Clinical Topic A-Z Clinical Speciality

Menopause

Menopause
D008593Menopause
Women's health
2013-06-01Last revised in June 2013

Menopause - Summary

Menopause is the time when menstruation ceases permanently due to the loss of ovarian follicular activity. It occurs with the final menstrual period and therefore can only be diagnosed with certainty after 12 months of spontaneous amenorrhoea. This can occasionally be premature, for example if there is a family history of premature menopause, or premature ovarian failure. In the UK, the average age at the menopause is 52 years.

The hormonal level alteration results in menopausal symptoms. About 80% of women in the UK will experience menopausal symptoms in their lifetime, and 45% of them will find the symptoms distressing. Menopausal symptoms are usually self limiting, lasting for between 2 and 5 years. Symptoms commonly include:

Hot flushes and night sweats.

Sleep disturbance.

Urinary and vaginal symptoms, including vaginal discomfort and dryness, dyspareunia, and recurrent urinary tract infections.

Many women will be able to manage their menopausal symptoms with lifestyle changes such as taking regular exercise, avoiding possible triggers for hot flushes, and ensuring good sleep hygiene. For some women, hormone replacement therapy (HRT) may be useful, but the risks and benefits of treatment must be considered for each woman.

The risks of combined HRT include a small increase in the risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), stroke, gallbladder disease requiring hospital admission, death from lung cancer, ovarian cancer, and dementia (in women aged over 65 years).

The risks of oestrogen-only HRT include a small increase in the risk of VTE, stroke, endometrial cancer, gallbladder disease requiring hospital admission, and ovarian cancer. Oestrogen-only HRT does not appear to significantly increase the risk of breast cancer.

The benefits of HRT include improved vasomotor and urogenital symptoms, and a reduction in the risks of osteoporosis.

Adverse effects of HRT include:

Oestrogen-related adverse effects such as fluid retention, bloating, breast tenderness, nausea, headaches, leg cramps, and dyspepsia.

Progestogen-related adverse effects such as fluid retention, breast tenderness, headaches or migraine, mood swings, depression, acne, lower abdominal pain, and headache.

Bleeding.

For women who are unable or unwilling to use HRT, treatment options include:

For vasomotor symptoms — a trial of paroxetine, fluoxetine, citalopram, venlafaxine, or clonidine.

For vaginal dryness — a vaginal lubricant or moisturizer.

For psychological symptoms — self-help groups, psychotherapy, counselling, or antidepressants, according to the individual.

Complementary therapies, such as red clover or black cohosh, are not recommended.

Have I got the right topic?

480months3060monthsFemale

This CKS topic covers the management of the menopause, including the place of hormone replacement therapy (HRT) and alternatives to HRT, and gives brief information on the management of the menopause in women with venous thromboembolism, breast cancer, and other comorbidities.

This CKS topic does not cover the management of cardiovascular disease or osteoporosis.

There are separate CKS topics on Amenorrhoea, CVD risk assessment and management, Contraception - assessment, Contraception - barrier methods and spermicides, Contraception - combined hormonal methods, Contraception - emergency, Contraception - IUS/IUD, Contraception - natural family planning, Contraception - progestogen-only methods, Contraception - sterilization, Dysmenorrhoea, Endometriosis, Menorrhagia, Osteoporosis - prevention of fragility fractures, Tamoxifen - managing adverse effects, and Urinary tract infection (lower) - women; there are also referral guidelines, published by the National Institute for Health and Care Excellence, for Breast cancer - suspected, Gynaecological cancer - suspected and Ovarian cancer.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in June 2013

March 2014 — minor update. Text amended to clarify the recommendations on how to stop cyclical combined HRT patches and continuous combined HRT patches.

May to June 2013 — reviewed. A literature search was conducted in April 2013 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No major changes to clinical recommendations have been made. However, the evidence summary on risks associated with the use of hormone replacement therapy has been updated in line with two recent Cochrane systematic reviews [Marjoribanks et al, 2012; Main et al, 2013].

Previous changes

February 2012 — minor update. Estraderm TTS 25® and Estraderm TTS 100® patches have been discontinued. The prescriptions for these products have been removed. Issued in March 2012.

January 2012 — minor update. Added updated information from the manufacturer's Summary of Product Characteristics (SPC) stating that venlafaxine may alter glycaemic control in people with diabetes mellitus [ABPI Medicines Compendium, 2011b]. Issued in January 2012.

January 2012 — minor update. Lundbeck Ltd, in collaboration with the Medicines and Healthcare products Regulatory Agency (MHRA), has published new safety data regarding the association of citalopram and escitalopram with dose-dependent QT interval prolongation [Lundbeck Ltd, 2011a; Lundbeck Ltd, 2011b; MHRA, 2011]. This topic has been updated to reflect their advice. Issued in January 2012.

May 2011 — interaction between SSRIs and tamoxifen added as stated in the most recent SPCs [ABPI Medicines Compendium, 2011a; ABPI Medicines Compendium, 2011a]. Issued in June 2011.

April 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

April 2011 — minor update. A prescription for estriol 0.01% vaginal cream (Gynest®) has been added. Issued in June 2011.

March 2011 — topic structure revised to ensure consistency across CKS topics — no changes to clinical recommendations have been made.

December 2010 — minor update. Premique® cycle tablets and Premarin® vaginal cream have been discontinued. The prescriptions have been removed. Issued in December 2010.

July 2010 — minor update. Harmogen tablets (estropipate 1.5 mg) have been discontinued. The prescriptions for this product have been removed. Issued in July 2010.

April 2009 — minor update. Estraderm TTS50® patches and EstraCombi® patches are being discontinued during May to July 2009. The prescriptions for these products have been removed. Estraderm TTS25® and Estraderm TTS100® patches will continue to be available. Issued in May 2009.

March 2009 — minor update to the evidence section for antidepressants. Text discussing a sensitivity analysis for antidepressants is now included. Issued in March 2009.

February 2009 — advice from the Medicines and Healthcare products Regularly Agency (MHRA) that tibolone increases the risk of breast cancer recurrence in women with a history of breast cancer has been included. Issued March 2009.

September 2008 — minor correction to Changes section. Issued in September 2008.

March 2008 — minor text update to the basis of the recommendation about possible risks of hormone replacement therapy.

October 2007 to January 2008 — converted from CKS guidance to CKS topic structure. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There have been no major changes to the recommendations for the use of hormone replacement therapy (HRT).

New recommendations about alternatives to HRT (e.g. clonidine and antidepressants) have been included.

July 2006 — minor update. The Commission on Human Medicines' (CHM) update on the risk of endometrial cancer with HRT and tibolone has been included. Evorel Pak® discontinued and prescriptions removed. Issued in July 2006.

April 2006 — minor update. Estradiol 100 mg implant discontinued and prescriptions removed. Issued in May 2006.

October 2005 — minor technical update. Issued in November 2005.

July 2005 — updated to incorporate the Referral guidelines for suspected cancer published by the National Institute for Health and Clinical Excellence. Issued in July 2005.

February 2005 — correction to table, Long-term benefits of HRT: results from the Women's Health Initiative study. Issued in February 2005.

November 2004 — updated to include the latest review of the evidence on long-term safety of HRT from the Committee on Safety of Medicines (CSM). Issued in November 2004.

March 2004 — reviewed. Validated in May 2004 and issued in July 2004.

June 2001 — rewritten. Validated in July 2001 and issued in October 2001.

April 1998 — reviewed.

September 1997 — written.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 April 2013.

HTAs (Health Technology Assessments)

No new HTAs since 1 April 2013.

Economic appraisals

No new economic appraisals relevant to England since 1 April 2013.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Dodin, S., Blachet, C., Marc, I, et al. (2013) Acupuncture for menopausal hot flushes (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Liua, Y.R., Jiang, Y.L., Huang, R.Q., et al. (2013) Hypericum perforatum L. preparations for menopause: a meta-analysis of efficacy and safety. Climacteric epub ahead of print. [Abstract]

Mackay, L., Kilbride, L., Adamson, K.A. and Chisholm, J. (2013) Hormone replacement therapy for women with type 1 diabetes mellitus (Cochrane Review). The Cochrane Library. Issue 6. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Shams, T., Firwana, B., Habib, F., et al. (2014) SSRIs for hot flashes: a systematic review and meta-analysis of randomized trials. Journal of General Internal Medicine 29(1), 204-213. [Abstract]

Primary evidence

No new randomized controlled trials published in the major journals since 1 April 2013.

Observational studies published since the last revision of this topic:

Manson, J.E., Chlebowski, R.T., Stafanick, M.L., et al. (2013) Menopause hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 310(13), 1353-1368. [Abstract]

Smith, N.L., Blondon, M., Wiggins, K.L., et al. (2014) Lower risk of cardiovascular events in postmenopausal women taking oral estradiol compared with oral conjugated equine estrogens. JAMA Internal Medicine 174(1), 25-31. [Abstract]

New policies

No new national policies or guidelines since 1 April 2013.

New safety alerts

No new safety alerts since 1 April 2013.

Changes in product availability

No changes in product availability since 1 April 2013.

Goals and outcome measures

Goals

To manage menopausal symptoms

Background information

Definitions

Menopause is the time when menstruation ceases permanently due to the loss of ovarian follicular activity. It occurs with the final menstrual period and is usually diagnosed clinically after 12 months of amenorrhoea [FSRH, 2010]. In industrialized societies, such as the UK, the average age at the menopause is 52 years [WHO, 1996a].

Perimenopause is the period before the menopause when the endocrinological, biological, and clinical features of approaching menopause commence. It ends 12 months after the last menstrual period. In this topic, the term 'perimenopause' refers to women who are experiencing symptoms due to decreasing oestrogen levels.

Premature menopause is menopause that occurs at an age less than two standard deviations below the mean age established for the reference population (see Cause of premature menopause). In practice, in developed countries, 45 years of age is the cut-off point, and in developing countries, 40 years of age is frequently used as a cut-off point. In this CKS topic, 45 years of age is used as the cut-off point.

[International Menopause Society, 1999; Rees et al, 2009; Rees, 2011]

Cause of the menopause

What causes the menopause?

Why the menopause occurs

Why does the menopause occur?

Each ovary has a finite number of oocytes. The number of oocytes is greatest before birth (between 20 and 28 weeks' gestation) and thereafter decreases until, at about 50 years of age, the stock becomes exhausted.

During the perimenopause;

Ovarian follicular activity begins to fail.

Oestrogen and inhibin levels decrease, and reduced negative feedback to the pituitary causes follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels to rise.

Levels of FSH fluctuate markedly from pre- to postmenopausal values on an almost daily basis during the transition to menopause.

Decreasing oestrogen levels begin to disrupt the menstrual cycle and may cause other menopausal symptoms such as hot flushes and night sweats.

Cycles tend to become anovulatory, and eventually follicular development stops. Estradiol production, which occurs in the granulosa and thecal cells surrounding the oocyte, becomes insufficient to stimulate the endometrium, and amenorrhoea occurs.

Eventually, the menopausal pattern of low oestrogen and persistently high FSH and LH levels is established.

[Ryan et al, 1999; Shaw et al, 2003; Monga, 2006; Rees et al, 2009]

Cause of premature menopause

What causes premature menopause?

Causes of premature menopause include:

A family history of premature menopause [van Asselt et al, 2004].

Premature ovarian failure. This may occur at any age and in most cases no cause is found [Rees et al, 2009]:

Causes of premature ovarian failure include chromosomal abnormalities, autoimmune disease, and enzyme deficiencies.

Premature ovarian failure is estimated to affect 1% of women younger than 40 years of age and 0.1% of women younger than 30 years of age.

In some women, premature ovarian failure is not synonymous with menopause, as 5–15% of women with presumed primary ovarian failure may retain intermittent ovarian function for years, and spontaneous ovulation and pregnancy are possible.

Iatrogenic causes of ovarian failure include [Rees et al, 2009]:

Bilateral oophorectomy or surgical menopause. Abrupt decreases in estradiol levels cause immediate menopause which may be intensely symptomatic.

Hysterectomy with ovarian conservation. Hysterectomy may lead to ovarian failure:

In the immediate post-operative period, which may be temporary or permanent.

At a later stage, when it may occur sooner than the time of natural menopause. The outcome may depend on ovarian function before hysterectomy. The diagnosis can be difficult as not all women have acute symptoms — some experts recommend annual follicle-stimulating hormone measurement in this situation to determine whether hormone replacement therapy is appropriate.

Chemotherapy for cancer. The risk of ovarian failure depends on the drug used, the dose, the interval between treatments, and the age of the woman. Prepubertal girls are more resistant to the effects of chemotherapeutic drugs.

Radiation to the pelvic area. A dose of more than 6 Gy usually results in sterility, although prepubertal girls are more resistant to irradiation.

Infection (most commonly tuberculosis and mumps). In most women who develop ovarian failure after mumps, normal ovarian function returns. Malaria, varicella, and shigella infection may also cause premature ovarian failure [Rees et al, 2009].

