Abstract
Objective: To estimate the effect of oestrogen-only and combined hormone replacement therapy (HRT) on the hazards of overall and age-specific all-cause mortality in healthy women aged 46 to 65 at first prescription.
Design: Matched cohort study.
Setting: Electronic primary care records from The Health Improvement Network (THIN) database, UK (1984−2017).
Population: 105,199 HRT users (cases) and 224,643 non-users (controls) matched on age and general practice.
Methods: Weibull-Double-Cox regression models adjusted for age at first treatment, birth cohort, type 2 diabetes, hypertension and hypertension treatment, coronary heart disease, oophorectomy/hysterectomy, body mass index, smoking, and deprivation status.
Main outcome measures: All-cause mortality.
Results: A total of 21,751 women died over an average of 13.5 years follow-up per participant, of whom 6,329 were users and 15,422 non-users. The adjusted hazard ratio (HR) of overall all-cause mortality in combined HRT users was 0.91 (95%CI 0.88−0.94), and in oestrogen-only users was 0.99 (0.93−1.07), compared to non-users. Age-specific adjusted HRs for participants aged 46-50, 51-55, 56-60, and 61-65 years at first treatment were 0.98 (0.92−1.04), 0.87 (0.82−0.92), 0.88 (0.82−0.93), and 0.92 (0.85−0.98), for combined HRT users compared to non-users, and 1.01 (0.84−1.21), 1.03 (0.89−1.18), 0.98 (0.86−1.12), and 0.93 (0.81−1.07) for oestrogen-only users, respectively.
Conclusions: Combined HRT was associated with a 9% lower risk of all-cause mortality and oestrogen-only formulation was not associated with any significant changes.
Funding: IFoA.
Keywords: Hormone replacement therapy, menopause, mortality, primary care records, THIN.
Tweetable abstract: Oestrogen-only HRT is not associated with all-cause mortality and combined HRT reduces the risks.
Introduction
Hormone Replacement Therapy (HRT) is an effective treatment for perimenopausal symptoms.1 Other known benefits include reduced osteoporosis and cardiovascular disease, and improved quality of life after menopause.2-4A major meta-analysis5 published in 2019 reported an increased risk of breast cancer associated with all types of HRT, and reports from the Million Women Study and an older meta-analysis showed an increased risk of gynaecological cancer.6-8 Since then many symptomatic women have been understandably cautious about taking HRT.
Past studies mostly focused on morbidity,4,7-10 or cause-specific mortality,11-13 whereas all-cause mortality summarizes the net effects of HRT and is arguably a more useful single measure of the major risks and benefits over time. Previous observational studies of HRT and all-cause mortality include a meta-analysis comprising 16,000 women of mean age 55 years, found a reduced overall risk of death in HRT users.14-18Pooled results from the Women’s Health Initiative’s (WHI) two trials showed no association of HRT with all-cause mortality.19 Other surveys and long-term cohort studies have variously reported no association between HRT and overall mortality,20,21 and increased risks of all-cause mortality,22 and the authors have called for further research.
Clinical variables are important confounders that influence mortality, and hence adjustment for these factors is required to obtain a more accurate estimate of effect-size and direction. Inclusion of healthy users compared to non-users in some studies may have introduced bias in favour of HRT users.14,17 The impact of oestrogen-only, and combined oestrogen and progesterone formulations on all-cause mortality has been reported in two papers,19,23 where one found no association, and the other found a reduced risk in younger users of combined HRT. The WHI19 results may not be generalisable to all users as each trial assessed only one dose, formulation, and route of administration of HRT. Other limitations of previous studies include the lack of age-specific information on the use of HRT and its long-term impact on all-cause mortality,2, 14,17,21 and little information about the handling of missing data14,17 or the presence of time-varying hazards.13, 16, 17
A matched cohort study where the controls have the same age and background as cases and have similar health characteristics with adjustment for confounding variables and a longer follow-up offers the potential to overcome some of the limitations in previous studies. Electronic primary care databases in the UK retain a wide range of information including comorbidities, treatment history, and some socio-demographic factors with a long term follow-up over many years. Mortality registration is regularly updated in primary care as general practitioners (GPs) are informed of the death of patients registered with them.24 While there has been extensive research on HRT, no published study to date has investigated all-cause mortality associated with HRT using UK primary care data.
The main aims of this study were to estimate the effect of oestrogen-only and combined HRT on the hazards of all-cause mortality in a large cohort of healthy women broadly representative of the British population, and to analyze age-specific effects of HRT initiation on mortality.
Methods