Hormone replacement therapy

Menopausal symptoms are extremely common but may be under-recognised and under-treated. Vasomotor symptoms (VMS, hot flushes and night sweats) are the most commonly reported symptoms, occurring in about 80% of postmenopausal women, with 25% of these women reporting a severe impact on quality of life.¹

Symptoms of the menopause often last far longer than most women anticipate. Frequent menopausal VMS persist in more than half of women for more than seven years.²

See also the articles on Menopause and its management, Hot flushes and Atrophic vaginitis.

What is hormone replacement therapy?³

Hormone replacement therapy (HRT) is an effective treatment for typical menopause-related symptoms. There are also other long-term health problems associated with the menopause for which HRT can be beneficial, particularly reducing the increased risk of osteoporosis.

However HRT is also associated with some increased risks of health problems and should only be used where the relief of symptoms outweighs the risk - this will be an individual decision. It should not be used to prevent possible future problems such as cardiovascular disease, in the absence of symptoms.

See also the separate HRT - initial consultation, HRT - Follow-up assessments and HRT - topical vaginal articles, including information on contra-indications, side-effects and indications for stopping HRT.

Indications for hormone replacement therapy

HRT with small doses of an oestrogen (together with a progestogen in women with a uterus) is appropriate for alleviating menopausal symptoms such as genitourinary syndrome of the menopause (GSM, previously known as atrophic vaginitis or urogenital atrophy) or VMS. Topical oestrogen used for GSM should usually be continued long-term, as symptoms are likely to recur if it is stopped.

The threshold for HRT use should be lower in women with early natural or surgical menopause (before age 45 years), since they are at a particularly high risk of osteoporosis. For early menopause, and premature ovarian insufficiency (before age 40 years) HRT would usually be given at least until the approximate age of natural menopause (until age 50 years). Women who have an early or premature menopause and have a significant contraindication to HRT, such as a past history of breast cancer, should be referred to a menopause specialist for advice.

Oestrogen given systemically in the perimenopausal and postmenopausal period or tibolone given in the postmenopausal period also diminish postmenopausal osteoporosis. Tibolone combines oestrogenic and progestogenic activity with weak androgenic activity. However, alternatives to HRT should be considered first if osteoporosis is the only concern and there are no menopausal symptoms.

Raloxifene hydrochloride is licensed for the treatment and prevention of postmenopausal osteoporosis. Raloxifene does not reduce menopausal vasomotor symptoms.

HRT does not protect against a decline in cognitive function and it should not be prescribed for this reason.

Experience of treating women who are over 65 years of age with HRT is limited. Starting HRT in women over the age of 60 years was not traditionally done in the UK; it is anecdotally more common now, but the risks and benefits, and lack of data on some of them, should be fully discussed.

Benefits and risks of hormone replacement therapy^{1 4}

Benefits of hormone replacement therapy⁵⁶

The benefits of HRT outweigh the risks for most women aged under 60 years. The potential benefits of HRT include:

Fragility fractures⁷

• The baseline risk of fragility fracture for women around menopausal age varies from one woman to another.

• The risk of fragility fracture is decreased while taking HRT, and this benefit is maintained during treatment but decreases once treatment stops; this benefit may continue for longer in women who take HRT for longer. This should be balanced against the fact that breast cancer risk increases with age, and there is little data on the risk of breast cancer in older women who take HRT.

Muscle mass and strength

There is limited evidence that HRT may improve muscle mass and strength.

Reduction in VMS

• HRT is the most effective treatment for reducing VMS.

• Maximum benefit is usually gained by three months, which is when the first review is timed.

See also the article on Hot flushes.

Improvement in quality of life

HRT can also improve sleep, muscle aches and pains and quality of life in symptomatic women.

Improvement in mood⁴

• HRT can improve mood and also depressive symptoms.

• HRT should be considered to alleviate low mood that arises as a result of the menopause. Menopause specific cognitive behavioural therapy may be beneficial too.

Improvement of urogenital symptoms (genitourinary syndrome of the menopause, GSM)⁸

• HRT is effective in improving the symptoms related to GSM.

• Topical oestrogen is effective in improving urinary symptoms in menopausal women; non-hormonal lubricants can also be used, ideally products which are physiologically similar to normal vaginal secretions. Some of these can be prescribed on the NHS.⁹

• Vaginal symptoms are improved, vaginal atrophy and pH decrease and there is improved epithelial maturation with topical oestrogen preparations compared to placebo or non-hormonal gels.¹⁰

See also the article on Atrophic vaginitis.