Prevalence of symptoms

How common are perimenopausal/menopausal symptoms?

About 80% of women in the UK will experience menopausal symptoms in their lifetime, and 45% of them will find the symptoms distressing [RCPE, 2003]:

Hot flushes occur in 70–80% of perimenopausal women [RCPE, 2003], and they are most common in the first year after the final menstrual period [Rees et al, 2009].

Vaginal symptoms (including dryness, discomfort, itching, and dyspareunia) occur in about 30% of women during the early postmenopausal period, and in up to 47% of women during the later postmenopausal period [Grady, 2006].

Most women manage the menopause themselves — only 10% seek medical advice [Roberts, 2007].

Racial, cultural, religious, sociological, and nutritional factors modify the intensity and incidence of menopausal symptoms [Lauritzen and Studd, 2005]:

About 70% of Western women report a high incidence of typical symptoms such as hot flushes and sweating [Rees et al, 2009].

Japanese women have a low incidence of menopausal symptoms, and there is no Japanese word for hot flushes. Their lack of symptoms may be a result of their high intake of soya products.

Duration of symptoms

How long are menopausal symptoms likely to last?

Without treatment:

Menopausal symptoms are usually self limiting (2–5 years), although some women may experience symptoms for many years [RCPE, 2003].

Hot flushes are usually present for less than 5 years; however, some women may continue to flush beyond the age of 60 years [Rees et al, 2009].

Vaginal symptoms (including dryness, discomfort, itching, and dyspareunia) generally persist or worsen with ageing [Grady, 2006].

Risk of chronic disease after the menopause

Are women more at risk of chronic disease after the menopause?

The risks of osteoporosis, urogenital atrophy, cardiovascular disease, and stroke all increase after the menopause [Rees et al, 2009].

Women with premature menopause are at increased risk of osteoporosis and cardiovascular disease (especially if they smoke), dementia, cognitive decline, and parkinsonism, but are at lower risk of breast cancer [Rocca et al, 2007a; Rocca et al, 2007b]. The mean life expectancy of women who experience menopause before 40 years of age is 2 years shorter than that of women who experience the menopause after 55 years of age [Rees et al, 2009].

Diagnosis and assessment

Diagnosis and assessment of menopause

Clinical features of the menopause

What are the clinical features of the menopause?

The diagnosis of menopause should be based on history, symptoms, and age of the woman, without relying on laboratory investigations. An examination may rule out other causes.

Symptoms

What are the symptoms of the menopause?

The perimenopause usually begins with a change to the menstrual pattern. Menstrual cycle length may shorten to 2–3 weeks or lengthen to many months. The amount of menstrual blood loss may change (it most commonly increases slightly).

In western societies, the most common symptoms are hot flushes, night sweats (the night-time manifestation of a hot flush), vaginal dryness, and sleep disturbance.

Hot flushes arise as a sudden feeling of heat in the upper body (face, neck, and chest) and spread upwards and downwards. Diffuse or patchy flushing of the skin is followed by sweating and tachycardia/palpitations. Hot flushes generally last only a few minutes; however, current smoking and a high body mass index may predispose a woman to more severe or frequent hot flushes.

Sleep disturbance is often due to night sweats but may also be due to mood disorders or primary sleep disorders. Chronically disturbed sleep can lead to irritability and difficulties with short-term memory and concentration.

Urinary and vaginal symptoms, such as vaginal discomfort and dryness, dyspareunia, and recurrent lower urinary tract infection, are common in the menopause. Symptoms of urogenital atrophy may appear for the first time more than 10 years after the last menstrual period.

Basis for recommendation

Basis for recommendation

Information on the clinical symptoms of the menopause is based on expert opinion in guidelines [WHO, 1996b; RCPE, 2003], review articles [Robinson and Cardozo, 2003; Grady, 2006; Ohayon, 2006; Roberts, 2007], and textbooks [Lauritzen and Studd, 2005; Rees et al, 2009].

Signs

What are the signs of the menopause?

An examination should be performed only if clinically indicated and to exclude other causes of amenorrhoea or irregular bleeding. See Differential diagnosis.

Basis for recommendation

Basis for recommendation

This recommendation is based on expert opinion in a text book: Management of the Menopause [Rees et al, 2009].

Investigations

What investigations should I consider?

Laboratory investigations are not routinely recommended for diagnosing the menopause. The diagnosis of menopause in women older than 45 years of age with typical menopausal symptoms is clinical.

Measurement of follicle-stimulating hormone (FSH) is of limited value and may cause confusion, as FSH levels fluctuate during the perimenopause:

Normal results do not exclude the menopause.

An increased concentration is suggestive of ovarian failure.

An increased concentration does not indicate an inability to conceive.

Measurement of luteinizing hormone, estradiol, progesterone, or testosterone level is of no value in diagnosing ovarian failure but is relevant in diagnosing other causes of secondary amenorrhoea, including polycystic ovary syndrome, and also in investigating infertility.

Follicle-stimulating hormone levels

Follicle-stimulating hormone levels

In women younger than 45 years of age, measurement of follicle-stimulating hormone (FSH) levels may be helpful if premature menopause is suspected. Serial measurements over time may be needed to make a diagnosis. High FSH levels (above 30 IU/L) suggest ovarian failure [Smellie et al, 2006; Rees et al, 2009; FSRH, 2010]:

If the woman is having periods, measure FSH on day 3–5 of the cycle, if possible [Smellie, Personal Communication, 2007].

If the woman is not having regular periods (for example those who are amenorrhoeic or oligomenorrhoeic and those who have had a hysterectomy), obtain two samples 2 weeks apart, as these may give information about residual cycle activity [Parker, 2004].

Women who have had a hysterectomy with conservation of ovaries may wish to know whether they are menopausal, as they may benefit from hormone replacement therapy. Women who have had a hysterectomy with ovarian conservation before 40 years of age may be at risk of early menopause [Rees et al, 2009]. Measure FSH on two or more occasions at least 1 or 2 months apart.

Women using hormonal contraception may wish to know whether they are menopausal so that they can discontinue contraception:

The menopause cannot be reliably diagnosed when using combined oral contraceptives (COCs), as the COC suppresses gonadotrophins; a low level may be impossible to interpret. Measure FSH when the woman is not taking oestrogen-based contraception either by stopping the COC or by changing to a progesterone only preparation. Allow 6 weeks between stopping treatment and measuring FSH [Parker, 2004].

Measure FSH on two or more occasions at least 1 or 2 months apart: an elevated serum FSH level (more than 30 IU/L) on two or more occasions is highly suggestive of ovarian failure, but these women may still be at risk of pregnancy [FSRH, 2010].

Basis for recommendation

Basis for recommendation

Recommendations for investigation of menopause are based on a guideline published by the Faculty of Sexual and Reproductive Healthcare [FSRH, 2010] and information in review articles [Smellie et al, 2006; Smellie, 2007].

Differential diagnosis

What else might be causing the symptoms?

The following symptoms are usually due to the menopause but can also be caused by other conditions:

Amenorrhoea. For further information, see the CKS topic on Amenorrhoea.

Irregular bleeding.

During the perimenopause, possible causes include endometrial polyps; uterine fibroids; adenomyosis; endometrial hyperplasia or cancer; and vulval, vaginal, or cervical lesions.

After menopause, possible causes include endometrial atrophy; vaginal atrophy; endometrial polyps; endometrial hyperplasia or cancer; and vulval, vaginal, or cervical lesions.

Hot flushes. If ovarian failure is uncertain, exclude other causes such as:

Endocrine causes, for example hyperthyroidism and pheochromocytoma.

Tumours, for example carcinoid tumour, pancreatic tumour, mastocytoma, and paraneoplastic syndrome.

Excess alcohol consumption.

Dumping syndrome.

Panic disorders.

Tuberculosis.

Drugs, for example nitrates, selective serotonin reuptake inhibitors, diltiazem, levodopa, gonadotrophin-releasing hormone agonists, and anti-oestrogens.

Vaginal atrophy. Trauma or infection may cause similar symptoms.

Symptoms that are associated with the menopause but are often due to other causes include:

Urinary incontinence. This is more likely to be due to mechanical factors, such as obesity, gynaecological surgery, or multiparity, than the menopause.

Mood changes (including anxiety, irritability, and depression). These symptoms are more likely to be associated with past problems and life stresses than the menopause alone. General population studies suggest that most women do not experience major changes in mood during the menopause transition; however, depression should be excluded (see the CKS topic on Depression).

Cognitive disturbances (such as forgetfulness or difficulty concentrating). Cross-sectional studies suggest that these symptoms are unlikely to be related to the menopause.

Loss of libido. This symptom can be attributed to androgen deficiency; however, non-hormonal factors, such as conflict between partners, insomnia, inadequate stimulation, life stresses, or depression, are also important contributors and should not be overlooked.

Muscle and joint pains. Pain and swelling resulting in restriction of mobility most often affects the small joints of the hands and feet, as well as the knees, elbows, and the cervical spine. These symptoms have been linked to a decrease in oestrogen levels, but osteoarthritis, rheumatoid arthritis, and mechanical trauma are common causes.

Skin changes. It is difficult to separate skin changes due to ageing, smoking, and sun exposure, from skin changes due to declining hormonal secretion and menopause. Soon after the menopause, skin collagen content and skin thickness decrease, resulting in decreased skin elasticity. Skin laxity and wrinkling increase abruptly.

Weight gain. This is unlikely to be solely due to the perimenopause or the menopause, as body weight in women tends to increase with age, especially beginning at or near the menopause (the average weight gain ranges from 2.25–4.19 kg). Body fat redistribution to the abdomen also occurs with age (independently of weight gain). This centralized abdominal fat distribution is an independent risk factor for cardiovascular disease in women. A longitudinal study of 418 women found that weight gain during the menopause was more likely to be due to alcohol consumption and lack of exercise.

Basis for recommendation

Basis for recommendation

Information on the differential diagnosis of menopause is based on expert opinion in guidelines [WHO, 1996b; SOGC, 2009], review articles [Sherburn et al, 2001; Panay et al, 2004; Hickey et al, 2005], and textbooks [Lauritzen and Studd, 2005; Rees et al, 2009]. The information on the relationship between weight gain and alcohol consumption and lack of exercise is based on a longitudinal study of weight and the menopause transition [Crawford et al, 2000].

Assessment of menopause

How should I assess a woman diagnosed with menopause?

Assess the stage of the menopause:

Ask the woman if she is still having periods, to determine whether she is perimenopausal or postmenopausal:

If her periods have stopped, record when the last period occurred.

If the woman is still having periods, ask about their frequency, heaviness, and duration.

Determine if the woman is younger than 45 years of age (premature menopause). See Scenario: Premature menopause.

Assess her symptoms and their severity:

Ask which symptoms the woman has, to determine if they would be likely to respond to hormone replacement therapy (HRT) (for example hot flushes, night sweats, and vaginal dryness) or whether other treatments may be more suitable (for example treatment for primary depression or primary insomnia).

Determine the severity of the symptoms and the extent to which they are affecting the woman's life.

Assess her risk of cardiovascular disease:

Women with, or at increased risk of, cardiovascular disease should have their cardiovascular risk factors managed. See the CKS topic on CVD risk assessment and management for more information.

Assess her risk of osteoporosis:

See the CKS topic on Osteoporosis - prevention of fragility fractures for more information.

Discuss the woman's expectations:

Ask why she has consulted (for example concern regarding the cause of the symptoms).

Ask if she would like treatment for her symptoms.

Determine what type of treatment may be appropriate:

Ask the woman if she would like treatment with HRT or without HRT.

For women requesting HRT, check that they are suitable for treatment:

Ask if they have any contraindications to HRT (for example a history of breast cancer or venous thromboembolism).

Discuss the risks and benefits of HRT.

Check and record body mass index and blood pressure.

Breast examination is not routinely necessary; however, discuss the national mammography screening programme and personal breast awareness with the woman before starting HRT.

Pelvic examination is not routinely required unless clinically indicated (that is, in a woman with past or current disease, symptoms, or family history).

Investigations are not routinely indicated before starting HRT.

For women who are not suitable for treatment with HRT (for example those who have contraindications to HRT) or do not want to use HRT, see Scenario: Managing the menopause without HRT.

Investigations before starting HRT

Investigations before starting hormone replacement therapy

Investigations are not routinely indicated before starting hormone replacement therapy unless:

There is a sudden change in menstrual pattern, intermenstrual bleeding, postcoital bleeding, or postmenopausal bleeding: consider doing an endometrial assessment.

There is a personal or family history of venous thromboembolism: consider doing a thrombophilia screen.

There is a high risk of breast cancer: mammography or MRI scan may be considered (as appropriate for the woman's age). For more information see the current NICE guidance on Familial breast cancer.

The woman has arterial disease or other risk markers for arterial disease: a lipid profile may be useful.

Basis for recommendation

Basis for recommendation

Assessment of menopause

These recommendations are based on pragmatic advice and published expert opinion in review articles [Korhonen et al, 1997; Grady, 2006; Roberts, 2007] and textbooks [Monga, 2006; Rees et al, 2009].

