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Hormone replacement therapy (HRT) and menopause

Vikram Sinai Talaulikar, MD MRCOG

Clinical Fellow, 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 average age is 51 in the UK), but some women may experience menopause in their 30s or 40s. For most women, menopause is not an illness, but a phase of natural transition in later life. Sometimes this change can be associated with symptoms that can be distressing. Such symptoms may last for several years. Treatment for menopausal symptoms includes hormone replacement therapy (HRT). This can work well, but it increases the chance of some health problems. Every woman needs to consider the benefits and risks of HRT carefully and decide whether to take it.

What happens in the menopause?

As women approach menopause, the functioning of their ovaries declines and the body makes less of the estrogen and progesterone hormones. Among other things, these hormones are responsible for bringing on periods. The 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. ‘Hot flushes’, suddenly feeling hot and going red in the face, are one of the most common symptoms associated with menopause. These may be associated with bouts of sweating during the day as well as at night. It is also common to find that the vagina feels dry and uncomfortable, which may make sex painful. Other symptoms include tiredness, irritability, trouble sleeping, feeling depressed and less interest in sex. These symptoms might be attributable to the changes in hormones or to changes in life around the time of menopause.

What is HRT?

HRT stands for hormone replacement therapy. It is also abbreviated as MHT for menopausal hormone therapy. It consists of the hormone estrogen either alone or combined with the hormone progesterone or therapy with other drugs such as tibolone. The aim is to replace some of the actions of estrogen that the body has stopped making at menopause. Not every woman who experiences menopausal symptoms needs treatment. Some women find that the symptoms do not bother them much, while others find them very distressing and affecting their quality of life. Most symptoms will pass within 2–5 years, although vaginal dryness is likely to get worse if not treated.

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

Women with an intact uterus need to take a combination of estrogen and progesterone as part of HRT. Taking estrogen alone can increase the chance of getting cancer of the womb lining (endometrial cancer). Adding progesterone to estrogen reduces this risk. Some common brands of combined HRT are Evorel Sequi, Evorel Conti, Nuvelle, Premique, Cycloprogynova, Kliovance, Kliofem and Prempak-C.
Cyclical HRT, estrogen-only for the first 14 days then both hormones for the second 14 days (monthly withdrawal bleeds) is often prescribed for women who are having menopausal symptoms but are still having periods or for those who have ceased having periods for less than 1 year. Continuous HRT, estrogen and progesterone, taken together daily (one a day) for 28 days (no withdrawal bleeds), is more suitable for women who have not had periods for more than 1 year.

Estrogen only HRT (no progesterone)

Women who have had a hysterectomy (removal of womb) can take estrogen-only HRT (without progesterone) as there is no chance of getting endometrial cancer. Some common brand names of estrogen-only HRT are Premarin, Estraderm and Evorel.

Forms of HRT

HRT is available for prescription in several different forms. It can be administered as a skin patch, tablet, gel, implant, vaginal ring, progestogen (derivative with progesterone-like activity) releasing uterine coil and vaginal cream or pessary. Some types work best for certain symptoms. As transdermal estrogen (patch) is associated with fewer risks than oral HRT, a transdermal route may be preferable for many women. This route is also advantageous for women with diabetes, hypertension and other cardiovascular risk factors especially with advancing age. Low-dose vaginal estrogen preparations can be used long-term in symptomatic women as required. There is no requirement to combine this with systemic progestogen treatment for endometrial protection. However, there is little evidence to prove the safety of vaginal preparations beyond 1 year of use; clinicians should therefore aim to use the lowest effective dose for symptom control and counsel women appropriately.

Tibolone

Tibolone (brand name Livial) is another type of hormone treatment, but it does not contain estrogen or progesterone. It does not affect the lining of the womb. This means that, if a woman starts taking it at least 1 year after the periods have stopped, she should not get any monthly periods. With tibolone, she is likely to have half as many hot flushes, less vaginal dryness, improved sexual satisfaction and more sexual arousal. Researchers have found that sex drive increases much more in women taking tibolone than in women taking combined HRT. Tibolone may slightly increase the chances of breast cancer, but less so than the combined HRT. If spotting or bleeding from the vagina occurs during the use of tibolone, further investigation is needed, because the product does not affect the endometrium. Some researchers have also found that tibolone lowers the level of 'good' cholesterol (high density lipoprotein (HDL) cholesterol) by about one-third. There is not enough research to show whether this drop in HDL cholesterol is harmful, or whether women who take tibolone are more likely to have a heart attack or a stroke.