Premature menopause/premature ovarian insufficiency (menopause at under the age of 40)

• Starting hormonal treatment (either with HRT or a combined hormonal contraceptive) and continuing treatment until at least the age of natural menopause (unless contra-indicated) reduces the risk of chronic diseases, including cardiovascular disease and osteoporosis.

• HRT may have a beneficial effect on blood pressure when compared with a combined hormonal contraceptive.

• Both HRT and combined hormonal contraceptives offer bone protection.

Risks associated with hormone replacement therapy⁴¹¹¹²

HRT can, in some women, increase the risk of venous thromboembolism, stroke, endometrial cancer (if oestrogen only HRT is inadvertently given to a woman who still has her uterus), breast cancer, and ovarian cancer.

The National Institute for Health and Care Excellence (NICE) reviewed the evidence on the risks associated with hormone replacement therapy (HRT) in 2024, when they also published a discussion aid which can be used in consultations, and the link given to the patient for perusal at home. On the same day that it was published, the British Menopause Society (BMS) issued a statement expressing their concern about some of the contents of the updated guideline. This section will address some of these differences in opinion.

Venous thromboembolism (VTE)

The risk of VTE associated with HRT is greater for oral than transdermal preparations; the relative risk is approximately double with oral preparations. The risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline risk. Women with risk factors for VTE, including a BMI of 30 or more, should be offered transdermal HRT rather than an oral preparation.

Coronary heart disease (CHD) and stroke ¹³

The baseline risk of coronary heart disease (CHD) and stroke for women around menopausal age varies from one woman to another, depending on the presence of cardiovascular risk factors. The 2024 NICE update stated that CHD risk, and the risk of mortality from CHD, do not increase with combined HRT, however the linked discussion aid showed one extra case of CHD per 1,000 women over five years. This counteracts opinion from the BMS and the International Menopause society that starting HRT below the age of 60, or within 10 years of the menopause, reduces the risk of cardiovascular disease as well as all-cause mortality, and that for those who start above the age of 60, there is no evidence of an increased risk.

The BMS statement says "The guideline scope excluded studies where oestrogen only and combined HRT were included together, which resulted in exclusion of the combined outcomes of WHI and the Cochrane review. The Cochrane review showed that starting hormone therapy less than 10 years after the menopause had lower mortality and coronary heart disease compared to placebo or no treatment. Women who started HRT more than 10 years after the menopause were not noted to have an increased risk of mortality or coronary heart disease". As of December 2024, NICE have not responded to the BMS statement. It is generally recommended that women with risk factors for any arterial disease also use transdermal HRT rather than an oral preparation.

Type 2 diabetes

HRT (either orally or transdermally) is not associated with an increased risk of developing type 2 diabetes and the use of HRT is not associated with adverse effects on blood glucose control.

Dementia

The likelihood of HRT affecting the risk of dementia is slightly increased where HRT is started at age 65 or older, with an extra nine cases per 1,000 women, over four years. This has limited relevance for the UK, as starting HRT over that age is not common practice.

Breast cancer^{4111214151617}

The question of breast cancer risk with HRT has periodically hit the headlines many times over the last few decades, contributing to significant changes in HRT use over the years. The 2002 Women's Health Institute study suggested that the risks were higher than previously thought, but in many ways the cohort studied are not the same as those to whom we prescribe HRT in the UK. Most of them started HRT >10 years after the menopause, which is much less common in the UK, and the HRT regimes used contained varieties of oestrogen and progestogens that are now less commonly used (conjugated equine oestrogens and medroxyprogesterone acetate). The study also did not differentiate between the development of new breast cancers and the growth of those already there; it is now thought that the main effect of HRT in this area is to increase the growth of an already present breast cancer.

In 2019, additional evidence was published by the Collaborative Group on Hormonal Factors in Breast Cancer, reporting on a meta-analysis of 108,647 women with breast cancer in prospective studies. This reported that, if the associations seen were largely causal, five years of HRT, starting at the age of 50, for women of average weight in developed countries would increase breast cancer incidence over the 20 years from 50 - 69 by:

• One case per 50 users of continuous combined HRT.

• One case per 70 users of sequential combined HRT.

• One case per 200 users of oestrogen only HRT.

There was some ongoing increased risk after stopping HRT, which increased with the duration of use of HRT, and there was no increase shown in women who used vaginal oestrogen only and did not have a past history of breast cancer. The possible risks of vaginal oestrogen for women with a history of breast cancer are discussed in some detail in the November 2024 update of the NICE guidance and this subject is covered in the leaflet HRT - topical vaginal.