Investigations before starting hormone replacement therapy

These recommendations are based on expert opinion in the textbook Management of the Menopause [Rees et al, 2009].

Management

Management

Scenario: Perimenopausal with uterus (HRT) : covers the management of menopausal symptoms with hormone replacement therapy (HRT) in perimenopausal women who have an intact uterus. A woman is considered to be perimenopausal from the time the clinical features of the menopause start to 12 months after the last menstrual period.

Scenario: Postmenopausal with uterus (HRT) : covers the management of menopausal symptoms with hormone replacement therapy (HRT) in postmenopausal women who have an intact uterus. A woman with a uterus is considered to be postmenopausal when she has not had a period for 12 months.

Scenario: Menopausal symptoms after a hysterectomy (HRT) : covers the management of menopausal symptoms with hormone replacement therapy (HRT) in women who have had a hysterectomy.

Scenario: Premature menopause : covers the management of women who have a menopause below the age of 45 years.

Scenario: Poor symptom control on HRT : covers management strategies for women who experience poor symptom control while taking HRT.

Scenario: Managing adverse effects of HRT : covers the management of adverse effects (e.g. bleeding) of HRT.

Scenario: Managing the menopause without HRT : covers the treatment options available for women who cannot, or do not wish to take HRT.

Scenario: Managing women with comorbidities : covers the management of women presenting with menopause with current or previous breast or endometrial cancer, or with a thromboembolic disease or known thrombophilia.

Scenario: Perimenopausal with uterus (HRT)

Scenario: Perimenopausal with uterus (HRT) for menopause

480months3060monthsFemale

Advice about managing symptoms of menopause, and HRT

What advice should I give about managing symptoms of menopause and starting hormone replacement therapy?

Advise about:

Modifying their lifestyle to reduce symptoms.

The risks and benefits of hormone replacement therapy (HRT).

The expected duration of treatment:

For vasomotor symptoms, most women require 2–3 years of treatment, but some women may need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue treatment. Symptoms may recur for a short time after stopping HRT.

Topical (vaginal) oestrogen may be required long term. Regular attempts (at least annually) to stop treatment are usually made. Symptoms may recur once treatment has stopped.

Possible adverse effects of HRT such as breast tenderness or enlargement, nausea, headaches, or bleeding.

Lifestyle advice for menopausal symptoms

What lifestyle advice can I give for menopausal symptoms?

Encourage all women to make lifestyle modifications to reduce menopausal symptoms:

Hot flushes and night sweats:

Taking regular exercise and losing weight (if applicable) may reduce the severity and frequency of flushes.

Wearing lighter clothing, sleeping in a cooler room, reducing stress, and avoiding possible triggers (such as spicy foods, caffeine, smoking, and alcohol) may also be helpful in reducing these symptoms.

Sleep disturbances:

Avoiding exercise late in the day and maintaining a regular bedtime can improve sleep.

Mood and anxiety disturbances:

Adequate sleep, regular physical activity, and relaxation exercises may help.

Cognitive symptoms:

Exercise and good sleep hygiene may improve subjective cognitive symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on expert opinion in the textbook Management of the Menopause [Rees et al, 2009].

There is evidence that smoking cigarettes and having a body mass index of more than 30 kg/m2 increases the likelihood of flushing.

The Royal College of Obstetricians and Gynaecologists has advised that women who are more active tend to suffer less from the symptoms of the menopause, and that the best type of exercise is aerobic, sustained, regular exercise such as swimming and running [RCOG, 2010]. However, a Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials (RCTs) on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011].

Advice about benefits of HRT

What advice should I give about the benefits of hormone replacement therapy?

Hormone replacement therapy (HRT) is effective for:

Treating vasomotor symptoms (for example hot flushes and night sweats).

Treating urogenital symptoms (for example vaginal dryness, dyspareunia as a result of vaginal dryness, recurrent urinary tract infections, and urinary frequency and urgency).

Managing sleep or mood disturbances caused by hot flushes and night sweats.

Preventing osteoporosis.

However, due to the risks associated with long-term use, HRT is not normally used as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age, except when other treatments are contraindicated, not tolerated, or ineffective.

There is no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer.

HRT has no role in the prevention or treatment of cardiovascular disease.

Basis for recommendation

Basis for recommendation

Hot flushes and night sweats

Good evidence indicates that oral or transdermal hormone replacement therapy (HRT), used as oestrogen alone or oestrogens combined with progestogens, is highly effective for reducing the frequency and severity of hot flushes and night sweats caused by the menopause.

Vaginal atrophy (dryness and dyspareunia)

There is evidence that HRT preparations (combined oral and transdermal oestrogens and progestogens, or intravaginal oestrogens) are effective for treating vaginal atrophy (dryness, burning, itching, and dyspareunia).

Recurrent urinary tract infection (UTIs)

Evidence from one systematic review suggests that oral and intravaginal oestrogen are effective for preventing UTIs, although some experts believe that this effect is only seen with intravaginal oestrogens [Rees et al, 2009]:

Recurrent UTIs may be prevented by treatment with vaginal but not oral HRT.

Long-term treatment may be required because symptoms recur when treatment is stopped.

Sleep disturbances

There is evidence that combined oral oestrogen and progestogen therapy provides a small statistically but not clinically meaningful improvement in sleep disturbances.

Incontinence

The British Menopause Society currently recommends the use of systemic or topical oestrogen for urinary frequency and urgency [Rees, 2011], although the evidence to support the use of oestrogens is conflicting.

A Cochrane systematic review found evidence that urinary incontinence may be improved with the use of local oestrogen treatment [Cody et al, 2012]. However, a previously published analysis of the Women's Health Initiative trial found that oestrogen therapy (alone and combined with progestogen therapy) increased the risk of urinary incontinence among continent women and worsened urinary incontinence among symptomatic women after 1 year [Hendrix et al, 2005].

Mood disorders

There is no evidence indicating that HRT has a direct effect on mood, irritability, or anxiety. However, experts suggest that if psychotherapy and antidepressants are ineffective, HRT may be appropriate for treating depression at the onset of menopause [SOGC, 2009].

Libido

In addition to relieving hot flushes and improving sleep, HRT improves urogenital atrophy, thinning, dryness, and loss of elasticity, all of which may cause dyspareunia. Libido may be improved with oestrogen alone but the addition of testosterone may be necessary, especially in young, oophorectomized women [Rees et al, 2009; Rees, 2011].

Osteoporosis

Evidence from a large Cochrane systematic review (search date: February 2012) shows that HRT is effective for the prevention of postmenopausal osteoporosis [Marjoribanks et al, 2012]; however, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen treatments are unsuitable.

The Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines, warns that because of the risks associated with long-term use, 'HRT should be used for prevention of osteoporosis only in women who are unable to use other medicines that are authorized for this purpose' [MHRA and CHM, 2007b].

The British National Formulary adds that HRT is an option where other treatments are contra-indicated, cannot be tolerated, or if there is a lack of response. HRT should not be considered as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age [BNF 65, 2013].

Colorectal cancer

Although some studies have demonstrated a lower risk of colon cancer in women treated with combined HRT [Writing Group for the Women's Health Initiative Investigators, 2002], a recent large Cochrane systematic review (search date: February 2012) found no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer [Marjoribanks et al, 2012].

Current evidence does not allow recommendation of HRT to prevent colorectal cancer [Rees et al, 2009; Goodman et al, 2011].

Cardiovascular disease

Evidence from a recent Cochrane systematic review (search date: April 2010) suggests that treatment with HRT has no role in the prevention or treatment of CVD in post-menopausal women. In fact, HRT causes an increase in the risk of stroke and venous thromboembolism (VTE). Furthermore, combination HRT is associated with an increased risk of non-fatal myocardial infarction [Main et al, 2013].

An open-label randomized controlled trial investigated the long-term effect of HRT on cardiovascular outcomes in recently postmenopausal women [Schierbeck et al, 2012]. This trial found evidence that after 10 years of randomized treatment, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction, without any apparent increase in risk of cancer, VTE, or stroke. However, further trials are needed.

Advice about possible risks of HRT

What advice should I give about the possible risks of hormone replacement therapy?

For combined hormone replacement therapy (HRT), advise that:

There is a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), and stroke. See Table 1 for more information.

There is also a small absolute increased risk of gallbladder disease requiring hospital admission, death from lung cancer, and dementia (in women aged over 65 years).

There is some evidence suggesting that combined HRT may be associated with an increased risk of ovarian cancer.

Table 1 . Combined HRT compared with placebo in postmenopausal women.
Outcomes Follow-up Absolute risk (95% CI) Relative risk (95% CI)
Placebo Combined HRT
Coronary events (MI or cardiac death)* 1 year 2 per 1000 4 per 1000 (95% CI 3 to 7) 1.89 (1.15 to 3.1)
VTE (DVT or PE) 1 year 2 per 1000 7 per 1000 (95% CI 4 to 11) 4.28 (2.49 to 7.34)
Coronary events (MI or cardiac death)* 5.6 years 18 per 1000 22 per 1000 (95% CI 18 to 27) 1.22 (0.98 to 1.52)
Stroke* 5.6 years 13 per 1000 18 per 1000 (95% CI 14 to 23) 1.38 (1.08 to 1.75)
Breast cancer (combined continuous HRT) 5.6 years 19 per 1000 23 per 1000 (95% CI 19 to 29) 1.26 (1.02 to 1.56)
* Only 33% of study sample were aged 50-59 years at baseline (i.e. the age women most likely to consider HT for vasomotor symptoms); mean participant age was 63 years. Ovarian cancer: a systematic review of (mainly) observational studies [Greiser et al, 2007] suggests that combined HRT may be associated with an increased risk of ovarian cancer. MI: myocardial infacrction; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism
Data adapted from: [Marjoribanks et al, 2012]

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on a large Cochrane systematic review (search date: February 2012) which assessed the evidence on the effects of long-term hormone replacement therapy (HRT) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women (average age of 60 years), both during HRT use and after stopping HRT use [Marjoribanks et al, 2012].

Combined HRT

The evidence showed a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), stroke, gallbladder disease requiring hospital admission, death from lung cancer, ovarian cancer, and dementia (in women aged over 65 years).

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review) [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Prescribing HRT

How should I prescribe hormone replacement therapy in perimenopausal women with an intact uterus?

When prescribing hormone replacement therapy (HRT), discuss the most suitable type of product with the woman.

Follow up the woman after 3 months initially, and once she is settled on treatment, follow up annually.

Consider referral if treatment is unsuccessful or there are 'red flag' symptoms such as unexplained bleeding.

Consider switching to a continuous combined preparation after the woman becomes postmenopausal.

Management of peri-menopausal women with HRT

How should I manage peri-menopausal women with hormone replacement therapy (intact uterus)?

Offer lifestyle advice.

Advise about the risks and benefits of hormone replacement therapy (HRT) and record in the notes.

For urogenital symptoms alone (for example vaginal dryness and dyspareunia):

Offer treatment with low-dose vaginal oestrogen (cream, pessary, tablet, or ring) or systemic, cyclical, combined HRT (oral or transdermal):

Low-dose vaginal oestrogen may be preferred if the woman does not wish to take, or cannot tolerate, systemic HRT.

For women with infrequent periods or women who cannot tolerate progestogens, a systemic 3-monthly regimen may be preferred.

The lowest effective amount of topical oestrogens should be used in order to minimize systemic absorption. Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated; investigation may include an endometrial biopsy to exclude endometrial malignancy. Long-term treatment is often required as symptoms can recur on cessation of therapy.

For vasomotor symptoms (for example hot flushes and night sweats), with or without urogenital symptoms:

Offer systemic cyclical combined HRT (oral or transdermal):

Prescribe HRT at the lowest effective dose for the shortest duration possible.

For women with infrequent periods or women who cannot tolerate progestogens, a 3-monthly regimen may be preferred.

Maximal benefit of systemic HRT is usually seen within 3 months, and treatment is generally continued for up to 5 years.

Oestrogen-only HRT is not recommended for women with an intact uterus.

For a full discussion on the choice of HRT preparations, see Type of product to offer.

Advise the woman that she may still get pregnant if contraception is not used:

A suitable method of contraception should be used for 1 year after the last menstrual period if the woman is more than 50 years of age, or for 2 years after the last menstrual period if the woman is less than 50 years of age.

For more information on the choice and duration of contraception in perimenopausal women, see Scenario: Approaching the menopause in the CKS topic on Contraception - assessment.

Basis for recommendation

Basis for recommendation

These recommendations are based on advice issued by the Commission on Human Medicines (formerly the Committee on Safety of Medicines) [CSM, 2003a] and on information from a textbook: Management of the menopause [Rees et al, 2009].

Vaginal oestrogens

Low-dose oestrogen therapy is preferred because it incurs no adverse endometrial effects and a progestogen is not required for endometrial protection [Rees et al, 2009; Rees, 2011]. Vaginal oestrogen therapy may be required long-term, as symptoms recur when treatment is stopped. However the endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain [CSM, 2003a].

