Hormone replacement therapy (HRT) for menopause

Dr Vikram Sinai Talaulikar, MD PhD FRCOG

Associate Specialist, Reproductive Medicine Unit, and Hon Associate Professor in Women’s Health, University College London Hospital, London, UK

Menopause, sometimes referred to as the ‘change of life’, happens when a woman's periods stop permanently – signalling the end of reproductive function. Menopause usually occurs when a woman is in her 50s (the median age in the UK is 51 with a range of 45–55), but some women may experience menopause much earlier, in their 40s, or even at a younger age.¹ For most women, menopause is a phase of natural transition in later life. However, for some, menopause may be induced abruptly by medical or surgical treatments.

About 80% of women experience menopause symptoms, of which about a third have severe, debilitating ones. Symptoms can last for a few months or years for some while they can continue for 10–15 years for others.¹ Treatments for menopausal symptoms include lifestyle interventions, non-hormonal therapies and hormone replacement therapy (HRT). Every woman’s menopause journey is unique and, if she decides to take HRT, she will need to carefully consider the benefits and risks of doing so and make an informed choice.

What happens in the menopause?

As women approach natural menopause, ovarian function declines, and the body produces less estrogen and progesterone. Among other roles, these hormones are responsible for triggering menstruation.^1,2 With lower levels, menstrual periods become less regular. They might be heavier or lighter, and last for more or fewer days than usual. The periods will become less frequent with time and eventually stop. Testosterone is another hormone produced by the ovaries, as well as the adrenal glands, and its levels gradually decline from the third decade of life.³

‘Hot flushes’, i.e. suddenly feeling hot and going red in the face, are among the most common symptoms associated with menopause. These may be accompanied by bouts of sweating during the day as well as at night. It is also common for the vagina to feel dry and uncomfortable, which can make sex painful. Other symptoms include tiredness, irritability, headaches, trouble sleeping, joint pain, mood fluctuations or low mood, heightened anxiety, palpitations and reduced interest in sex.¹ These symptoms may be attributable to changes in hormone levels and can overlap with other life changes around the time of menopause. For some women, symptoms start very early during the perimenopause, when hormones and periods fluctuate, while for others they may appear only after periods stop.

What is HRT?

HRT (hormone replacement therapy), also referred to as MHT (menopausal hormone therapy), involves taking estrogen alone or estrogen combined with progesterone, or other drugs such as tibolone.⁴ The treatment aims to replace the estrogen no longer produced by the body after menopause. Not every woman who experiences menopausal symptoms needs HRT, but it should not be denied to women who choose it when the benefits outweigh the risks.

What are the types of HRT?
Combined HRT (estrogen and progesterone/progestogen)

Women with an intact uterus need to take progesterone or progestogen (derivative with progesterone-like activity) in addition to estrogen. Taking estrogen alone can increase the risk of endometrial cancer (cancer of the uterine lining), and this risk is minimized by taking progesterone.

Cyclical HRT, estrogen-only for the first 14 days then both hormones for the second 14 days (with monthly withdrawal bleeds) is often prescribed for women who are having menopausal symptoms but are still having periods in perimenopause or for those who have ceased having periods for less than 1 year.

Continuous HRT, estrogen and progesterone taken together daily without breaks (no withdrawal bleeds), is more suitable for women who have not had periods for an year or more.

Estrogen-only HRT (no progesterone/progestogen)

Women who have had a hysterectomy (removal of uterus) can take estrogen-only HRT (without progesterone) as they are not at risk of endometrial cancer. In some situations, such as in those with endometriosis or a history of endometrial tumor, both estrogen and progesterone may need to be prescribed despite hysterectomy to prevent recurrence of endometriosis or any residual endometrial tissue stimulation in pelvic areas.

How is HRT administered?

HRT is available for prescription in several different forms. It can be administered as a skin patch, oral tablets or capsules, gel, spray, implant, vaginal ring, vaginal pessary or cream, and progestogen-releasing uterine coil. Some types work best for certain symptoms. Because transdermal estrogen (patch/gel/spray/implant) is associated with lower risk of thrombosis than oral HRT, it is generally preferred for women with medical risk factors such as high body mass index (BMI), diabetes, hypertension, or other cardiovascular conditions, especially with advancing age. Unlike oral HRT, transdermal estrogen largely bypasses liver metabolism, resulting in minimal stimulation of hepatic clotting factor production and a lower associated risk of thrombosis.^2,4

