT users had lower incidence of type 2 diabetes, heart failure, and somewhat less osteoporosis, and oestrogen-only users developed more hypertension and CHD events than the non-users during follow-up. Although the current NICE guideline states that oestrogen-only HRT is associated with little or no change in the risk of breast cancer and combined HRT can be associated with increased risk of breast cancer, we observed the increased incidence of breast cancer for both types of HRT. However, this did not translate into increased mortality in HRT users. This may be because women are more likely to die from cardiovascular disease, osteoporosis, and dementia than from breast cancer, and so benefits in these conditions will offset risks from rarer conditions.45 It is, therefore, important to disseminate a balanced information on the potential benefits and risks of HRT and not to overestimate the possible risks, to allow women and their GPs to make an informed choice.