Systemic hormone replacement therapy (HRT)

There is evidence that HRT is effective for treating vasomotor and urogenital symptoms, managing sleep or mood disorders, and preventing osteoporosis.

Combined oestrogen and progestogen cyclical preparations are recommended in perimenopausal women because they produce predictable withdrawal bleeding, whereas continuous regimens often cause unpredictable bleeding [Rees et al, 2009].

Treatment for vasomotor symptoms should be continued for at least 1 year; otherwise, symptoms recur. Menopausal symptoms usually resolve within 2–5 years, but some women experience symptoms for many years, even into their seventies and eighties [Rees et al, 2009].

Due to the increased risk of endometrial cancer, oestrogen-only HRT should not be used in women with an intact uterus [Goodman et al, 2011].

Contraception

Hormone replacement therapy does not suppress ovulation and does not provide contraceptive cover [FSRH, 2010].

Follow up

What follow up is required?

Review the woman 3 months after starting hormone replacement therapy (HRT) and once she is settled on treatment, follow up annually.

At the initial 3-month review:

Assess the effectiveness of treatment and if necessary, adjust treatment to achieve better symptom control. See Scenario: Poor symptom control on HRT for more information.

Enquire about any adverse effects and manage appropriately. See Scenario: Managing adverse effects of HRT for more information.

Enquire about bleeding patterns.

Check body weight and blood pressure.

Stop HRT immediately if blood pressure is above systolic 160 mmHg or diastolic 95 mmHg.

Once each year, repeat the above checks and also:

Consider switching from cyclical HRT to continuous combined HRT, if appropriate. See the section on Switching to continuous combined preparation for more information.

Interrupt treatment with intravaginal oestrogen and consider stopping systemic HRT, to re-assess the need for continued use.

Discuss the advantages and disadvantages of continuing HRT. In particular, discuss the increased risk of breast cancer with long-term HRT. See Advice about possible risks of HRT for more information.

Perform a breast examination if indicated by personal or family history. Encourage breast awareness and participation in the national breast screening programme as appropriate for their age.

Perform a pelvic examination if clinically indicated (for example if there is unscheduled bleeding, especially if heavy, prolonged, or recurrent). Encourage participation in the national cervical screening programme.

Measurement of oestrogen levels (estradiol) is rarely indicated.

However, if the clinical response to HRT is poor (that is, poor symptomatic relief), measurement of oestrogen levels may be used:

To establish whether absorption of transdermal HRT is adequate in women in whom poor absorption is suspected. If poor absorption is confirmed, prescribe oral HRT.

Rarely, in women with persisting symptoms where poor compliance is suspected.

Measurement of follicle stimulating hormone level is not indicated.

Basis for recommendation

Basis for recommendation

Initial and annual review

These recommendations are based on the British National Formulary [BNF 65, 2013], The Commission on Human Medicine, formerly the Committee on Safety of Medicines, [CSM, 2003a], and published expert opinion [Rees et al, 2009; Menopause Matters, 2011b].

An initial review is recommended at 3 months, as most menopausal symptoms respond by then. When the woman is settled on treatment, an annual review is recommended because the risks and benefits of HRT for each woman change over time and need to be discussed regularly [Menopause Matters, 2011b].

Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated and may include endometrial biopsy to exclude endometrial malignancy [CSM, 2003a].

Rarely, conjugated equine oestrogens may cause severe hypertension that returns to normal when treatment is stopped [Rees et al, 2009]. The BNF lists blood pressure above systolic 160 mmHg or diastolic 95 mmHg as one of several reasons to stop HRT immediately [BNF 65, 2013].

Measurement of oestrogen

This recommendation is based on a Best Practice in primary care pathology article [Smellie et al, 2006].

Measurement of follicle-stimulating hormone (FSH)

Follicle-stimulating hormone should not be measured because it does not reflect the adequacy of the oestrogen dose and levels may remain increased despite an adequate oestrogen effect [Goodman et al, 2011].

Referring women who have started HRT

When should I refer women who have started hormone replacement therapy?

Refer women who are taking cyclical hormone replacement therapy (HRT) if:

There is a change in pattern of withdrawal bleeds or breakthrough bleeding.

There is multiple treatment failure, for example three or more regimens have been tried.

Refer to a team specializing in the management of gynaecological cancer (depending on local arrangements), any persistent or unexplained bleeding after cessation of HRT for 6 weeks.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in textbooks [Monga, 2006; Rees et al, 2009].

Abnormal bleeding requires investigation if [Rees et al, 2009]:

The pattern of withdrawal bleeding or breakthrough bleeding changes while taking monthly cyclical therapy.

There is breakthrough bleeding that persists for more than 4–6 months or does not lessen while taking a 3-monthly regimen.

Switching to continuous combined preparation

When should I switch from cyclical therapy to a continuous combined preparation?

Consider switching from cyclical hormone replacement therapy (HRT) to continuous combined HRT when the woman is considered to be postmenopausal. However, it may be difficult to decide when the woman is postmenopausal.

Women are generally considered to be postmenopausal if:

They are more than 54 years of age (it is estimated that 80% of women will be postmenopausal by this age).

They have had previous amenorrhoea or increased levels of follicle-stimulating hormone (FSH). Women who experienced 6 months of amenorrhoea or had increased FSH levels in their mid-40s are likely to be postmenopausal after taking several years of cyclical HRT.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a textbook [Rees et al, 2009].

Stopping HRT

When should I consider stopping hormone replacement therapy?

Consider a trial withdrawal (if a woman is symptom-free) after 1–2 years.

Advise the woman that symptoms may recur for a short time once HRT is stopped.

Counsel the woman about the possible risks of HRT if she wishes to continue treatment, particularly if treatment is being used for longer than 5 years.

Topical (vaginal) oestrogen may be required long term as symptoms can recur once treatment has stopped.

Stop treatment at least annually to re-assess the need for continued treatment.

For information on how HRT should be stopped, see How to stop HRT.

Be aware that HRT may need to be stopped immediately (depending on clinical judgement and pending investigation and treatment) if any of the following occur:

Sudden severe chest pain (even if not radiating to left arm).

Sudden breathlessness (or cough with blood-stained sputum).

Unexplained swelling or severe pain in the calf of one leg.

Severe stomach pain.

Serious neurological effects, including unusual severe, prolonged headache, especially:

If it is the first time, or getting progressively worse, or

There is sudden partial or complete loss of vision, or

Sudden disturbance of hearing or other perceptual disorders, or

Dysphasia, or

Bad fainting attack or collapse, or

First unexplained epileptic seizure, or

Weakness, motor disturbances, or very marked numbness suddenly affecting one side or one part of body.

Hepatitis, jaundice, or liver enlargement.

Blood pressure above systolic 160 mmHg or diastolic 95 mmHg.

Prolonged immobility after surgery or leg injury.

Detection of a risk factor which contraindicates treatment (see Contraindications).

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on pragmatic advice, published expert opinion [RCPE, 2003], and information in a textbook [Rees et al, 2009].

Vasomotor symptoms usually resolve within 2–5 years, but some women experience symptoms for many years [Rees et al, 2009].

Topical oestrogens

Endometrial effects should not be incurred with low dose oestrogens such as vaginal estriol (cream or pessary) or estradiol (tablet or ring). A progestogen is not needed with such low dose preparations [Rees et al, 2009].

The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain. The Medicines and Healthcare products Regulatory Agency (MHRA) have advised that treatment with topical oestrogens should be interrupted at least annually to re-assess the need for continued treatment [CSM, 2003a].

Stopping treatment immediately

The information on when to stop hormone replacement therapy immediately is based on the British National Formulary [BNF 65, 2013].

Scenario: Postmenopausal with uterus (HRT)

Scenario: Postmenopausal with uterus (HRT) for menopause

480months3060monthsFemale

Advice about managing symptoms of menopause, and HRT

What advice should I give about managing symptoms of menopause and starting hormone replacement therapy?

Advise about:

Modifying their lifestyle to reduce symptoms.

The risks and benefits of hormone replacement therapy (HRT).

The expected duration of treatment:

For vasomotor symptoms, most women require 2–3 years of treatment, but some women may need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue treatment. Symptoms may recur for a short time after stopping HRT.

Topical (vaginal) oestrogen may be required long term. Regular attempts (at least annually) to stop treatment are usually made. Symptoms may recur once treatment has stopped.

Adverse effects of HRT such as breast tenderness or enlargement, nausea, headaches, or bleeding.

Lifestyle advice for menopausal symptoms

What lifestyle advice can I give for menopausal symptoms?

Encourage all women to make lifestyle modifications to reduce menopausal symptoms:

Hot flushes and night sweats:

Taking regular exercise and losing weight (if applicable) may reduce the severity and frequency of flushes.

Wearing lighter clothing, sleeping in a cooler room, reducing stress, and avoiding possible triggers (such as spicy foods, caffeine, smoking, and alcohol) may also be helpful in reducing these symptoms.

Sleep disturbances:

Avoiding exercise late in the day and maintaining a regular bedtime can improve sleep.

Mood and anxiety disturbances:

Adequate sleep, regular physical activity, and relaxation exercises may help.

Cognitive symptoms:

Exercise and good sleep hygiene may improve subjective cognitive symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a textbook [Rees et al, 2009].

There is evidence that smoking cigarettes and having a body mass index of more than 30 kg/m2 increases the likelihood of flushing.

The Royal College of Obstetricians and Gynaecologists has advised that women who are more active tend to suffer less from the symptoms of the menopause, and that the best type of exercise is aerobic, sustained, regular exercise such as swimming and running [RCOG, 2010]. However, a Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011].

Advice about benefits of HRT

What advice should I give about the benefits of hormone replacement therapy?

Hormone replacement therapy (HRT) is effective for:

Treating vasomotor symptoms (for example hot flushes and night sweats).

Treating urogenital symptoms (for example vaginal dryness, dyspareunia as a result of vaginal dryness, recurrent urinary tract infections, and urinary frequency and urgency).

Managing sleep or mood disturbances caused by hot flushes and night sweats.

Preventing osteoporosis.

However, due to the risks associated with long-term use, HRT is not normally used as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age, except when other treatments are contraindicated, not tolerated, or ineffective.

There is no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer.

HRT has no role in the prevention or treatment of cardiovascular disease.

Basis for recommendation

Basis for recommendation

Hot flushes and night sweats

Good evidence indicates that oral or transdermal hormone replacement therapy (HRT), used as oestrogen alone or oestrogens combined with progestogens, is highly effective for reducing the frequency and severity of hot flushes and night sweats caused by the menopause.

Vaginal atrophy (dryness and dyspareunia)

There is evidence that HRT preparations (combined oral and transdermal oestrogens and progestogens, or intravaginal oestrogens) are effective for treating vaginal atrophy (dryness, burning, itching, and dyspareunia).

Recurrent urinary tract infection (UTIs)

Evidence from one systematic review suggests that oral and intravaginal oestrogen are effective for preventing UTIs, although some experts believe that this effect is only seen with intravaginal oestrogens [Rees et al, 2009]:

Recurrent UTIs may be prevented by treatment with vaginal but not oral HRT.

Long-term treatment may be required because symptoms recur when treatment is stopped.

Sleep disturbances

There is evidence that combined oral oestrogen and progestogen therapy provides a small statistically but not clinically meaningful improvement in sleep disturbances.

Incontinence

The British Menopause Society currently recommends the use of systemic or topical oestrogen for urinary frequency and urgency [Rees, 2011] although the evidence to support the use of oestrogens is conflicting.

A Cochrane systematic review found evidence that urinary incontinence may be improved with the use of local oestrogen treatment [Cody et al, 2012]. However, a previously published analysis of the Women's Health Initiative trial found that oestrogen therapy (alone and combined with progestogen therapy) increased the risk of urinary incontinence among continent women and worsened urinary incontinence among symptomatic women after 1 year [Hendrix et al, 2005].

Mood disorders

There is no evidence indicating that HRT has a direct effect on mood, irritability, or anxiety. However, experts suggest that if psychotherapy and antidepressants are ineffective, HRT may be appropriate for treating depression at the onset of menopause [SOGC, 2009].

Libido

In addition to relieving hot flushes and improving sleep, HRT improves urogenital atrophy, thinning, dryness, and loss of elasticity, all of which may cause dyspareunia. Libido may be improved with oestrogen alone but the addition of testosterone may be necessary, especially in young, oophorectomized women [Rees et al, 2009; Rees, 2011].

Osteoporosis

Evidence from a large Cochrane systematic review (search date: February 2012) shows that HRT is effective for the prevention of postmenopausal osteoporosis [Marjoribanks et al, 2012]; however, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen treatments are unsuitable.

The Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines, warns that because of the risks associated with long-term use, 'HRT should be used for prevention of osteoporosis only in women who are unable to use other medicines that are authorized for this purpose' [MHRA and CHM, 2007b].

The British National Formulary adds that HRT is an option where other treatments are contra-indicated, cannot be tolerated, or if there is a lack of response. HRT should not be considered as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age [BNF 65, 2013].