Low-dose vaginal estrogen preparations can be used in women with genitourinary symptoms for as long as required.⁴ There is no need to combine them with systemic progesterone/progestogen treatment for endometrial protection. 17-beta estradiol is the preferred body-identical estrogen, while natural micronized progesterone (body-identical) and dydrogesterone (body-similar) are the preferred first-line progestogens, as these have a superior breast and thrombotic safety profile.^2,4 Currently, most clinical guidelines recommend testosterone replacement (gel, cream or implant), in addition to estrogen and progesterone, for those with persistent menopause-induced low libido. It is important that other causes of low libido, such as vaginal dryness, pain, relationship problems or use of medications like selective serotonin reuptake inhibitors (SSRIs) are ruled out before initiating testosterone. While some women report additional benefits of improved energy, mood and cognition when they take testosterone, currently there is little to no evidence to support these indications.³

What is Tibolone?

Tibolone is another type of oral hormone treatment. It does not contain estrogen or progesterone but, instead, acts on estrogen, progesterone and testosterone receptors. It is a bleed-free form of HRT.⁴ Tibolone use is associated with fewer hot flushes, less vaginal dryness, improved libido and bone protection. It is often used as a second-line option to estrogen- and progesterone-containing HRT preparations but can be particularly useful in women with hormone sensitivity, chronic pelvic pain, uterine fibroids and/or endometriosis.^4,5

What are the benefits of HRT?
Reduction of vasomotor symptoms such as hot flushes and night sweats

HRT is the most effective medical treatment for reducing vasomotor symptoms such as hot flushes and night sweats. Vasomotor symptoms usually improve within 3–4 weeks of starting treatment and maximal benefit is gained by about 3–6 months.

Improvement in quality of life

HRT may improve sleep, muscle aches/pains, mood changes, headaches and overall quality of life in symptomatic women. Many women experience improved mood and libido levels, and fewer depressive symptoms.

Improvement of urogenital symptoms

HRT significantly improves vaginal dryness and dyspareunia and can improve sexual function in some women. HRT is also effective in improving stress incontinence (leaking urine on cough or sneeze). It may also relieve the symptoms of urinary frequency, as it has some effect on the urinary bladder and urethral tissues. It can prevent recurrent urinary tract infections secondary to vaginal dryness.

Reduction in risk of osteoporosis

HRT is effective in preserving bone mineral density.^2,4 Women taking HRT have a significantly decreased incidence of fractures with long-term use. Although bone density declines after discontinuation of HRT, some studies have demonstrated that women who take HRT for a few years around the time of the menopause may have a long-term protective effect for many years after stopping HRT. HRT is now considered a first-line medical option for treatment of osteoporosis in postmenopausal women under the age of 60. Other non-HRT drugs can be prescribed for osteoporosis in women who do not wish to take HRT or who are not suitable for HRT prescription.

Effect on cardiovascular disease

The relationship between HRT and cardiovascular disease has been controversial, but the timing and duration of HRT, as well as pre-existing cardiovascular disease, are likely to affect cardiovascular health. Recent evidence suggests that HRT reduces the incidence of coronary heart disease if it is started within 10 years of the menopause or under the age of 60. For every 1000 women, when given at the right time, HRT can save six lives and prevent eight women from suffering heart disease.^4,6 A Cochrane review, which assessed HRT and cardiovascular health, included 19 trials with a total of 40,410 postmenopausal women. On subgroup analysis according to when treatment was started with respect to onset of menopause, those who started HRT within 10 years of menopause onset had lower rates of all-cause mortality and coronary heart disease events (defined as coronary death or non-fatal myocardial infarction). In those who started treatment more than 10 years after the onset of menopause, there appeared to be little effect on death or coronary heart disease between groups (high-quality evidence).⁶

Other benefits

HRT has a protective effect on tissue loss in tissues such as skin, bones, joints and mucous membranes. In some groups of women (with genetic or familial risk of dementia or premature/early menopause), there may be a possible benefit in terms of reduction in long-term risk of Alzheimer's disease.⁷ Further research is required to confirm this finding. Most studies have demonstrated a reduction in risk of colorectal cancer in women taking oral combined HRT.⁸

What are the risks associated with HRT?

There are side-effects and risks associated with taking HRT. For most women, the increased risks are very small, but women need to talk to their healthcare professionals to weigh up their individual risks and benefits. Most clinical guidelines recommend that women should take the lowest dose of HRT that effectively controls their symptoms and continue for as long as the benefits outweigh the risks.^2,4 There is no maximum duration of time for women to take HRT; for the women who continue to have symptoms, the benefits of HRT usually outweigh any risks.