What are the benefits of HRT?

For most symptomatic women, use of HRT for 5 years or less is safe and effective. Benefits of HRT are detailed below.

Reduction in vasomotor symptoms such as hot flushes and night sweats

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

Improvement in quality of life

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

Improvement of urogenital symptoms

HRT significantly improves vaginal dryness and sexual function. 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.

Reduction in osteoporosis (brittle bones) risk

HRT is effective in preserving bone mineral density. 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. However, HRT is not a treatment of first choice only for treatment of osteoporosis if there is no other indication for its use. Other drugs can be prescribed for osteoporosis.

Effect on cardiovascular disease

The relationship between HRT and cardiovascular disease is 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 women, who are above the age of 60 years when they start HRT, have an increased risk of coronary heart disease. However, HRT reduces the incidence of coronary heart disease if it is started within 10 years of the menopause. For every 1000 women, when given at the right time, HRT can save six lives and prevent eight women from suffering heart disease at the cost of five extra women experiencing blood clots. A Cochrane review which assessed HRT and cardiovascular health included 19 trials with a total of 40,410 postmenopausal women. The findings were dominated by the three largest trials. The authors found high quality evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or revascularization. However, there was an increased risk of stroke in those in the hormone therapy arm for combined primary and secondary prevention. Venous thromboembolic events were increased on hormone therapy relative to placebo. On subgroup analyses according to when treatment was started in relation to the menopause. Those who started hormone therapy less than 10 years after the menopause had lower mortality and coronary heart disease (composite of death from cardiovascular causes and non-fatal myocardial infarction), although they were still at increased risk of venous thromboembolism compared to placebo or no treatment. There was no strong evidence of effect on risk of stroke in this group. In those who started treatment more than 10 years after the menopause there was high quality evidence that it had little effect on death or coronary heart disease between groups, but there was an increased risk of stroke and venous thromboembolism.

Other benefits

HRT has a protective effect against connective tissue loss in tissues such as skin, bones, joints and mucous membranes. There may be a possible reduction in the long-term risk of Alzheimer's disease and all cause dementia in those women who take HRT. Although some research studies have suggested an improvement in cognition in women who start taking HRT early in menopause, further research is required to confirm this finding. Most studies have demonstrated a reduction in risk of colorectal cancer with use of oral combined HRT.

What are the risks associated with HRT?

There are several 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. Doctors are advised that women should take the lowest dose of HRT that controls their symptoms for the shortest duration of time possible. However, there is no maximum duration of time for women to take HRT; for the women who continue to have symptoms, the benefits from HRT usually outweigh any risks.
The principle risks of HRT are thromboembolic disease (blood clots in veins and lungs), stroke, cardiovascular event, gallbladder disease, breast 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. However, reanalysis of some of the data and findings from recent studies over the past decade have shown that, in women with symptoms or other indications, initiating HRT near menopause will probably provide a favorable benefit : risk ratio.

Venous thromboembolism

Oral HRT (combined estrogen and progesterone or estrogen-only) increases the risk of venous thromboembolism (VTE – venous blood clots), pulmonary embolism (blood clot in lungs) and stroke. The risk of VTE is increased two to three times with oral HRT. In one large study, over 5 years, less than one in 100 women taking HRT got a blood clot in their lungs. However, this was approximately twice the number of women who were not taking HRT. Overall this risk is significantly less than the risk 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 is low and mortality risks from VTE are low. The type, dose and delivery system of both estrogen and progesterone influence the risk of thromboembolic disease. The VTE risk appears to be higher among users of estrogen plus progesterone 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.

Stroke

The risk of stroke appears to be increased in women taking estrogen-only and combined HRT. The risk is estimated to be one additional case per 1000 women using combined or estrogen-only HRT between 50 and 59 years and three additional cases per 1000 women between 60 and 69 years compared to non-HRT users (for a 5-year use period). The WHI study revealed an overall increased incidence of stoke in women using estrogen and progestogen therapy or estrogen alone. Reanalyses of the combined data from the estrogen and progesterone study and that of the estrogen alone study revealed a smaller increase in incidence of stroke in women who commenced HRT between the ages of 50 and 59. The effects of 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.