Colorectal cancer

Although some studies have demonstrated a lower risk of colon cancer in women treated with combined HRT [Writing Group for the Women's Health Initiative Investigators, 2002], a recent large Cochrane systematic review (search date: February 2012) found no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer [Marjoribanks et al, 2012].

Current evidence does not allow recommendation of HRT to prevent colorectal cancer [Rees et al, 2009; Goodman et al, 2011].

Cardiovascular disease

Evidence from a recent Cochrane systematic review (search date: April 2010) suggests that treatment with HRT has no role in the prevention or treatment of CVD in post-menopausal women. In fact, HRT causes an increase in the risk of stroke and venous thromboembolism (VTE). Furthermore, combination HRT is associated with an increased risk of non-fatal myocardial infarction [Main et al, 2013].

An open-label randomized controlled trial investigated the long-term effect of HRT on cardiovascular outcomes in recently postmenopausal women [Schierbeck et al, 2012]. This trial found evidence that after 10 years of randomized treatment, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction, without any apparent increase in risk of cancer, VTE, or stroke. However, further trials are needed.

Advice about possible risks of HRT

What advice should I give about the possible risks of hormone replacement therapy?

For combined hormone replacement therapy (HRT), advise that:

There is a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), and stroke. See Table 1 for more information.

There is also a small absolute increased risk of gallbladder disease requiring hospital admission, death from lung cancer, and dementia (in women aged over 65 years).

There is some evidence suggesting that combined HRT may be associated with an increased risk of ovarian cancer.

Table 1 . Combined HRT compared with placebo in postmenopausal women.
Outcomes Follow-up Absolute risk (95% CI) Relative risk (95% CI)
Placebo Combined HRT
Coronary events (MI or cardiac death)* 1 year 2 per 1000 4 per 1000 (95% CI 3 to 7) 1.89 (1.15 to 3.1)
VTE (DVT or PE) 1 year 2 per 1000 7 per 1000 (95% CI 4 to 11) 4.28 (2.49 to 7.34)
Coronary events (MI or cardiac death)* 5.6 years 18 per 1000 22 per 1000 (95% CI 18 to 27) 1.22 (0.98 to 1.52)
Stroke* 5.6 years 13 per 1000 18 per 1000 (95% CI 14 to 23) 1.38 (1.08 to 1.75)
Breast cancer (combined continuous HRT) 5.6 years 19 per 1000 23 per 1000 (95% CI 19 to 29) 1.26 (1.02 to 1.56)
* Only 33% of study sample were aged 50-59 years at baseline (i.e. the age women most likely to consider HRT for vasomotor symptoms); mean participant age was 63 years. Ovarian cancer: a systematic review of (mainly) observational studies [Greiser et al, 2007] suggests that combined HRT may be associated with an increased risk of ovarian cancer. MI: myocardial infarction; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism
Data adapted from: [Marjoribanks et al, 2012]

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on a large Cochrane systematic review (search date: February 2012) which assessed the evidence on the effects of long-term hormone replacement therapy (HRT) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women (average age of 60 years), both during HRT use and after stopping HRT use [Marjoribanks et al, 2012].

Combined HRT

The evidence showed a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), stroke, gallbladder disease requiring hospital admission, death from lung cancer, ovarian cancer, and dementia (in women aged over 65 years).

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review) [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Advice about benefits and risks of tibolone

What advice should I give about the risks and benefits of tibolone?

Advise the woman that tibolone is beneficial in that it:

Is effective for treating vasomotor symptoms (such as hot flushes and night sweats).

Reduces postmenopausal osteoporosis (although other drugs are preferred).

May improve sexual functioning.

Discuss the risks of tibolone:

Tibolone is associated with a small increased risk of stroke and endometrial cancer.

Limited data suggest that it may be associated with:

A small increased risk of breast cancer.

An increased risk of breast cancer recurrence in women with a history of breast cancer.

In younger women, the risk profile of tibolone is broadly similar to that for conventional combined hormone replacement therapy (see Advice about possible risks of HRT).

For women over 60 years of age, the risks associated with tibolone start to outweigh the benefits because of the increased risk of stroke.

Basis for recommendation

Basis for recommendation

These recommendations are based on randomized controlled trials and a recently published assessment of the benefit-risk balance published by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA and CHM, 2007a; MHRA, 2009]. The MRHA assessed the balance of benefits and risks for tibolone after the Long-term Intervention on Fractures with Tibolone (LIFT) study was terminated because of an increased risk of stroke in those assigned tibolone compared with those assigned placebo.

Stroke

The LIFT study identified a significantly (2.2-times) increased risk of stroke, mostly ischaemic, in tibolone users; risk increased from the first year of treatment. Baseline risk of stroke is strongly age-dependent, and the absolute risk with tibolone therefore increases with older age.

The manufacturer advises that the decision to prescribe tibolone should be based on an assessment of the woman's overall risks and, particularly in women over 60 years of age, should include consideration of the risk of stroke [ABPI Medicines Compendium, 2013b].

Breast cancer

There are limited clinical trial data for breast cancer risk in healthy women. However, the LIBERATE study in women with previous breast cancer was stopped because it could not establish non-inferiority of tibolone compared with placebo.

The Million Women Study identified a significantly increased risk of breast cancer in tibolone users (relative risk [RR] 1.5, 95% CI 1.3 to 1.7), which is similar to that for oestrogen-only HRT (RR 1.3, 95% CI 1.2 to 1.4) and significantly lower than that for combined HRT (RR 2.0, 95% CI 1.9 to 2.1). Risk increased with longer duration of use and returned to baseline within a few years of stopping treatment.

A Clinical Evidence review (search date: June 2010) found high-quality evidence which showed that, compared with placebo, tibolone is associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer [Burbos and Morris, 2011].

Venous thromboembolism (VTE)

The few data available do not suggest an increased risk of VTE compared with combined hormone replacement therapy (HRT) users or with non-users.

Coronary heart disease

No conclusions can be drawn from the available data. In view of the increased risk of stroke associated with tibolone, an increase in coronary events is biologically plausible. In studies, tibolone caused a marked dose-dependent decrease in high-density lipoprotein cholesterol levels (–22.4% after 2 years); total triglyceride and lipoprotein (a) levels were also reduced. A decrease in total cholesterol and very low-density lipoprotein cholesterol levels was not dose dependent, and low-density lipoprotein cholesterol levels did not change. The clinical implication of these findings is not yet known.

Endometrial cancer

The MHRA reviewed the evidence on effects of tibolone on the endometrium and have concluded that:

Most studies show an increased risk of having endometrial cancer diagnosed in women using tibolone. Two large epidemiological studies identified a significant increase in the risk of endometrial cancer in association with tibolone use that increased with increasing duration of use.

Although a causal relationship has not been proven, women who are prescribed tibolone have an increased risk of having endometrial cancer diagnosed than both never-users and users of combined HRT. The reason for this increase is not clear.

For more detailed information, see the MHRA website.

Prescribing HRT

How should I prescribe hormone replacement therapy?

When prescribing hormone replacement therapy (HRT), discuss the most suitable type of product with the woman.

Follow up the woman after 3 months initially, and once she is settled on the treatment, follow up annually.

Consider referral if treatment is unsuccessful or there are 'red flag' symptoms such as unexplained bleeding.

Management of post-menopausal women with HRT

How should I manage post-menopausal women with hormone replacement therapy (intact uterus)?

Offer lifestyle advice.

Advise the woman about the risks and benefits of hormone replacement therapy (HRT) or tibolone, as appropriate, and record this in her notes.

For urogenital symptoms alone (for example vaginal dryness, dyspareunia, recurrent urinary tract infections, or urinary frequency and urgency):

Offer treatment with low-dose vaginal oestrogen (cream, pessary, tablet or ring) or systemic continuous combined HRT (oral or transdermal):

Low-dose vaginal oestrogen may be preferred if the woman does not wish to take, or cannot tolerate, systemic HRT.

The lowest effective amount of topical oestrogens should be used in order to minimize systemic absorption. Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated; investigation may include an endometrial biopsy to exclude endometrial malignancy. Long-term treatment is often required as symptoms can recur on cessation of therapy.

For vasomotor symptoms (for example hot flushes and night sweats) with or without urogenital symptoms:

Offer systemic continuous combined HRT (oral or transdermal), or tibolone.

Prescribe HRT at the lowest effective dose for the shortest duration possible.

Maximal benefit of systemic HRT is usually seen within 3 months, and treatment is generally continued for up to 5 years.

Oestrogen-only HRT is not recommended for women with an intact uterus.

If the woman requires treatment for decreased libido, consider offering tibolone (licensed use).

For a full discussion on the choice of HRT preparations, see Type of product to offer.

Advise the woman that she may still get pregnant if contraception is not used:

A suitable method of contraception should be used for 1 year after the last menstrual period if the woman is more than 50 years of age, or for 2 years after the last menstrual period if the woman is younger than 50 years of age.

For more information on the choice and duration of contraception in perimenopausal women, see Scenario: Approaching the menopause in the CKS topic on Contraception - assessment.

Basis for recommendation

Basis for recommendation

These recommendations are based on advice issued by the Commission on Human Medicines (formerly the Committee on Safety of Medicines) [CSM, 2003a] and on information from a textbook: Management of the menopause [Rees et al, 2009].

Vaginal oestrogens

Low-dose oestrogen therapy is preferred because it incurs no adverse endometrial effects and a progestogen is not required for endometrial protection [Rees et al, 2009; Rees, 2011]. Vaginal oestrogen therapy may be required long-term, as symptoms recur when treatment is stopped. However the endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain [CSM, 2003a].

Continuous combined hormone replacement therapy (HRT)

There is evidence that HRT is effective for treating vasomotor and urogenital symptoms, managing sleep or mood disorders, and preventing osteoporosis. There is no evidence that HRT has a role in the treatment or prevention of cardiovascular disease.

Cyclical HRT preparations may be used in postmenopausal women; however, continuous combined preparations are generally preferred because they do not induce bleeding. Furthermore, continuous combined HRT may have a reduced risk of endometrial cancer compared with cyclical HRT [Rees et al, 2009].

Treatment for vasomotor symptoms should be continued for at least 1 year; otherwise, symptoms recur. Menopausal symptoms usually resolve within 2–5 years, but some women experience symptoms for many years, even into their seventies and eighties [Rees et al, 2009].

Due to the increased risk of endometrial cancer, oestrogen-only HRT should not be used in women with an intact uterus [Goodman et al, 2011].

Tibolone

There is evidence that tibolone is effective for treating vasomotor symptoms and may improve sexual function.

Tibolone is licensed for the [ABPI Medicines Compendium, 2013b]:

Treatment of oestrogen deficiency symptoms in postmenopausal women, more than one year after menopause.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.

Contraception

Hormone replacement therapy does not suppress ovulation and does not provide contraceptive cover [FSRH, 2010].

Follow up

What follow up is required?

Review the woman 3 months after starting hormone replacement therapy (HRT) and once she is settled on treatment, follow up annually.

At the initial 3-month review:

Assess the effectiveness of treatment and if necessary, adjust treatment to achieve better symptom control. See Scenario: Poor symptom control on HRT for more information.

Enquire about any adverse effects and manage appropriately. See Scenario: Managing adverse effects of HRT for more information.

Enquire about bleeding patterns.

Check body weight and blood pressure.

Stop HRT immediately if blood pressure is above systolic 160 mmHg or diastolic 95 mmHg.

Once each year, repeat the above checks and also:

Consider switching from cyclical HRT to continuous combined HRT, if appropriate.

Interrupt treatment with intravaginal oestrogen and consider stopping systemic HRT, to re-assess the need for continued use.

Discuss the advantages and disadvantages of continuing HRT. In particular, discuss the increased risk of breast cancer with long-term HRT. See Advice about possible risks of HRT for more information.

Perform a breast examination if indicated by personal or family history. Encourage breast awareness and participation in the national breast screening programme as appropriate for their age.

Perform a pelvic examination if clinically indicated (for example if there is unscheduled bleeding, especially if heavy, prolonged, or recurrent). Encourage participation in the national cervical screening programme.

Measurement of oestrogen levels (estradiol) is rarely indicated.

However, if the clinical response to HRT is poor (that is, poor symptomatic relief), measurement of oestrogen levels may be used:

To establish whether absorption of transdermal HRT is adequate in women in whom poor absorption is suspected. If poor absorption is confirmed, prescribe oral HRT.

Rarely, in women with persisting symptoms where poor compliance is suspected.

Measurement of follicle stimulating hormone level is not indicated.

Basis for recommendation

Basis for recommendation

Initial and annual review

These recommendations are based on the British National Formulary [BNF 65, 2013], The Commission on Human Medicine, formerly the Committee on Safety of Medicines, [CSM, 2003a], and published expert opinion [Rees et al, 2009; Menopause Matters, 2011b].

An initial review is recommended at 3 months, as most menopausal symptoms respond by then. When the woman is settled on treatment, an annual review is recommended because the risks and benefits of HRT for each woman change over time and need to be discussed regularly [Menopause Matters, 2011b].

Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated and may include endometrial biopsy to exclude endometrial malignancy [CSM, 2003a].

Rarely, conjugated equine oestrogens may cause severe hypertension that returns to normal when treatment is stopped [Rees et al, 2009]. The BNF lists blood pressure above systolic 160 mmHg or diastolic 95 mmHg as one of several reasons to stop HRT immediately [BNF 65, 2013].

Measurement of oestrogen

This recommendation is based on a Best Practice in primary care pathology article [Smellie et al, 2006].

Measurement of follicle-stimulating hormone (FSH)

Follicle-stimulating hormone should not be measured because it does not reflect the adequacy of the oestrogen dose and levels may remain increased despite an adequate oestrogen effect [Goodman et al, 2011].

Referring women who have started HRT or tibolone

When should I refer women who have started hormone replacement therapy or tibolone?

For women taking continuous combined hormone replacement therapy (HRT), refer if:

Breakthrough bleeding persists for more than 4–6 months after starting therapy.

A bleed occurs after amenorrhoea.

For women taking tibolone, refer for gynaecological investigation to exclude endometrial malignancy if they bleed beyond 6 months of starting treatment, or after stopping treatment with tibolone.

Refer if there is multiple treatment failure, for example three or more regimens have been tried.

Refer to a team specializing in the management of gynaecological cancer (depending on local arrangements), any persistent or unexplained bleeding after cessation of HRT for 6 weeks.

Basis for recommendation

Basis for recommendation

Hormone replacement therapy

These recommendations are based on expert opinion in textbooks on the management of menopause [Monga, 2006; Rees et al, 2009].

Abnormal bleeding requires investigation if [Rees et al, 2009]:

The pattern of withdrawal bleeding or breakthrough bleeding changes while taking monthly cyclical therapy.

There is breakthrough bleeding that persists for more than 4–6 months or does not lessen while taking a 3-monthly regimen.

Tibolone

This recommendation is based on advice issued by the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA and CHM, 2007a; MHRA, 2009]. The MHRA reviewed the evidence on effects of tibolone on the endometrium and concluded that:

Most studies show an increased risk of having endometrial cancer diagnosed in women using tibolone.

Although a causal relationship has not been proven, women who are prescribed tibolone have an increased risk of having endometrial cancer diagnosed than both never-users and users of combined hormone replacement therapy. The reason for this increase is not clear.

Women who bleed beyond 6 months of treatment, or after stopping treatment with tibolone should be referred for gynaecological investigation to exclude endometrial malignancy.

Stopping HRT

When should I consider stopping hormone replacement therapy?

If systemic hormone replacement therapy (HRT) is being used for symptom control, consider a trial withdrawal (if a woman is symptom-free) after 1–2 years.

Advise the woman that symptoms may recur for a short time once HRT is stopped.

Counsel the woman about the possible risks of HRT if she wishes to continue treatment, particularly if treatment is being used for longer than 5 years.

Topical (vaginal) oestrogen may be required long term as symptoms can recur once treatment has stopped.

Stop treatment at least annually to re-assess the need for continued treatment.

For information on how HRT should be stopped, see How to stop HRT.

Be aware that HRT may need to be stopped immediately (depending on clinical judgement, and pending investigation and treatment), if any of the following occur:

Sudden severe chest pain (even if not radiating to left arm).

Sudden breathlessness (or cough with blood-stained sputum).

Unexplained swelling or severe pain in calf of one leg.

Severe stomach pain.

Serious neurological effects, including unusual severe, prolonged headache, especially:

If it is the first time, or getting progressively worse, or

There is sudden partial or complete loss of vision, or

Sudden disturbance of hearing or other perceptual disorders, or

Dysphasia, or

Bad fainting attack or collapse, or

First unexplained epileptic seizure, or

Weakness, motor disturbances, or very marked numbness suddenly affecting one side or one part of body.

Hepatitis, jaundice, or liver enlargement.

Blood pressure above systolic 160 mmHg or diastolic 95 mmHg.

Prolonged immobility after surgery or leg injury.

Detection of a risk factor which contraindicates treatment (see Contraindications).

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on pragmatic advice, published expert opinion [RCPE, 2003], and information in a textbook [Rees et al, 2009].

Vasomotor symptoms usually resolve within 2–5 years, but some women experience symptoms for many years [Rees et al, 2009].

Topical oestrogens

Endometrial effects should not be incurred with low dose oestrogens such as vaginal estriol (cream or pessary) or estradiol (tablet or ring). A progestogen is not needed with such low dose preparations [Rees et al, 2009].

The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain. The Medicines and Healthcare products Regulatory Agency (MHRA) have advised that treatment with topical oestrogens should be interrupted at least annually to re-assess the need for continued treatment [CSM, 2003a].

Stopping treatment immediately

The information on when to stop hormone replacement therapy immediately is based on the British National Formulary [BNF 65, 2013].

Scenario: Menopausal symptoms after a hysterectomy (HRT)

Scenario: Menopausal symptoms after a hysterectomy (HRT) for menopause

480months3060monthsFemale

Advice about managing symptoms of menopause, and HRT

What advice should I give about managing symptoms of menopause and starting hormone replacement therapy?

Advise the woman about:

Modifying their lifestyle to reduce symptoms.

The risks and benefits of hormone replacement therapy (HRT).

The expected duration of treatment:

For vasomotor symptoms, most women require 2–3 years of treatment, but some women may need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue treatment. Symptoms may recur for a short time after stopping HRT.

Topical (vaginal) oestrogen may be required long term. Regular attempts (at least annually) to stop treatment are usually made. Symptoms may recur once treatment has stopped.

Possible adverse effects of HRT such as breast tenderness or enlargement, nausea, headaches, or bleeding.

Lifestyle advice for menopausal symptoms

What lifestyle advice can I give for menopausal symptoms?

Encourage all women to make lifestyle modifications to reduce menopausal symptoms:

Hot flushes and night sweats:

Taking regular exercise and losing weight (if applicable) may reduce the severity and frequency of flushes.

Wearing lighter clothing, sleeping in a cooler room, reducing stress, and avoiding possible triggers (such as spicy foods, caffeine, smoking, and alcohol) may also be helpful in reducing these symptoms.

Sleep disturbances:

Avoiding exercise late in the day and maintaining a regular bedtime can improve sleep.

Mood and anxiety disturbances:

Adequate sleep, regular physical activity, and relaxation exercises may help.

Cognitive symptoms:

Exercise and good sleep hygiene may improve subjective cognitive symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Rees et al, 2009].

There is evidence that smoking cigarettes and having a body mass index of more than 30 kg/m2 increases the likelihood of flushing.

The Royal College of Obstetricians and Gynaecologists has advised that women who are more active tend to suffer less from the symptoms of the menopause, and that the best type of exercise is aerobic, sustained, regular exercise such as swimming and running [RCOG, 2010]. However, a Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials (RCTs) on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011].

Advice about benefits of HRT

What advice should I give about the benefits of hormone replacement therapy?

Hormone replacement therapy (HRT) is effective for:

Treating vasomotor symptoms (for example hot flushes and night sweats).

Treating urogenital symptoms (for example vaginal dryness, dyspareunia as a result of vaginal dryness, recurrent urinary tract infections, and urinary frequency and urgency).

Managing sleep or mood disturbances caused by hot flushes and night sweats.

Preventing osteoporosis.

However, due to the risks associated with long-term use, HRT is not normally used as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age, except when other treatments are contra-indicated, not tolerated, or ineffective.

There is no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer.

HRT has no role in the prevention or treatment of cardiovascular disease.

Basis for recommendation

Basis for recommendation

Hot flushes and night sweats

Good evidence indicates that oral or transdermal hormone replacement therapy (HRT), used as oestrogen alone or oestrogens combined with progestogens, is highly effective for reducing the frequency and severity of hot flushes and night sweats caused by the menopause.

Vaginal atrophy (dryness and dyspareunia)

There is evidence that HRT preparations (combined oral and transdermal oestrogens and progestogens, or intravaginal oestrogens) are effective for treating vaginal atrophy (dryness, burning, itching, and dyspareunia).

Recurrent urinary tract infection (UTIs)

Evidence from one systematic review suggests that oral and intravaginal oestrogen are effective for preventing UTIs, although some experts believe that this effect is only seen with intravaginal oestrogens [Rees et al, 2009]:

Recurrent UTIs may be prevented by treatment with vaginal but not oral HRT.

Long-term treatment may be required because symptoms recur when treatment is stopped.

Sleep disturbances

There is evidence that combined oral oestrogen and progestogen therapy provides a small statistically but not clinically meaningful improvement in sleep disturbances.

Incontinence

The British Menopause Society currently recommends the use of systemic or topical oestrogen for urinary frequency and urgency [Rees, 2011] although the evidence to support the use of oestrogens is conflicting.

A Cochrane systematic review found evidence that urinary incontinence may be improved with the use of local oestrogen treatment [Cody et al, 2012]. However, a previously published analysis of the Women's Health Initiative trial found that oestrogen therapy (alone and combined with progestogen therapy) increased the risk of urinary incontinence among continent women and worsened urinary incontinence among symptomatic women after 1 year [Hendrix et al, 2005].

Mood disorders

There is no evidence indicating that HRT has a direct effect on mood, irritability, or anxiety. However, experts suggest that if psychotherapy and antidepressants are ineffective, HRT may be appropriate for treating depression at the onset of menopause [SOGC, 2009].

Libido

In addition to relieving hot flushes and improving sleep, HRT improves urogenital atrophy, thinning, dryness, and loss of elasticity, all of which may cause dyspareunia. Libido may be improved with oestrogen alone but the addition of testosterone may be necessary, especially in young, oophorectomized women [Rees et al, 2009; Rees, 2011].

Osteoporosis

Evidence from a large Cochrane systematic review (search date: February 2012) shows that HRT is effective for the prevention of postmenopausal osteoporosis [Marjoribanks et al, 2012]; however, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen treatments are unsuitable.

The Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines, warns that because of the risks associated with long-term use, 'HRT should be used for prevention of osteoporosis only in women who are unable to use other medicines that are authorized for this purpose' [MHRA and CHM, 2007b].

The British National Formulary adds that HRT is an option where other treatments are contra-indicated, cannot be tolerated, or if there is a lack of response. HRT should not be considered as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age [BNF 65, 2013].

Colorectal cancer

Although some studies have demonstrated a lower risk of colon cancer in women treated with combined HRT [Writing Group for the Women's Health Initiative Investigators, 2002], a recent large Cochrane systematic review (search date: February 2012) found no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer [Marjoribanks et al, 2012].

Current evidence does not allow recommendation of HRT to prevent colorectal cancer [Rees et al, 2009; Goodman et al, 2011].

Cardiovascular disease

Evidence from a recent Cochrane systematic review (search date: April 2010) suggests that treatment with HRT has no role in the prevention or treatment of CVD in post-menopausal women. In fact, HRT causes an increase in the risk of stroke and venous thromboembolism (VTE). Furthermore, combination HRT is associated with an increased risk of non-fatal myocardial infarction [Main et al, 2013].

An open-label randomized controlled trial investigated the long-term effect of HRT on cardiovascular outcomes in recently postmenopausal women [Schierbeck et al, 2012]. This trial found evidence that after 10 years of randomized treatment, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction, without any apparent increase in risk of cancer, VTE, or stroke. However, further trials are needed.

Advice about the possible risks of HRT

What advice should I give about the possible risks of hormone replacement therapy?

For oestrogen-only HRT, advise that:

There is a small absolute increased risk of VTE, stroke, and endometrial cancer. See Table 1 for more information.

There is also a small absolute increased risk of gallbladder disease requiring hospital admission.

There is some evidence suggesting that oestrogen-only HRT may be associated with an increased risk of ovarian cancer.

Oestrogen-only HRT does not appear to significantly increase the risk of breast cancer.

Table 1 . Oestrogen-only HRT compared with placebo in postmenopausal women.
Outcomes Follow-up Absolute risk (95% CI) Relative risk (95% CI)
Placebo Oestrogen only HRT
Coronary events (MI or cardiac death)* 7.1 years 41 per 1000 38 per 1000 (95% CI 32 to 46) 0.94 (95% CI 0.78 to 1.13)
Stroke* 7.1 years 23 per 1000 32 per 1000 (95% CI 25 to 40) 1.34 (95% CI 1.07 to 1.68)
VTE (DVT or PE)* 7.1 years 16 per 1000 21 per 1000 (95% CI 16 to 28) 1.32 (95% CI 1 to 1.74)
Breast cancer* 7.1 years 30 per 1000 24 per 1000 (95% CI 19 to 31) 0.79 (95% CI 0.61 to 1.01)
* Only 33% of study sample were aged 50-59 years at baseline (i.e. the age women most likely to consider HRT for vasomotor symptoms); mean participant age was 63 years. Endometrial cancer is a well documented adverse effect of unopposed oestrogen in women with a uterus, although current evidence does not show a statistically significant difference between oestrogen-only HRT and placebo for this outcome. However, the women in the included studies were closely monitored for endometrial hyperplasia if they had a uterus. Ovarian cancer: a systematic review of (mainly) observational studies [Greiser et al, 2007] suggests that combined HRT may be associated with an increased risk of ovarian cancer. MI: myocardial infarction; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism
Data adapted from: [Marjoribanks et al, 2012]

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on a large Cochrane systematic review (search date: February 2012) which assessed the evidence on the effects of long-term hormone replacement therapy (HRT) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women (average age of 60 years), both during HRT use and after stopping HRT use [Marjoribanks et al, 2012].