The risks associated with HRT use are thromboembolic disease (blood clots in veins and lungs), stroke, cardiovascular events, gallbladder disease, breast cancer, ovarian cancer and endometrial cancer. Large studies, such as the Women’s Health Initiative (WHI) and the Million Women Study (MWS), caused concerns and controversy over the use of HRT when their findings were published 20 years ago.^8,9 However, reanalysis of some of the data and findings from recent studies over the past two decades have shown that, in women with symptoms or other indications, initiating HRT near menopause will usually provide a favorable benefit-to-risk ratio.

Venous thromboembolism

Oral HRT (combined estrogen and progesterone or estrogen-only) increases the risk of venous thromboembolism (VTE) i.e. venous blood clots, pulmonary embolism (blood clot in lungs) and stroke.^4,5,8,10 The risk of VTE is increased two to three times with oral HRT. In one large study, over 5 years, fewer than one in 100 women taking HRT suffered pulmonary embolism. However, this was approximately twice the number of women who were not taking HRT. Overall, this risk is significantly less than that associated with pregnancy. The risk increases with age and with other risk factors such as obesity, previous thromboembolic disease, smoking and immobility. In healthy women below 60 years, the absolute risk of VTE and mortality risk from VTE are low.^4,5,8,10 The type, dose and delivery system of both estrogen and progestogen influence the risk of thromboembolic disease. The VTE risk appears to be higher among users of estrogen plus progestogen than among users of estrogen alone. The risk is increased especially during the first year of treatment. Previous users of HRT have a similar risk to never users. In ‘high-risk’ individuals who require HRT, transdermal preparations are preferred as transdermal or intrauterine HRT preparations are not associated with an increased risk of VTE in women without pre-existing medical problems.^4,5 There is no risk of VTE from use of vaginal estrogen preparations.⁵

Stroke

The risk of stroke appears to be increased in women taking oral estrogen-only or combined HRT.⁴ The risk is estimated at one additional case per 1000 women aged 50–59 years and three additional cases per 1000 women aged 60–69 years compared to non-HRT users (for a 5-year use period).⁵ The WHI study also revealed an overall increased incidence of stroke in women using both oral combined and estrogen alone HRT.^8,10 Reanalysis of data from combined HRT and estrogen-only HRT subgroups revealed a smaller increase in incidence of stroke in women who commenced HRT between the ages of 50 and 59 as compared to those who commenced HRT later.^4,8,10 The effects of oral HRT on stroke may be dose-related and so the lowest effective dose is usually prescribed in women who have significant risk factors for stroke. Transdermal estrogen and progestogen or the intrauterine progestogen coil and vaginal estrogens do not appear to be associated with an increased risk of stroke in women without pre-existing medical risk factors.⁴

Breast cancer

Data regarding the effect of HRT on the incidence of breast cancer are still contentious. Combined HRT is associated with a small increase in breast cancer risk and the risk is a little higher for women who take HRT over the age of 60. The risk increases slowly in the first 5 years of use of HRT, then increases further if use continues. However, the absolute risk is small at around one extra case of breast cancer per 1000 women per year.^{4,8,11,12,13,14} This is similar in magnitude to the risk associated with late menopause, early menarche and not having children, and the risk is much higher with obesity. The risk is also similar in magnitude to that of drinking two units of alcohol daily.⁴ The risk returns to that of a non-user within about 5 years of stopping HRT. Mortality from breast cancer is not significantly increased in an HRT user. Combined HRT increases breast density and therefore the risk of having an abnormal mammogram. The risk of breast cancer with estrogen-only HRT is lower than with combined HRT and, in some studies, has been shown to be reduced compared with non-users.^{4,8,9,10,13,14} It is important to note that the increased risk of breast cancer associated with systemic HRT does not appear to apply to women using vaginal estrogen. Similarly, this increased risk is not thought to apply to women using HRT for premature (< 40 years) or early (< 45 years) menopause when treatment is continued until the average age of natural menopause (approximately 51 years).⁴

Endometrial cancer

Estrogen-only HRT substantially increases the risk of endometrial cancer in women with a uterus. However, the use of continuous combined HRT (estrogen and progesterone) or cyclical progesterone for at least 12 days every month almost eliminates this risk.^2,4,13 It is generally recommended to switch from cyclical to a continuous combined form of HRT between 1–5 years of starting HRT (mainly in women above 45) as continuous combined HRT is associated with a reduced risk of endometrial cancer in the long-term. Progesterone dose should be adjusted to match the estrogen dose appropriately as per local clinical guidelines.⁴