Breast cancer

Data regarding the true effect of HRT on the incidence of breast cancer are still contentious. Combined HRT slightly increases the risk of breast cancer. The risk is a little higher for women who take HRT over the age of 60. The risk goes up slowly in the first 5 years of use of HRT, then more quickly if its use continues. However, the absolute risk is small at around one extra case of breast cancer per 1000 women per year. The risk is greatest in lean women. This is similar in magnitude to the risk associated with late menopause, early menarche, not having children and obesity. This is also similar in magnitude to drinking two to three units of alcohol daily. The risk returns to that of a non-user within 5 years of stopping HRT. Mortality from breast cancer is not significantly increased in an HRT user. Breast cancers found in women who take HRT are easier to treat than those in women not on HRT. Combined HRT also increases breast density and the risk of having an abnormal mammogram. The risk of breast cancer with estrogen-only HRT is less than with combined HRT. Most observational studies do not demonstrate an increased risk of breast cancer in women taking estrogen-only HRT for up to 5 years.

Endometrial cancer

Estrogen-only HRT substantially increases the risk of endometrial cancer in women with a womb (uterus). The use of continuous combined HRT (both estrogen + progesterone) or cyclical progesterone for at least 10–12 days every month eliminates this risk. Tibolone does not increase the risk of either endometrial hyperplasia or endometrial cancer.

Heart disease

Women who are over 60 and take HRT for more than 10 years after the menopause have an increased risk of heart disease. (The underlying risk of heart disease is low.) Over 5 years, nearly two in 100 women taking HRT were at risk of heart disease, compared with 1.5 in 100 women not taking HRT.

Ovarian cancer

A recent study looking at the results of 52 previous studies did find a statistically significant higher risk of ovarian cancer (43%) in current HRT users compared with HRT non-users, even in those with less than 5 years of HRT use. It is important to put the risk in context; in real terms, for every 1000 women using HRT for 5 years, there will be just one additional ovarian cancer diagnosis. Furthermore, if prognosis is typical, there will be one additional ovarian cancer death for every 1700 users. In ex-HRT users, risks decreased with increased time since HRT use had stopped, but risks during the first few years after stopping remained significant.

Other risks

Taking HRT for a year or more increases the risk of gallbladder disease (gallstones).

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 which one may experience on HRT are detailed below.

  • Estrogen related – breast tenderness, leg cramps, skin irritation, indigestion, nausea and headaches.

  • Progesterone related – premenstrual syndrome-like symptoms, fluid retention, bloating, backache, depression, mood swings and pelvic pain.

Nausea can be reduced by taking the HRT tablet 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 put on some weight when they first start to take HRT, after a while their weight is the same as it was before treatment. Women also 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. Water retention can also be experienced with HRT. Many of these common side-effects simply go away when the woman has been on HRT for a while. Sometimes a change of product helps.
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 tends to be heavy or irregular on sequential combined HRT, then the dose of progesterone can be doubled or increased in duration to 21 days. If there is persistent irregular vaginal bleeding after 6 months of starting HRT, further investigations are required. If predominantly progesterone-induced side-effects are experienced, then the progesterone dose can be halved or the duration of taking progesterone reduced to 7–10 days. If significant nausea or migraine headaches occur with oral preparations, patches can be an alternative option worth considering. Progesterone related side-effects can often be minimized if Mirena coil (intrauterine system) is used as the progesterone arm of HRT.

When should HRT not be taken?

HRT is not prescribed in certain conditions such as pregnancy and breast-feeding, undiagnosed abnormal vaginal bleeding, venous thrombosis or thromboembolic disease (blood clots), active heart disease, current or past breast cancer, current or past endometrial cancer, other estrogen-dependent cancers, active liver disease and uncontrolled high blood pressure. Women who would like to consider HRT but have one of these conditions should seek specialist advice.

What tests are needed before or after starting HRT?

When starting HRT, the healthcare professionals will discuss age, symptoms and medical conditions before looking at the risks and benefits of HRT which are specific to the individual. These can change and will be discussed at every 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 lining of the womb and a biopsy of the womb lining may need to 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 a mammography or MRI scan and referral to familial breast cancer services depending on the level of risk. A blood test for lipid profile will often be requested if there are risk factors associated with cardiovascular disease.

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

The choice of delivery route and type of HRT depends partly on patient preference but there are also 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 less than 1 year ago. 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; or it has been at least 2 years since their last menstrual period if they had a premature menopause. Topical preparations such as vaginal creams and pessaries are effective for symptoms of vaginal dryness, painful sex and urinary frequency. However, around 10–25% of women still have symptoms with local estrogen, so will require systemic HRT in addition. For other menopausal symptoms, oral, transdermal or other forms of systemic HRT are necessary for effective symptom relief.