Oestrogen-only HRT

The evidence showed a small absolute increased risk of venous thromboembolism, stroke, and gallbladder disease.

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Although the Cochrane systematic review showed no statistically significant difference between oestrogen-only HRT and placebo for endometrial cancer, endometrial cancer is a well documented adverse effect of unopposed oestrogen in women with a uterus [Rees et al, 2009; Marjoribanks et al, 2012].

Prescribing HRT

How should I prescribe hormone replacement therapy?

When prescribing hormone replacement therapy (HRT), discuss the most suitable type of product with the woman (depending on which symptoms predominate).

Consider the possibility of subtotal hysterectomy.

Follow up the woman after 3 months initially, and once she is settled on the treatment, follow up annually.

Consider referral if treatment is unsuccessful or there are 'red flag' symptoms such as unexplained bleeding.

Management with HRT after hysterectomy

How should I manage women who have had a hysterectomy with hormone replacement therapy?

Offer lifestyle advice.

Advise the woman about the risks and benefits of oestrogen-based hormone replacement therapy (HRT) and record this in her notes.

For urogenital symptoms alone (for example vaginal dryness and dyspareunia):

Offer treatment with low-dose vaginal oestrogen (cream, pessary, tablet, or ring) or systemic oestrogen replacement therapy (oral or transdermal):

Low-dose vaginal oestrogen may be preferred if the woman does not wish to take, or cannot tolerate, systemic oestrogen.

Long-term treatment is often required as symptoms can recur on cessation of therapy.

For vasomotor symptoms (for example hot flushes, night sweats), with or without urogenital symptoms:

Offer systemic unopposed oestrogen replacement therapy (oral or transdermal).

Symptoms generally respond to systemic therapy within 4 weeks of starting treatment and have a maximal therapeutic effect at 3 months.

For decreased libido:

Seek specialist advice if considering testosterone patches or implants.

For a full discussion on the choice of HRT preparations, see Type of product to offer.

Basis for recommendation

Basis for recommendation

These recommendations are based on advice issued by the Commission on Human Medicines (formerly the Committee on Safety of medicines) [CSM, 2003a] and on information from a textbook: Management of the menopause [Rees et al, 2009].

Vaginal oestrogens

Low-dose oestrogen therapy is preferred because it incurs no adverse endometrial effects and a progestogen is not required for endometrial protection [Rees et al, 2009; Rees, 2011]. Vaginal oestrogen therapy may be required long term, as symptoms recur when treatment is stopped. However the endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain [CSM, 2003a].

Oestrogen therapy

Hysterectomized women should be given oestrogen alone as there is no need for progestogen. Furthermore, combined HRT may entail a greater risk of breast cancer than with oestrogen alone [Rees et al, 2009]. In non-hysterectomized women, progestogens are added to oestrogen therapy to reduce the risk of endometrial hyperplasia and carcinoma which occurs with unopposed oestrogen.

Treatment for vasomotor symptoms should be continued for at least 1 year; otherwise, symptoms recur. Menopausal symptoms usually resolve within 2–5 years, but some women experience symptoms for many years, even into their seventies and eighties [Rees et al, 2009].

Libido

There is evidence that loss of libido can be improved by testosterone supplementation, particularly after surgical menopause. Specialist advice should be sought because it is not successful in all women and other factors such as marital problems may be involved [Rees et al, 2009].

Testosterone patches are licensed for women with surgically induced menopause (in women receiving concomitant oestrogen therapy), but they are not recommended for women naturally menopausal or those taking conjugated oestrogens. Safety and efficacy of testosterone patches have not been established beyond 1 year of treatment [BNF 65, 2013].

Benefits of HRT

There is evidence that HRT is effective for treating vasomotor and urogenital symptoms, managing sleep or mood disorders, and preventing osteoporosis. See Advice about benefits of HRT for more information.

Issues to consider in subtotal hysterectomy

Are there any specific issues I should consider in a woman who has had a subtotal hysterectomy?

A remnant of endometrial tissue may be present in women who have had a subtotal hysterectomy (in which the main part of the uterus is removed but the cervix is retained).

To test for the presence of endometrial tissue, prescribe a 3-month course of cyclical hormone replacement therapy (HRT):

If withdrawal bleeding occurs, endometrial tissue is present, and combined HRT should be started. For further information on management, see Scenario: Postmenopausal with uterus (HRT).

If the woman does not have withdrawal bleeding, endometrial tissue is unlikely to be present, and oestrogen-only HRT may be started. For further information on management, see Management with HRT after hysterectomy.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a textbook [Rees et al, 2009].

Follow up

What follow up is required?

Review the woman 3 months after starting hormone replacement therapy (HRT) and once she is settled on treatment, follow up annually.

At the initial 3-month review:

Assess the effectiveness of treatment and if necessary, adjust to achieve better symptom control. See Scenario: Poor symptom control on HRT for more information.

Enquire about any adverse effects and manage appropriately. See Scenario: Managing adverse effects of HRT for more information.

Enquire about bleeding patterns.

Check blood pressure and body weight.

Stop HRT immediately if blood pressure is above systolic 160 mmHg or diastolic 95 mmHg.

Once each year, repeat the above checks and also:

Interrupt treatment with intravaginal oestrogen and consider stopping systemic HRT, to re-assess the need for continued use.

Discuss the advantages and disadvantages of continuing HRT, in particular, discuss the increased risk of breast cancer with long-term HRT. See Advice about the possible risks of HRT for more information.

Perform a breast examination if indicated by personal or family history. Encourage breast awareness and participation in the national breast screening programme as appropriate for their age.

Perform a pelvic examination if clinically indicated (for example if there is unscheduled bleeding, especially if heavy, prolonged, or recurrent). Encourage participation in the national cervical screening programme.

Measurement of oestrogen levels (estradiol) is rarely indicated.

However, if the clinical response to HRT is poor (that is, poor symptomatic relief), measurement of oestrogen levels may be used:

To establish whether absorption of transdermal HRT is adequate in women in whom poor absorption is suspected. If poor absorption is confirmed, prescribe oral HRT.

Rarely, in women with persisting symptoms where poor compliance is suspected.

Measurement of follicle stimulating hormone level is not indicated.

Basis for recommendation

Basis for recommendation

Initial and annual review

These recommendations are based on the British National Formulary [BNF 65, 2013], The Commission on Human Medicine, formerly the Committee on Safety of Medicines, [CSM, 2003a], and published expert opinion [Rees et al, 2009; Menopause Matters, 2011b].

An initial review is recommended at 3 months, as most menopausal symptoms respond by then. When the woman is settled on treatment, an annual review is recommended because the risks and benefits of HRT for each woman change over time and need to be discussed regularly [Menopause Matters, 2011b].

Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated and may include endometrial biopsy to exclude endometrial malignancy [CSM, 2003a].

Rarely, conjugated equine oestrogens may cause severe hypertension that returns to normal when treatment is stopped [Rees et al, 2009]. The BNF lists blood pressure above systolic 160 mmHg or diastolic 95 mmHg as one of several reasons to stop HRT immediately [BNF 65, 2013].

Measurement of oestrogen

This recommendation is based on a Best Practice in primary care pathology article [Smellie et al, 2006].

Measurement of follicle-stimulating hormone (FSH)

Follicle-stimulating hormone should not be measured because it does not reflect the adequacy of the oestrogen dose and levels may remain increased despite an adequate oestrogen effect [Goodman et al, 2011].

Referring women who have started HRT

When should I refer women who have started hormone replacement therapy?

Refer to secondary care if there is multiple treatment failure (for example three or more regimens have been tried).

Basis for recommendation

Basis for recommendation

This recommendation is based on pragmatic advice and expert opinion in a textbook [Rees et al, 2009].

Stopping HRT

When should I consider stopping hormone replacement therapy?

Consider a trial withdrawal (if a woman is symptom-free) after 1–2 years.

Advise the woman that symptoms may recur for a short time once HRT is stopped.

Counsel the woman about the possible risks of HRT if she wishes to continue treatment, particularly if treatment is being used for longer than 5 years.

Topical (vaginal) oestrogen may be required long-term as symptoms can recur once treatment has stopped.

Stop treatment at least annually to re-assess the need for continued treatment.

Women with premature menopause usually take HRT up to the average age of the natural menopause (52 years); at that time, therapy is reassessed. Some women will still be symptomatic.

For information on how HRT should be stopped, see How to stop HRT.

Be aware that HRT may need to be stopped immediately (depending on clinical judgement, and pending investigation and treatment) if any of the following occur:

Sudden severe chest pain (even if not radiating to left arm).

Sudden breathlessness (or cough with blood-stained sputum).

Unexplained swelling or severe pain in calf of one leg.

Severe stomach pain.

Serious neurological effects, including unusual severe, prolonged headache, especially:

If it is the first time, or getting progressively worse, or

There is sudden partial or complete loss of vision, or

Sudden disturbance of hearing or other perceptual disorders, or

Dysphasia, or

Bad fainting attack or collapse, or

First unexplained epileptic seizure, or

Weakness, motor disturbances, or very marked numbness suddenly affecting one side or one part of body.

Hepatitis, jaundice, or liver enlargement.

Blood pressure above systolic 160 mmHg or diastolic 95 mmHg.

Prolonged immobility after surgery or leg injury.

Detection of a risk factor which contraindicates treatment (see Contraindications).

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on pragmatic advice, published expert opinion [RCPE, 2003] and information in a textbook [Rees et al, 2009].

Vasomotor symptoms usually resolve within 2–5 years, but some women experience symptoms for many years [Rees et al, 2009].

Topical oestrogens

Endometrial effects should not be incurred with low dose oestrogens such as vaginal estriol (cream or pessary) or estradiol (tablet or ring). A progestogen is not needed with such low dose preparations [Rees et al, 2009].

The endometrial safety of long-term or repeated use of topical vaginal oestrogens is uncertain. The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that treatment with topical oestrogens should be interrupted at least annually to re-assess the need for continued treatment [CSM, 2003a].

Stopping treatment immediately

The information on when to stop hormone replacement therapy immediately is based on the British National Formulary [BNF 65, 2013].

Scenario: Premature menopause

Scenario: Premature menopause

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Advice for women before starting HRT

What advice should I give about managing symptoms and starting hormone replacement therapy?

Advise the woman about:

Modifying their lifestyle to reduce symptoms.

The risks and benefits of hormone replacement therapy (HRT).

The expected duration of treatment:

For vasomotor symptoms, most women require 2–3 years of treatment, but some women may need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue treatment. Symptoms may recur for a short time after stopping HRT.

Topical (vaginal) oestrogen may be required long term. Regular attempts (at least annually) to stop treatment are usually made. Symptoms may recur once treatment has stopped.

Possible adverse effects of HRT such as breast tenderness or enlargement, nausea, headaches, or bleeding.

Lifestyle advice for menopausal symptoms

What lifestyle advice can I give for menopausal symptoms?

Encourage all women to make lifestyle modifications to reduce menopausal symptoms:

Hot flushes and night sweats:

Taking regular exercise and losing weight (if applicable) may reduce the severity and frequency of flushes.

Wearing lighter clothing, sleeping in a cooler room, reducing stress, and avoiding possible triggers (such as spicy foods, caffeine, smoking, and alcohol) may also be helpful in reducing these symptoms.

Sleep disturbances:

Avoiding exercise late in the day and maintaining a regular bedtime can improve sleep.

Mood and anxiety disturbances:

Adequate sleep, regular physical activity, and relaxation exercises may help.

Cognitive symptoms:

Exercise and good sleep hygiene may improve subjective cognitive symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Rees et al, 2009].

There is evidence that smoking cigarettes and having a body mass index of more than 30 kg/m2 increases the likelihood of flushing.

The Royal College of Obstetricians and Gynaecologists has advised that women who are more active tend to suffer less from the symptoms of the menopause, and that the best type of exercise is aerobic, sustained, regular exercise such as swimming and running [RCOG, 2010]. However, a Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials, on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011].

Advice about benefits of HRT

What advice should I give about the benefits of hormone replacement therapy?

Hormone replacement therapy (HRT) is effective for:

Treating vasomotor symptoms (for example hot flushes and night sweats).

Treating urogenital symptoms (for example vaginal dryness, dyspareunia as a result of vaginal dryness, recurrent urinary tract infections, and urinary frequency and urgency).

Managing sleep or mood disturbances caused by hot flushes and night sweats.

Preventing osteoporosis.

