Long term safety of HRT
This month saw the publication of a much awaited study looking into the long-term safety of HRT.
The previous studies that were published in 2002 and 2004, which made the headlines at the time, were looking at conjugated equine oestrogen orally and medroxyprogesterone acetate. They raised some concerns that this form of HRT increased the occurrence of invasive breast cancer, stroke, and coronary heart disease but this was based on a combination of HRT medications that are rarely used now.
The current UK recommendation is that women should have a review of whether they have a continued need to be on HRT after 5 years of use and that there is no evidence for women to remain on HRT long term. However, studies have reported that menopausal vasomotor symptoms persisted for 7-12 years in many women, and some vasomotor symptoms persisted in 42.1% of women aged 60-65 years, which suggests that not few numbers of women continue to suffer from vasomotor symptoms even after age 65 years.
There has long been a suspicion that HRT regimes different to that published in the 2000’s would have a lower risk, but this is the first time that a large population based study has been reported. This study looked at healthcare records for women on Medicare (the state health care system in the USA) and looked at 19 million women between 1999 and 2020.
So what were the findings?
Oestrogen only HRT
For women who didn’t require progesterone i.e. those who had no uterus, the benefits were greatest.
Generally, risk reduction was greater for estradiol (vs conjugated oestrogen), vaginal and transdermal (vs oral), and low or medium (vs high dose).
Having estradiol (the form of oestrogen now used in HRT) alone was associated with significant reductions in all cause mortality risk. Vaginal, transdermal, and oral estradiol was associated with 30%, 20%, and 11% reduction of mortality risk, respectively.
It was also associated with reduced risks of three cancers (breast, lung, and colorectal), four cardiovascular conditions (congestive heart failure [CHF], venous thromboembolism (blood clots), atrial fibrillation, and acute myocardial infarction (heart attack)), and dementia.
For breast cancer oral estradiol exhibited significantly greater risk reductions than transdermal and vaginal oestrogen and interestingly the old fashioned conjugated estrogen was associated with a greater (23%) reduction of breast cancer risk than estradiol (12%).
Combined HRT
Most women still have a uterus and therefore require progesterone to protect the endometrium.
Estradiol + progestin
Estradiol + progestin exhibited 7%-17% reduction in mortality risk.
Oral oestrogen with progestin was associated with increased risk of breast cancer by 10%. However if the oestrogen was given transdermally with a progestin there was no increased risk.
If oestrogen was combined with a progestins there was a significant risk reductions in endometrial cancer (45%), ovarian cancer (21%), ischemic heart disease (5%), CHF (5%), and venous thromboembolism (5%).
Estradiol + micronised progesterone
There was no reduction in mortality risk.
There was a 19% increased risk of breast cancer, this did not appear to be significantly mitigated by using transdermal estradiol.
If oestrogen was combined with progesterone the only benefit was a risk reduction in CHF (4%).
Conclusions
Women who do not have a uterus can be reassured that HRT is safe, and indeed is likely to provide health benefits overall when used for more than 5 years.
For women who do have a uterus the benefits are less clear, but using a transdermal estradiol appears to be safer for breast cancer risk, and using a progestin rather than micronised progesterone may result in some risk reductions.
References
Baik, Seo H. PhD; Baye, Fitsum MS; McDonald, Clement J. MD. Use of menopausal hormone therapy beyond age 65 years and its effects on women's health outcomes by types, routes, and doses. Menopause ():10.1097/GME.0000000000002335, April 9, 2024. | DOI: 10.1097/GME.0000000000002335