Hormone replacement therapy (HRT) (also known as hormone therapy (HT) or menopausal hormonal therapy (MHT)) is prescribed to relieve the symptoms of menopause, which can be life changing. HRT is used by millions of women, sometimes over extended periods. A range of hormone combinations are available, each with different efficacy and side effects. HRT can bring several improvements to quality of life, and it can prevent osteoporosis. Concerns about adverse effects, particularly the increased risk of breast cancer associated with HRT,1 has, however, resulted in a substantial decrease in HRT use over the past 17 years.2 Breast cancer is the most common cancer in women, with more than 55 000 women in the UK affected each year,3 so different drug use scenarios might result in substantial differences in the number of women who develop breast cancer, even though the risk differences between hormones might seem relatively small. Current clinical guidelines recommend use of HRT for no longer than five years and have signalled that more information is needed about the risks of breast cancer associated with different types of HRT.45
Randomised trials using enrolled participants are now impractical to investigate the risks of breast cancer associated with HRT because of the numbers required and the length of follow-up. Trials would also be difficult to justify ethically, given the known harms that are associated with some types of HRT. Earlier trials have been limited, focusing on specific age groups possibly unrepresentative of women likely to request HRT or selecting specific types of HRT6 (the largest being the Women’s Health Initiative trial),7 or, because the design failed to distinguish between treatment types, looking only at overall effect or association.8910 Observational studies are more feasible but require access to large datasets covering lengthy time periods; so far only the Million Women Study has approached the requisite power.10 A recent meta-analysis published after our study commenced, pooled information from 24 prospective observational studies to provide more comprehensive data on the details of exposure and breast cancer risks for the most commonly prescribed oestrogens and progestogens.11 This meta-analysis reported that the risk of breast cancer is increased for both oestrogen only and oestrogen-progestogen current users, with, respectively, a 17% and 60% increase for 1-4 years of use and a 33% and 108% increase for 5-14 years of use. The results also showed a remaining increased risk even after discontinuation of HRT. As with many meta-analyses, however, the included studies were conducted in different settings, had different selection criteria, and had different definitions of exposure, so the data and original study designs were heterogeneous. The study provided information for the most commonly used HRT preparations, albeit with notably smaller statistical power for dydrogesterone—a progestogen previously found to be associated with a low increased risk of breast cancer.12 At publication, the focus of publicity was the higher than expected associations with breast cancer risks than had been suggested by earlier trials. The Medicine and Healthcare products Regulatory Agency subsequently raised an HRT drug safety alert specific to breast cancer, but this has since been questioned as having caused “considerable anxiety,” particularly for women who might need HRT for reasons other than menopausal symptoms.13
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Our study focused on exposure to all the commonly prescribed types of HRT in the UK over the past 20 years in a representative primary care population. We assessed the differences in risks associated with the individual component hormones used in HRT, including dydrogesterone. Our findings are based on prospectively collected electronic health records from the two largest UK primary care databases linked to secondary care data sources. We analysed these separately and then combined the results. In contrast with data and analytical designs used in studies included in the recent meta-analysis,11 our data were homogeneous, and the analytical approach was common. This has allowed us to gain a realistic picture of exposure in the UK to component hormones used in HRT, and the associations with increased breast cancer risk of specific treatments, providing consistently derived information for patients and doctors.