4 Min In Learning
Follow this topic
Bookmark
Record learning outcomes
Hormone replacement therapy (HRT) is designed to alleviate the symptoms experienced by women during the menopausal transition but also has recognised additional health benefits. Although HRT has had a chequered history, there has recently been a surge of interest in its use. Why has there been such controversy surrounding HRT and do the potential benefits outweigh any risks?
Key points
- The menopausal transition is a normal physiological change that occurs in women around the age of 50.
- The transition gives rise to a wide range of uncomfortable symptoms, including hot flushes, night sweats and sleep disturbance.
- Hormone replacement therapy (HRT) is known to be an effective treatment for menopausal symptoms.
- HRT use declined in the early 2000s following data suggesting an increased risk of breast cancer.
- More recent analyses of the original data indicate that the potential health benefits of HRT far outweigh any risks.
Symptom burden
The main indication for HRT is managing menopausal symptoms, which is the point in time when a woman’s periods have stopped completely for 12 consecutive months. The menopause is a normal physiological change that typically occurs in women at an average age of 50 years.
While not strictly an illness, low oestrogen levels before the menopause – the perimenopause – can commonly cause vasomotor symptoms such as hot flushes and night sweats.
Some women also experience depression, mood changes, musculoskeletal pain, vaginal dryness and low libido. The prevalence of menopausal symptoms is high, with estimates suggesting that 75% of women are affected – 25% report that their symptoms are severe. Around a third of women experience these symptoms for up to seven years.
In addition, a report by the House of Commons Women and Equalities Committee revealed how 81% of those in the menopause transition had difficulty sleeping, and 75% were affected by problems with memory (the so-called ‘brain fog’) and concentration.
Despite a high symptom burden, many women fail to seek treatment. According to a survey by the British Menopause Society, among women aged between 45 and 65 years, only half had consulted a healthcare professional about their symptoms.
Given the potentially huge numbers of women affected by the menopausal transition, there was an urgent need to find a treatment to mitigate the associated symptoms. Fortunately, such a treatment has been available since the 1940s although its use has been inconsistent.
History
In 1935, researchers described the successful use of an oral solution of oestrogen for managing dysmenorrhoea or menstrual cramps. Later, in 1942, the US Food and Drug Administration approved the use of conjugated equine oestrogens for treating menopausal symptoms.
However, it was not until 1965 that the product was approved for use in the UK. This hormonal therapy came in two forms: oestrogen alone or oestrogen in combination with a progestogen.
Oestrogen alone is used for women without a uterus, whereas a progestogen is added for those with an intact uterus, since unopposed oestrogen is associated with a significant increase in the risk of endometrial hyperplasia and endometrial cancer.
Sequential vs continuous HRT
Combined HRT containing a progestogen with oestrogen can be used either sequentially or continuously. The choice of regimen depends on whether a woman is peri- or post-menopausal.
For a perimenopausal woman who is still having periods, sequential HRT is used with a progestogen added for the last 12-14 days of her cycle. This regimen effectively mimics the normal menstrual cycle, producing a monthly withdrawal bleed.
In contrast, once a woman has reached the menopause, a continuous regimen is used – a progestogen is taken every day, keeping hormone levels stable and without a monthly bleed.
Both continuous and sequential HRT regimens can be administered orally or transdermally. Transdermal HRT is generally recommended, although both forms are effective for vasomotor symptoms. However, the choice of formulation should be down to the patient once the options have been explained.
Furthermore, modern HRT formulations include what are termed ‘bioidentical’ hormones, which are indistinguishable from those produced in the body, rather than being synthetic or extracted from animals (the original conjugated equine oestrogens were extracted from horses).
Effectiveness
The efficacy of HRT for relieving menopausal symptoms has been demonstrated in countless clinical trials. In general, HRT is well tolerated, and reduces symptom frequency and intensity by nearly 90%, typically within one month of initiation.
Urogenital symptoms
Women with vaginal symptoms such as dryness, itching, burning, vaginal atrophy and painful sexual intercourse benefit from the use of vaginal oestrogen therapy, but without the need for a progestogen. An OTC product, Gina (estradiol 10mcg), is available to manage these symptoms.
Reduced libido
For women with low sexual desire, NICE recommends that testosterone gel is added to their HRT regimen. Currently, none of the available testosterone gels (e.g. Testim, Tostran or Testogel) is approved for use in women, yet these are often used off-label for low libido.
One such product, AndroFeme, received MHRA approval in August 2025 for hypoactive sexual desire dysfunction in postmenopausal women on optimised hormone replacement therapy. However, there is currently no licensed version available, but one is expected in 2026.
Topical testosterone gels are rubbed onto the lower abdomen or thighs and allowed to dry before dressing.
Adverse effects
The most common acute adverse effects from HRT are bleeding and breast tenderness. In fact, bleeding is very common and experienced by up to 60% of women due to the presence of additional oestrogen, which stimulates shedding of the uterus lining and occurs during a monthly bleed.
Bleeding can persist for the first 3 to 6 months and typically resolves after that. Similarly, breast tenderness also normally settles within a few weeks.