Complicating these figures is the fact that the baseline risk of breast cancer for women around menopausal age in the UK varies from one woman to another, with factors such as obesity and family history playing a part. The magnitude of the risk from obesity is the same or higher than that from HRT. The NICE discussion aid published with the November 2024 update quantifies the increased risk as follows, for women who have their menopause at ≥45 and take HRT for five years from the age of 50, with extra cancers measured over the 20 years from 50 - 69:

• An extra 20 cases per 1,000 women who take combined HRT, over 20 years, ie one extra case per 1,000 women per year. This is not significantly different from figures given by the BMS and by the 2019 meta-analysis mentioned above.

• An extra 10 cases per 1,000 women who take oestrogen only HRT, over 20 years, ie one extra case per 2,000 women per year. This is double the risk given in the 2019 met-analysis, but the absolute increase is small.

There are currently three differences in opinion between NICE and the BMS:

• The first is on the question of whether oestrogen only HRT affects breast cancer risk - the BMS says that it 'is associated with little or no change in risk'. Both organisations agree that the risk from oestrogen only HRT is less than that from combined HRT.

• The second is on the question of whether HRT increases a woman's risk of breast cancer mortality. The BMS, and the International menopause society, say that there is no effect, whereas the updated NICE guidance says that there is a 'very small increase'. The BMS statement disputes NICE's interpretation of the evidence, saying "this is factually incorrect as there was no statistically significant increase. It is also stated elsewhere that the breast cancer mortality data were derived from RCTs and a meta-analysis when in fact the mortality data came from a letter in The Lancet. The meta-analysis did not report on breast cancer mortality". With the absolute number of extra cases being small, the detailed figures on possible extra mortality may not be something that comes up in most consultations; if there are doubts on the risk: benefit balance for any individual woman, it would be sensible to seek advice from a menopause specialist.

• The third is on the degree to which the choice of progestogen used affects the risk of breast cancer. NICE says 'there is insufficient evidence to establish whether the increase in risk of breast cancer is different with preparations containing micronised progesterone or dydrogesterone from what it is with preparations containing other progestogens'. The BMS statement comments that the NICE update was based on a meta-analysis which included very few women using micronised progesterone, and that data was excluded which suggests a reduced risk with micronised progesterone or dydrogesterone compared with other synthetic progestogens.

Ovarian cancer¹⁸
The Collaborative Group on Epidemiological Studies of Ovarian Cancer published a meta-analysis of 52 epidemiological studies in 2015.

• During prospective follow-up, 12,110 postmenopausal women, 55% (6,601) of whom had used HRT, developed ovarian cancer.

• Among women last recorded as current users of HRT, the risk was increased even with fewer than five years of use (relative risk (RR) 1.43).

• Combining current or recent use (any duration but stopped less than five years before diagnosis) resulted in an RR of 1.37. This risk was similar for oestrogen-only and combined oestrogen-progestogen HRT and was increased for the two most common types of ovarian cancer (serous and endometrioid). The risk declined the longer ago use had stopped, although about 10 years after stopping long-term HRT there was still an excess of serous or endometrioid tumours (RR 1.25).

• The authors of the meta-analysis concluded that women who use hormone therapy for five years from around the age of 50 years have about one extra ovarian cancer per 1,000 users and, if its prognosis is typical, about one extra ovarian cancer death per 1,700 users.

Endometrial cancer

• Oestrogen-only HRT substantially increases the risk of endometrial cancer in women with a uterus; any such prescriptions given inadvertently should prompt a significant event analysis.

• The use of cyclical progestogen for at least ten days per 28-day cycle lowers this risk. Switching to continuous combined HRT after 1 - 5 years of HRT use removes the risk; long-term use of continuous combined HRT significantly decreases the risk of endometrial cancer.

Hormone replacement therapy and contraception

• Contraception is needed along with HRT. HRT is not a contraceptive and a woman is considered potentially fertile for two years after her last menstrual period if she is aged under 50 years and for one year if she is aged over 50 years.

• For many women oestrogen HRT and a levonorgestrel intrauterine device (LNG-IUD) are an optimal combination.

• Alternatively, the progestogen-only contraceptive pill can be given to women who are taking cyclical combined HRT.

• Women aged 50 years and over should not be prescribed the combined oral contraceptive pill.

See also the separate Contraception from 40 to the menopause article.

Starting hormone replacement therapy

See the separate HRT - initial consultation article.

Follow-up of a woman taking hormone replacement therapy

The separate HRT - follow-up assessments article gives advice about following up women taking HRT and when to stop HRT.

Initial follow-up after starting HRT should occur at about 3 months if HRT has been started or changed, then at least annually thereafter, unless there are clinical indications for an earlier review (such as treatment ineffectiveness or adverse effects).¹ Most symptoms are likely to have responded to oestrogen in this time period and any residual problems may require alternative management.