It is all in the name: The importance of correct terminology in hormone replacement therapy

In 2003, David Sturdee and Alastair MacLennan wrote an editorial in which they argued for a change in the terminology of hormone replacement therapy (HRT). ¹ Sixteen years on the European Menopause and Andropause Society and many European publications use the term ‘menopausal hormone therapy or MHT’ in place of HRT, as does the 2016 International Menopause Society Recommendation, while the North American Menopause Society Position Statement refers to HT (i.e. hormone therapy) rather than HRT. Both MHT and HT still lack specificity and represent no significant advancement on the term HRT. Yet the need for correct terminology could not be more urgent. The global increase in life expectancy to 74 years for women, ² while the median age of the menopause remains at 51 years ³ means that an increasing number of women will live a significant portion of their adult lives in the menopause. The WHI publications in 2003/4 reported on the dangers of HRT, in particular with respect to breast cancer ⁴ and dementia ⁵ risk. This resulted in a dramatic reduction in HRT prescription and use. ⁶ However, the findings from the WHI studies have been re-appraised, and the new perspective is reflected in the guidance published by NICE in 2015 in which they recommended that more women be offered HRT as the benefits are now perceived to outweigh the risks for most women. ⁷ However, controversy continues to surround HRT, and there are probably few areas in medicine where the misuse of terminology causes quite as much confusion and mayhem as in HRT.

The term ‘HRT’ could be applied to any situation where an exogenous hormone is administered to ‘replace’ a hormone that for whatever reason, the body is no longer producing. This could therefore include the use of insulin in diabetes or thyroxin in hypothyroidism, but conventionally ‘HRT’ refers to the administration of sex hormones to women with menopausal symptoms, either because of premature ovarian failure or more commonly to peri-menopausal women or to women who have attained natural menopause or menopause from surgery, radiotherapy or chemotherapy. The hormones are usually estrogen, progesterone and testosterone – the three known important hormones that the ovaries produce during the pre-menopausal phase. Estrogen is arguably the most commonly ‘replaced’ hormone in HRT, as it has been shown to be most effective in alleviating symptoms such as hot flushes and nights sweats, dry skin and hair and vaginal dryness, ⁸ to name just a few symptoms of the menopause. In conventional HRT progestogens are given to ameliorate the unwanted effects of oestrogen in women with intact uteri – irregular vaginal bleeding, the development of hyperplasia and the development of endometrial cancer. ⁹ Thus in women who have had a prior hysterectomy, estrogen-only HRT (estrogen replacement therapy or ERT) suffices. Perhaps because testosterone is often viewed as a ‘male’ hormone, it is often not offered to women as part of HRT – yet the ovaries produce testosterone in significant and measurable quantities in the premenopausal phase. Testosterone sub-serves important functions in its own right, such as promoting a general sense of well-being and energy levels, and improving mood, emotions, libido, quality of sleep and concentration. ¹⁰ Arguably therefore adequate HRT should include the routine administration of testosterone as well as estrogen, but in reality very few women on HRT are offered testosterone, and often many decline it when offered.

It is often not appreciated by healthcare professionals and the public that the risk and side-effect profile of estrogen given alone is vastly different from that when estrogen is given with a progestogen. The evidence is consistent that combined estrogen-progestogen HRT is associated with an increased risk of breast cancer, especially when the progestogen is administered orally. The progestogen is the plausible culprit. The WHI study ⁴ which compared combined HRT use against placebo showed that the risk of breast cancer was significantly increased by 24% for all breast cancers in women who used oral combined HRT [HR 1.24 (95% CI 1.02–1.50)]. This means that 124 in 10,000 women who receive combined HRT will develop breast cancer compared to 100 in 10,000 women who do not. Moreover, this result was preceded and supported by other observational studies.^11–13 The absolute risk of developing breast cancer on HRT remains low and this is a key message that needs to be communicated clearly to women and health professionals. The current best evidence suggests that for 50-year-old women in the UK who have started experiencing symptoms of the menopausal transition and who are considering taking combined estrogen and progestogen HRT for five years – if 1000 such women take HRT for five years, 66 would be expected to get breast cancer by the age of 70. If these women did not take HRT, then 58 would be expected to get breast cancer. A difference of 8 in 1000. Most of that increase happens in the first five years when the women are taking HRT.

On the other hand, the WHI study that compared ERT to placebo confirmed that after 10.7 years, there was a 22% significantly reduced risk (RR) of breast cancer (0.78, 95% CI 0.63–0.96). ¹⁴ Moreover, the overall cumulative rate (20% cumulative reduced rate in the incidence of breast cancer compared to placebo, including the post-treatment follow-up) remained significantly lower after a median of 13 years’ follow-up (RR 0.80, 95% CI 0.65–0.97). ¹⁵ The combined WHI studies point to oral progestogens as the plausible culprit for the increased risk of breast cancer. This is an important fact.

It has also long been known that the route of administration of HRT influences risk. On the basics, any estrogen that bypasses the liver should not influence the risk of thrombosis. Therefore, estrogen patches, gel and implants should not increase the risk of venous thrombosis, pulmonary embolism and thrombotic strokes, and this assumption is indeed supported by established evidence. This means that oral estrogens, whether in the combined pill, or in combined HRT or in ERT, increase the risk of thrombosis. This is supported by an observational study in postmenopausal women, which showed that the risk differed according to the route of administration of HRT and oestrogen dose. ¹⁶ Influential publications do not often differentiate between combined HRT and ERT when the risks described above are very different. Ultimately, the reports are misleading and affect a lot of women. For example, a recent publication reported on the increased risks of thrombo-embolism from oral HRT, ¹⁷ and the bottom line in the popular press was quite simply that ‘HRT causes blood clots’, with no attempts to clarify what has been known for decades and was explained in the paper – that transdermal administration or subcutaneous implant HRT do not pose similar risks. ¹⁸ Similarly another publication reported that HRT could increase the odds ratio of developing Alzheimer’s disease by 9%–17%, ¹⁹ yet this study, being a case-control study, could not possibly arrive at conclusions about odds-ratios of developing a disease. The message that was left with women was that HRT could cause dementia. Few medical reports are as emotive as the issues surrounding HRT. It is therefore absolutely imperative that researchers and healthcare professionals report findings accurately and with a sense of responsibility, and the use of correct terminology goes some way towards getting the balance right. Use of correct terminology could help women to understand the absolute and relative risks of breast cancer posed by ERT versus combined HRT versus other lifestyle factors and therefore help them make better informed choices.

We do not necessarily expect to succeed where Sturdee and MacLennan failed, but we seek to raise the issue again. Keeping it relatively simple, we suggest that any study published should be explicit on the type of hormone used, and that the stand-alone term ‘HRT’ should be rendered obsolete by all journals. Here are our proposals:

Estrogen-only HRT abbreviated to ‘ERT’

Combined estrogen and progestogen HRT: cEP-HRT

Estrogen and testosterone HRT: cET-HRT

Estrogen, progesterone and testosterone HRT: cEPT-HRT

The above are the most common combinations of hormones given to menopausal women, and we believe that the use of the above terminology and abbreviations would be a good starting point. In our view, it is incumbent upon the healthcare professionals/researchers directly involved with looking after women with menopausal issues to take the lead in initiating this urgent and long-overdue change in terminology. The menopause journals should lead over other journals, and menopause specialists and researchers should tackle this issue directly and convene a consensus conference to resolve the issue of correct terminology. Women deserve better and will be best served when they are given accurate, evidence-based information in a consistent and easily understood format.