Contraindications
HRT is not suitable for certain patient groups, including:
- Those with a past or current history of breast cancer or known/suspected oestrogen-dependent cancer
- Where there is undiagnosed vaginal bleeding
Use of HRT is also associated with an increased risk of ischaemic stroke in women with migraine, especially the oral form. Although this is not a contraindication, caution is still advised.
Controversy
By the 1990s, millions of women were using HRT for symptomatic relief of menopausal symptoms. In addition, numerous epidemiological studies also suggested a cardiovascular benefit from HRT, prompting the authors of a 1991 review to conclude that the “bulk of this evidence strongly supports a protective effect of oestrogens that is unlikely to be explained by a confounding factor”.
But in 1998, the Heart and Estrogen/Progestin Replacement Study (HERS) study found no cardiovascular or mortality benefits from HRT in women with established cardiovascular disease – and there was worse to come.
In 2002, the findings of the Women’s Health Initiative (WHI), which included more than 27,000 post-menopausal women aged 50 to 79, were published. The trial, which was halted early, revealed that using combined HRT increased the risk of breast cancer, heart disease, stroke and blood clots.
The WHI findings caused a significant reduction in HRT prescribing as women became increasingly concerned about the associated cancer risks. Based on the findings of the WHI, HRT manufacturers are required to add warnings to their product information about the risks of cardiovascular disease, cancer and dementia. However, more recent analyses of the original WHI data suggest that some of these risks have been exaggerated.
A 2025 study concluded that neither oestrogen-only nor combination HRT affected cardiovascular disease risk. Additionally, starting HRT before the age of 60 and/or at or near the menopause significantly reduces both all-cause mortality and cardiovascular disease.
The use of transdermal HRT (both oestrogen-only and combined) for one to two years results in a significant improvement in bone mineral density and a reduction in fracture risk. Furthermore, transdermal HRT appears to be more effective than oral therapy.
The use of HRT was also found to reduce the risk of cognitive impairment and potentially delay onset of Alzheimer’s disease.
What about breast cancer risk?
In a 20-year follow-up study of women enrolled in the WHI trial, it was found that oestrogen-only HRT was associated with a 22% lower incidence of breast cancer and a 40% lower risk of breast cancer-related mortality.
In contrast, the use of combined HRT led to a 28% higher incidence of breast cancer but without any change in breast cancer-related deaths. However, it now seems clear that the risk of breast cancer was attributable to a particular progesterone, medroxyprogesterone acetate, which is not in common use today.
Table 1: Breast cancer risk with HRT
| Type of HRT | Duration of use (years) | Approximate excess cases |
|---|
| Continuous combined | 5 | 1 in 50 |
| Sequential combined | 5 | 1 in 70 |
| Oestrogen-only | 5 | 1 in 200 |
| Any type | 10 | Roughly double (i.e. for 5 years) |
Source: The lancet. 2019;394(10204):1159-1168
Timing of HRT initiation
What has become increasingly clear is that when a woman starts HRT has an important impact on any subsequent risk. The WHI trial included older women, and it now seems that starting HRT within 10 years of the menopause is beneficial.
In fact, a recent retrospective analysis of 120 million patient records in a US health database revealed that perimenopausal women who had used oestrogen therapy for at least 10 years before menopause had approximately 60% lower odds of developing breast cancer, heart attack and stroke compared with those who were postmenopausal or postmenopausal and not using oestrogen therapy.
FDA removes black box warnings
In 2025, and in recognition of the recognised benefits of HRT, the FDA removed several black box warnings. (A black box warning is the most stringent safety indicator issued by the FDA for prescription medicines, indicating that the drug carries a significant risk of adverse events.)
The removal of the black box warning relates to the risk of cardiovascular disease, stroke, breast cancer and probable dementia, and applies to both oestrogen-only and combined HRT. However, warnings remain in place for the risk of endometrial cancer for systemic oestrogens.
The FDA also advises that HRT should be started within 10 years of menopause onset or before age 60 for systemic HRT. However, the EMA has said there is no new evidence to support amending HRT warnings and is unlikely to make similar labelling changes.
While the MHRA does not have a black box warning system, SPCs outline the risk and benefits of HRT.
The ‘Davina effect’
For many women, the fear of breast cancer from treatment meant they had to endure a wide range of menopausal symptoms. However, in recent years, HRT prescribing has increased. In 2015/16, only 3.1 million items were dispensed, but by 2024/25 the number had shot up to 14.7 million. What’s more, the number of women in receipt of HRT climbed from around 1 million in 2015/16 to 2.8 million in 2024/25.
This increase has been driven largely by increased awareness of the benefits of HRT, as highlighted in a documentary by TV presenter, Davina McCall, in 2021, which described her own experience of the menopause.
In 2022, a second documentary by McCall inspired another wave of women to come forward and request HRT. Such celebrity endorsement has a powerful effect on health-seeking behaviours, and more women are now coming forward and seeking treatment with HRT as a means of alleviating the symptoms associated with menopause transition.
|
|
Share:
In Learning
This is your ultimate guide to pharmacy learning. Here you can find modules, articles, scenarios and more to improve your knowledge and support your learning in the pharmacy.