Heart disease

Results from the WHI study, which initially included women of all age groups (50–79 years), suggested an increase in risk of cardiovascular disease in women using combined HRT;⁸ however, the long-term follow-up data showed no evidence of such a detrimental effect.^4,6 In women below 60 years of age, who used estrogen-only HRT, a significant decrease in coronary events was noted. Evidence from more recent studies and meta-analyses suggests that HRT started before the age of 60 or within 10 years of the menopause is associated with a reduction in atherosclerosis progression, coronary heart disease and death from cardiovascular causes, as well as all-cause mortality.^4,5,10 Long-term follow-up data from the WHI study showed no increase in cardiovascular events, cardiovascular mortality or all-cause mortality in women who started HRT more than 10 years after the menopause.^4,6,10

Ovarian cancer

Observational study data have suggested a small increased risk of ovarian cancer with HRT use. The WHI randomized placebo-controlled trial results, including long-term follow-up, did not demonstrate a statistically significant increase in ovarian cancer risk with HRT use. It has been suggested that there may be a slight increase in the risk of developing serous and endometrioid ovarian cancer associated with HRT use, but the absolute risk remains very small.⁴

Other risks

Some studies have found that taking HRT for a year or more can increase the risk of gallbladder disease, particularly gallstone formation.¹³

What are the common side-effects of HRT and how can they be minimized?

Women react differently to HRT, so there is no one preparation that is better than any other. Some of the common side-effects of HRT are:

• Estrogen-related – breast tenderness, leg cramps, skin irritation, indigestion, nausea, headache
• Progesterone-related – premenstrual syndrome-like symptoms, fluid retention, bloating, backache, depression, mood swings, pelvic pain
• Testosterone-related - oily skin, acne, hirsutism, scalp hair loss, voice changes, clitoromegaly with high doses

Nausea can be reduced by taking HRT tablets at night with food instead of in the morning, or by changing from tablets to another type of HRT. There is no evidence of weight gain with HRT. Researchers have found that, although women may gain some weight when they first start to take HRT (largely due to temporary fluid retention), after a while their weight returns to what it was before treatment. Women tend to gain weight during the menopause, so any weight gain may not be a result of HRT. The body’s fat distribution also changes, with an increase in fat around the waist and less around the hips and buttocks. Many of the common side-effects disappear with continued use of HRT. Sometimes a change of product may help.

Monthly sequential preparations should produce regular, predictable and acceptable period-like bleeds. Erratic breakthrough bleeding is common in the first 3–6 months of continuous combined and long-cycle HRT regimens (with no regular period-like bleeds).

If bleeding is persistently heavy or irregular on sequential or continuous combined HRT, the dose of progesterone can be doubled or increased in duration, or the type of progestogen can be changed. If there is persistent irregular vaginal bleeding after 6 months of starting HRT, further investigations are required as per local guidelines.

About 10% of women can be sensitive to various progestogens and several types/routes or doses/regimens of progestogens may need to be tried before finding one that works. If significant nausea or migraine headaches occur with oral preparations, patches or gels and intrauterine coil can be alternative options worth considering.

When should HRT not be taken?

HRT should not be prescribed to women who are pregnant or breastfeeding, or have undiagnosed abnormal vaginal bleeding, active venous thrombosis or thromboembolic disease, active heart disease, current or past breast cancer, current or past endometrial cancer, other estrogen-dependent cancer, active liver disease or uncontrolled high blood pressure. Women with any of these conditions should seek specialist advice as they may be able to consider HRT on an individualized basis after active treatment for the condition has finished.

What tests are needed before or after starting HRT?

When starting HRT, healthcare professionals should consider age, symptoms and medical conditions before looking at the risks and benefits of HRT which are specific to the individual. These can change and should be discussed on annual review. Tests are usually not necessary before starting HRT unless there is a sudden change in menstrual pattern such as persistent heavy/irregular periods, bleeding between periods or after intercourse and postmenopausal bleeding 1 year after the last period. In these situations, a pelvic ultrasound scan is recommended to assess the endometrium and, if indicated, a biopsy may be performed. If there is a personal or family history of VTE, a thrombophilia screen (blood test to look for a tendency to develop blood clots easily) may be helpful. If there is a high risk of breast cancer, it is prudent to consider mammography or an MRI scan and referral to familial breast cancer services depending on the level of risk. A blood test for lipid profile should be considered if there are risk factors associated with cardiovascular disease.

How to decide which preparation of HRT to start – cyclical or continuous/systemic or local?

The choice of delivery route and type of HRT depend partly on patient preference but there are other advantages to certain delivery routes. It is recommended that women should be prescribed sequential combined HRT (giving monthly periods) if the last menstrual period was within 1 year of presentation. Women can be prescribed continuous combined HRT (without periods) if they have received sequential combined HRT for at least 1 year; or if it has been at least 1 year since their last menstrual period. Topical preparations such as vaginal creams, gel and pessaries are effective for symptoms of vaginal dryness, painful sex and urinary frequency. About 20–25% of women have genitourinary symptoms with systemic HRT, so will require vaginal estrogen in addition.