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-identicle’ or ‘body-identicle’ HRT?

Most commercially available combined HRT preparations contain progestogens, compounds which have progesterone-like actions. Micronized progesterones are natural progesterones devoid of any androgenic and glucocorticoid activities. These seem to be the optimal progesterone in terms of cardiovascular effects, blood pressure, VTE, probably stroke and even breast cancer. Utrogestan is the only one currently available to prescribe in the UK.

What are the alternatives to HRT?

For women who are unable to have HRT, 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. For hot flushes and night sweats, antidepressants or selective serotonin reuptake inhibitors such as Venlafaxine and Clonidine (blood pressure lowering agent) are oral medications which are most commonly prescribed. Alternative therapies including homeopathy and acupuncture are also offered at specialist clinics, but have no effect other than placebo. Testosterone gel is prescribed by some clinics to improve libido. The evidence for effectiveness of these medications is limited but many women choose these options to avoid the risks associated with HRT. For those 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 chemicals that are found in some plants. They act like a weak form of estrogen. Soya products such as tofu and miso are rich in phytoestrogens, as are beans, lentils, certain fruits and celery. One can also get over-the-counter supplements such as red clover pills from some pharmacies and health food shops. The research into phytoestrogens is not as robust as that for HRT. Most of the research shows that they do not help reduce hot flushes. Phytoestrogens also probably do not help with the sexual problems or bladder infections linked with the menopause. Because phytoestrogens act like estrogen in the body, it is possible that they could increase the chance of breast cancer and cancer of the lining of the womb (endometrial cancer). However, there is not enough good research to determine whether this happens or not. Black cohosh is a popular herbal product. Most good quality research suggests that black cohosh does not make any difference to hot flushes. Some people taking black cohosh get stomach pains, feel dizzy and nauseated, and have headaches when they take it. Black cohosh may cause liver problems in some women. One should always inform the healthcare professional when taking herbal products as they can sometimes react with other drug treatments.

Is a follow-up needed after starting HRT?

Women are generally asked to attend for a follow-up consultation 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 every year to review the ongoing need for and safety of continuing HRT. Both mammography and cervical screening as per national guidelines are recommended in the postmenopausal women on HRT.

When should HRT be stopped?

Most women are able to stop taking HRT after their menopausal symptoms diminish, which is usually 2–5 years after they start. 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.

Further reading
Websites

British Menopause Society - www.thebms.org.uk/
International Menopause Society - www.imsociety.org/

Journals

  1. 1de Villiers TJ, Pines A, Panay N, et al; Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric. 2013 Jun;16(3):316-37. doi: 10.3109/13697137.2013.795683.
  2. Rossouw JE, Anderson GL, Prentice RL, et al; Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002 Jul 17;288(3):321-33.
  3. Lethaby A, Hogervorst E, Richards M, et al; Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2008 Jan 23;(1):CD003122.
  4. Beral V; Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27.
  5. Sare GM, Gray LJ, Bath PM; Association between hormone replacement therapy and subsequent arterial and venous vascular events: a meta-analysis. Eur Heart J. 2008 Aug;29(16):2031-41. doi: 10.1093/eurheartj/ehn299. Epub 2008 Jul 3.
  6. Chlebowski RT, Hendrix SL, Langer RD, et al; Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomized Trial. JAMA. 2003 Jun 25;289(24):3243-53.
  7. Formoso G, Perrone E, Maltoni S, et al; Short and long term effects of tibolone in postmenopausal women. Cochrane Database Syst Rev. 2012 Feb 15;2:CD008536. doi: 10.1002/14651858.CD008536.pub2.
  8. Panay N, Hamoda H, Arya R, et al; The 2013 British Menopause Society & Women's Health Concern recommendations on hormone replacement therapy. Menopause Int. 2013 Jun;19(2):59-68. doi: 10.1177/1754045313489645. Epub 2013 May 23.
  9. Boardman HMP, Hartley L, Eisinga A, Main C, Roqué i Figuls M, Bonfill Cosp X, Gabriel Sanchez R, Knight B. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database of Systematic Reviews 2015, Issue 3. Art. No.: CD002229. DOI: 10.1002/14651858.CD002229.pub4.
  10. Renoux C, Dell'aniello S, Garbe E, Suissa S. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study. BMJ. 2010 Jun 3;340:c2519. doi: 10.1136/bmj.c2519.