Since its introduction in the 1940s, the use of menopausal hormone therapy (MHT) has been heavily debated with data leading to questions about effectiveness and increased risk of breast cancer and cardiovascular disease.
The use of estrogen following menopause originally became popular in the late 1960s and increased following the FDA approval of estrogen for the prevention of osteoporosis.(1) However following the publication of results from the Women’s Health Initiative (WHI) randomised trial in 2002 the use of MHT rapidly declined as data showed an increased risk of cardiovascular disease and breast cancer, (2) which ultimately led to the trial being terminated early. Following the dissemination of these results in the media, many healthcare professionals and patients alike were put off the use of MHT.
But since this initial publication what have we learnt?
In follow-up publications from the WHI, results were less clear. Data showed that in the conjugated equine oestrogens (CEE) plus medroxyprogesterone acetate (MPA) arm, women who had not previously used MHT had no increased breast cancer risk over the duration of the trial and in the CEE only arm, the incidence of breast cancer was actually significantly decreased. (3) After 10 years of using MHT, those in the CEE only arm also had significantly lower total mortality. (4) Find out more about managing patient’s fear of breast cancer in our EMAS symposium report.
In 2006, follow-up data was published around coronary disease outcomes which for the first time included age-stratification. The results showed that as with breast cancer in the CEE arm, risk was reduced in women aged 50-59 years but destructive in women over 60 years. (5) Data highlighted that in women under the age of 59 or who are less than 10 years from menopause onset total mortality was reduced by 30%. (6) You can learn more about the relationship between MHT and CHD on our blog post from EMAS.
To explain the difference between initial WHI study results and early observational results, a timing hypothesis was created. This hypothesis suggests that the impact of hormones differs drastically depending on when they are initiated, with initiation close to the onset of menopause more favourable than later down the line for impact on conditions including breast cancer, osteoporosis, stroke, endometrial and colon cancer. However the timing hypothesis is disputed with regards to cardiovascular disease and cognitive decline. Data from the ELITE study (Early versus Late Intervention Trial with Estradiol) showed that carotid intima-media thickness reduced significantly over 5 years on the drug compared to placebo however this benefit was only observed in women within 6 years of the onset of menopause but not observed in those who were more than 10 years from the onset of menopause.(7)
So what does this data mean in relation to prescribing MHT to women?
When prescribing MHT, HCPs should consider that patients may suffer with some adverse effects, however many of these are not life-threatening and can be mitigated with adjustment to dose and combination of MHT. More serious conditions linked to use of MHT such as cancer risk have been found to be small or not significantly increased in healthy young women compared to those ore placebo. With the release of more data, a number of professional societies have realised updated guidance including the National Institute for Health and Care Excellence (NICE), which suggests that MHT is efficacious in relieving symptoms and is safe to prescribe to women at or around the onset of menopause.
1. Osteoporosis. National Institutes of Health Consensus Development Conference Statement, April 2-4, 1984. Department of Health & Human Services.
2. Rossouw, J.E. et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 288,321-333 (2002).
3. Anderson G.L. et al. Prior hormone therapy and breast cancer risk in the Women’s Health Initiative randomized trial of estrogen and progestin. Maturitas 55, 107-115 (2006).
4. Anderson G.L. et al. Conjugated equine oestrogen and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomized placebo-controlled trial. Lancet Oncol. 13, 476-486 (2012).
5. Hsia. J et al. Conjugated equine estrogens and coronary heart disease: the Women’s Health Initiative. Arch.Intern.Med, 166, 357-365 (2006).
6. Rossouw, J.E. et al. Postmenopausal hormone therapy and cardiovascular disease by age and years since menopause.
7. Hodis, H.N et al. Effects of early versus postmenopausal treatment with estradiol. N. Engl. J. Med. 374, 1221-1231 (2016).