Is HRT contraceptive?

HRT is not a contraceptive. Women are potentially fertile for up to 2 years after the last menstrual period if under 50 years of age and for 1 year above 50 years. Women should therefore use appropriate contraception during this time to avoid pregnancy.

What should be done if HRT medicine is forgotten?

If doses of HRT have been forgotten, the doses that have been forgotten should not be taken. The next scheduled dose should be taken when remembered.

What is ‘bio-identical’ or ‘body-identical’ HRT?

Currently, most clinical guidelines in the UK and around the world recommend use of HRT preparations, which contain body-identical hormones (combination of estradiol with natural progesterone). In contrast, so-called bio-identical HRT preparations are custom-made combinations of similar hormones. These are not regulated by medicines regulatory authorities and there is insufficient evidence regarding their long-term safety and efficacy, hence they are not currently recommended by professional menopause societies.

What are the alternatives to HRT?

For women who are unable to have HRT, have side-effects from it or wish not to take it, other medications or treatments may be prescribed to help control menopausal symptoms. For vaginal dryness and painful sex, vaginal lubricants and moisturisers are often effective. There are also preparations such as vaginal DHEA pessaries or oral ospemifene, a selective estrogen receptor modulator.

For hot flushes and night sweats, antidepressants or selective serotonin reuptake inhibitors or selective norepinephrine reuptake inhibitors (citalopram, sertraline or venlafaxine) and clonidine (blood pressure lowering agent) or gabapentin/pregabalin are oral medications which are most commonly prescribed. Cognitive behavioral therapy and hypnosis can be effective for vasomotor symptoms, sleep and anxiety.

Some women choose alternative therapies including homeopathy and acupuncture.

Novel therapies include the neurokinin-3 (NK3)-receptor antagonists fezolinetant and elinzanetant, which block hypothalamic receptors and reduce hot flushes and night sweats. All these therapies have their pros and cons and need to be individualized based on the patient’s unique clinical situation.

For women who wish to consider any of these alternatives, they should talk to their healthcare professionals in detail about the risks versus benefits of these treatment options and make an informed choice.

Phytoestrogens are plant-derived compounds with weak estrogen-like activity. Dietary phytoestrogens may help alleviate menopausal symptoms in some women. Soya products such as tofu and miso are rich in phytoestrogens, as are beans, lentils, certain fruits and celery. Research evidence on phytoestrogens is not as robust as that for HRT.

Some women opt for herbal therapies for menopause, but they are often not recommended by medical guidelines due to lack of robust scientific evidence. Healthcare professionals should always be informed about use of herbal products as they can react with other drug treatments.

Is follow-up needed after starting HRT?

Women should generally be followed up with a consultation at about 3 months after starting HRT. Most symptoms are likely to have responded to estrogen in this time period and any residual problems may require alternative management. If the chosen HRT suits the woman and appears effective, she is often asked to see her GP or the specialist clinic once or twice a year to review the ongoing need for and safety of continuing HRT. Both mammography and cervical screening as per national guidelines are recommended in postmenopausal women on HRT. Bone health advice is important as part of menopause consultations.

When should HRT be stopped?

Many women will stop taking HRT after their menopausal symptoms diminish, which is usually 3–7 years after they start.¹ Gradually decreasing HRT dose is usually recommended, rather than stopping suddenly. There may be a relapse of menopausal symptoms after stopping HRT, but these should pass within a few months. If symptoms persist for several months after stopping HRT, especially particularly severe symptoms, treatment may need to be restarted, usually at a lower dose. After stopping HRT, additional treatment may be needed for vaginal dryness and to prevent osteoporosis.

HRT is one of the options in the toolbox for management of menopause symptoms and quality of life besides non-hormonal therapies and lifestyle interventions.¹⁵ For most women who take HRT for menopause symptoms and quality of life issues, benefits outweigh the risks.¹³ Whether to stop HRT or continue long-term is an individual decision for the woman to make with advice from her healthcare professional. There is no time limit for taking HRT and it can be continued as long as benefits for symptoms and long-term health continue to outweigh potential risks.^4,15

Further reading
Websites

British Menopause Society - www.thebms.org.uk/
International Menopause Society - www.imsociety.org/
Menopause Research and Education Fund - https://mref.uk/
Menopause and Cancer - https://menopauseandcancer.org/

References

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