However, due to the risks associated with long-term use, HRT is not normally used as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age, except when other treatments are contra-indicated, not tolerated, or ineffective.

There is no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer.

HRT has no role in the prevention or treatment of cardiovascular disease.

Basis for recommendation

Basis for recommendation

Hot flushes and night sweats

Good evidence indicates that oral or transdermal hormone replacement therapy (HRT), used as oestrogen alone or oestrogens combined with progestogens, is highly effective for reducing the frequency and severity of hot flushes and night sweats caused by the menopause.

Vaginal atrophy (dryness and dyspareunia)

There is evidence that HRT preparations (combined oral and transdermal oestrogens and progestogens, or intravaginal oestrogens) are effective for treating vaginal atrophy (dryness, burning, itching, and dyspareunia).

Recurrent urinary tract infection (UTIs)

Evidence from one systematic review suggests that oral and intravaginal oestrogen are effective for preventing UTIs, although some experts believe that this effect is only seen with intravaginal oestrogens [Rees et al, 2009]:

Recurrent UTIs may be prevented by treatment with vaginal but not oral HRT.

Long-term treatment may be required because symptoms recur when treatment is stopped.

Sleep disturbances

There is evidence that combined oral oestrogen and progestogen therapy provides a small statistically but not clinically meaningful improvement in sleep disturbances.

Incontinence

The British Menopause Society currently recommends the use of systemic or topical oestrogen for urinary frequency and urgency [Rees, 2011] although the evidence to support the use of oestrogens is conflicting.

A Cochrane systematic review found evidence that urinary incontinence may be improved with the use of local oestrogen treatment [Cody et al, 2012]. However, a previously published analysis of the Women's Health Initiative trial found that oestrogen therapy (alone and combined with progestogen therapy) increased the risk of urinary incontinence among continent women and worsened urinary incontinence among symptomatic women after 1 year [Hendrix et al, 2005].

Mood disorders

There is no evidence indicating that HRT has a direct effect on mood, irritability, or anxiety. However, experts suggest that if psychotherapy and antidepressants are ineffective, HRT may be appropriate for treating depression at the onset of menopause [SOGC, 2009].

Libido

In addition to relieving hot flushes and improving sleep, HRT improves urogenital atrophy, thinning, dryness, and loss of elasticity, all of which may cause dyspareunia. Libido may be improved with oestrogen alone but the addition of testosterone may be necessary, especially in young, oophorectomized women [Rees et al, 2009; Rees, 2011].

Osteoporosis

Evidence from a large Cochrane systematic review (search date: February 2012) shows that HRT is effective for the prevention of postmenopausal osteoporosis [Marjoribanks et al, 2012]; however, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen treatments are unsuitable.

The Medicines and Healthcare products Regulatory Agency (MHRA) and its independent adviser, the Commission on Human Medicines, warns that because of the risks associated with long-term use, 'HRT should be used for prevention of osteoporosis only in women who are unable to use other medicines that are authorized for this purpose' [MHRA and CHM, 2007b].

The British National Formulary adds that HRT is an option where other treatments are contra-indicated, cannot be tolerated, or if there is a lack of response. HRT should not be considered as first-line treatment for long-term prevention of osteoporosis in women over 50 years of age [BNF 65, 2013].

Colorectal cancer

Although some studies have demonstrated a lower risk of colon cancer in women treated with combined HRT [Writing Group for the Women's Health Initiative Investigators, 2002], a recent large Cochrane systematic review (search date: February 2012) found no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer [Marjoribanks et al, 2012].

Current evidence does not allow recommendation of HRT to prevent colorectal cancer [Rees et al, 2009; Goodman et al, 2011].

Cardiovascular disease

Evidence from a recent Cochrane systematic review (search date: April 2010) suggests that treatment with HRT has no role in the prevention or treatment of CVD in post-menopausal women. In fact, HRT causes an increase in the risk of stroke and venous thromboembolism (VTE). Furthermore, combination HRT is associated with an increased risk of non-fatal myocardial infarction [Main et al, 2013].

An open-label randomized controlled trial investigated the long-term effect of HRT on cardiovascular outcomes in recently postmenopausal women [Schierbeck et al, 2012]. This trial found evidence that after 10 years of randomized treatment, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction, without any apparent increase in risk of cancer, VTE, or stroke. However, further trials are needed.

Advice about the possible risks of HRT

What advice should I give about the possible risks of hormone replacement therapy?

For combined hormone replacement therapy (HRT), advise that:

There is a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), and stroke. See Table 1 for more information.

There is also a small absolute increased risk of gallbladder disease requiring hospital admission, death from lung cancer, and dementia (in women aged over 65 years).

There is some evidence suggesting that combined HRT may be associated with an increased risk of ovarian cancer.

For oestrogen-only HRT, advise that:

There is a small absolute increased risk of VTE, stroke, and endometrial cancer. See Table 2 for more information.

There is also a small absolute increased risk of gallbladder disease requiring hospital admission.

There is some evidence suggesting that oestrogen-only HRT may be associated with an increased risk of ovarian cancer.

Oestrogen-only HRT does not appear to significantly increase the risk of breast cancer.

Table 1 . Combined HRT compared with placebo in postmenopausal women.
Outcomes Follow-up Absolute risk (95% CI) Relative risk (95% CI)
Placebo Combined HRT
Coronary events (MI or cardiac death)* 1 year 2 per 1000 4 per 1000 (95% CI 3 to 7) 1.89 (1.15 to 3.1)
VTE (DVT or PE) 1 year 2 per 1000 7 per 1000 (95% CI 4 to 11) 4.28 (2.49 to 7.34)
Coronary events (MI or cardiac death)* 5.6 years 18 per 1000 22 per 1000 (95% CI 18 to 27) 1.22 (0.98 to 1.52)
Stroke* 5.6 years 13 per 1000 18 per 1000 (95% CI 14 to 23) 1.38 (1.08 to 1.75)
Breast cancer (combined continuous HRT) 5.6 years 19 per 1000 23 per 1000 (95% CI 19 to 29) 1.26 (1.02 to 1.56)
* Only 33% of study sample were aged 50-59 years at baseline (i.e. the age women most likely to consider HRT for vasomotor symptoms); mean participant age was 63 years. Ovarian cancer: a systematic review of (mainly) observational studies [Greiser et al, 2007] suggests that combined HRT may be associated with an increased risk of ovarian cancer. MI: myocardial infarction; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism
Data adapted from: [Marjoribanks et al, 2012]
Table 2 . Oestrogen-only HRT compared with placebo in postmenopausal women.
Outcomes Follow-up Absolute risk (95% CI) Relative risk (95% CI)
Placebo Oestrogen only HRT
Coronary events (MI or cardiac death)* 7.1 years 41 per 1000 38 per 1000 (95% CI 32 to 46) 0.94 (95% CI 0.78 to 1.13)
Stroke* 7.1 years 23 per 1000 32 per 1000 (95% CI 25 to 40) 1.34 (95% CI 1.07 to 1.68)
VTE (DVT or PE)* 7.1 years 16 per 1000 21 per 1000 (95% CI 16 to 28) 1.32 (95% CI 1 to 1.74)
Breast cancer* 7.1 years 30 per 1000 24 per 1000 (95% CI 19 to 31) 0.79 (95% CI 0.61 to 1.01)
* Only 33% of study sample were aged 50-59 years at baseline (i.e. the age women most likely to consider HRT for vasomotor symptoms); mean participant age was 63 years. Endometrial cancer is a well documented adverse effect of unopposed oestrogen in women with a uterus, although current evidence does not show a statistically significant difference between oestrogen-only HRT and placebo for this outcome. However, the women in the included studies were closely monitored for endometrial hyperplasia if they had a uterus. Ovarian cancer: a systematic review of (mainly) observational studies [Greiser et al, 2007] suggests that combined HRT may be associated with an increased risk of ovarian cancer. MI: myocardial infarction; VTE: venous thromboembolism; DVT: deep vein thrombosis; PE: pulmonary embolism
Data adapted from: [Marjoribanks et al, 2012]

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on a large Cochrane systematic review (search date: February 2012) which assessed the evidence on the effects of long-term hormone replacement therapy (HRT) on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women (average age of 60 years), both during HRT use and after stopping HRT use [Marjoribanks et al, 2012].

Combined HRT

The evidence showed a small absolute increased risk of breast cancer, coronary event (myocardial infarction [MI] or cardiac death), venous thrombo-embolism (VTE), stroke, gallbladder disease requiring hospital admission, death from lung cancer, ovarian cancer, and dementia (in women aged over 65 years).

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review) [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Oestrogen-only HRT

The evidence showed a small absolute increased risk of VTE and stroke.

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Although the Cochrane systematic review showed no statistically significant difference between oestrogen-only HRT and placebo for endometrial cancer, endometrial cancer is a well documented adverse effect of unopposed oestrogen in women with a uterus [Rees et al, 2009; Marjoribanks et al, 2012].

Management of premature menopause

How should I manage premature menopause?

When prescribing hormone replacement therapy (HRT), discuss the most suitable type of product with the woman.

Follow up the woman after 3 months initially, and once she is settled on the treatment, follow up annually.

Consider referral if treatment is unsuccessful or there are 'red flag' symptoms such as unexplained bleeding.

Reassess the need for HRT after the age of the natural menopause.

Management of premature menopause

How can I manage women with a premature menopause?

For the purposes of this guideline, premature menopause is menopause which occurs in women younger than 45 years of age.

Refer women who are younger than 40 years of age to a gynaecologist.

Offer lifestyle advice.

Offer systemic oestrogen replacement therapy; systemic hormone replacement therapy (HRT) or the combined oral contraceptive pill (COC) may be used.

HRT: the HRT regimen used will depend on whether or not the woman has undergone a hysterectomy, still has some ovarian activity, and still has periods.

For women who are still having periods, offer combined, systemic (oral or transdermal), cyclical HRT. For women with infrequent periods or women who cannot tolerate progestogens, a systemic 3-monthly regimen may be preferred.

For women who have had a hysterectomy, offer oral or transdermal unopposed oestrogen replacement therapy.

COC: the decision to prescribe the COC will depend on the woman's age and the presence of associated risk factors (for example smoking).

Advise the woman that she may still become pregnant if contraception is not used.

See the Scenario: Approaching the menopause in the CKS topic on Contraception - assessment for a detailed discussion on the choice and duration of contraception in perimenopausal women.

Testosterone implants and patches (licensed) may be considered for treating decreased libido (especially in oophorectomized women); however, seek specialist advice before prescribing these.

Basis for recommendation

Basis for recommendation

These recommendations are based on advice issued by the Commission on Human Medicine (formerly the Committee on Safety of Medicines) [CSM, 2003a] and on information from a textbook: Management of the menopause [Rees et al, 2009]. In addition, expert reviewers of this CKS topic recommend that women less than 40 years of age should be referred for investigation to determine the cause of premature menopause (for example primary ovarian failure) and to discuss fertility if appropriate. Women who have primary ovarian failure may continue to ovulate infrequently and require advice on appropriate contraception.

Hormone replacement therapy (HRT)

Women who have premature menopause require treatment to prevent osteoporosis and to treat menopausal symptoms. There is evidence that HRT reduces the risk of hip fracture, as well as other osteoporotic fractures.

Hysterectomized women should be given oestrogen alone as there is no need for progestogen. Furthermore, combined HRT may entail a greater risk of breast cancer than with oestrogen alone [Rees et al, 2009]. In non-hysterectomized women, progestogens are added to oestrogen therapy to reduce the risk of endometrial hyperplasia and carcinoma which occurs with unopposed oestrogen [Rees et al, 2009].

The combined oral contraceptive (COC) containing oestrogen and progestogen

The COC is often prescribed for younger women because it does not have the stigma of old age that HRT may have. However, trial evidence on when to recommend treatment with a COC is limited [Rees et al, 2009; SOGC, 2009]. The COC is perhaps more useful when contraception is still thought to be required (ovulation can occur for several years after premature ovarian failure in some women).

The dose of ethinylestradiol used in standard pills is sufficient to provide control of menopausal symptoms and osteoporosis prophylaxis; however, oral contraceptives provide oestrogen for only 3 weeks in every 4 (the fourth week being pill-free). For women who are oestrogen deficient, the lack of oestrogen during this pill-free week can cause symptoms, and it may be more appropriate to provide oestrogen continuously, as with most forms of HRT.

Testosterone

There is evidence that loss of libido can be improved by testosterone supplementation, particularly after surgical menopause. Treatment is not always successful, as other factors such as marital problems may be involved, and testosterone may cause potentially serious adverse effects [Rees et al, 2009].

Follow-up

What follow-up is required?

Review 3 months after starting hormone replacement therapy (HRT) and once the woman is settled on treatment, follow up annually.

At the initial 3-month review:

Assess the effectiveness of treatment and if necessary, adjust treatment to achieve better symptom control. See Scenario: Poor symptom control on HRT for more information.

Enquire about any adverse effects and manage appropriately. See Scenario: Managing adverse effects of HRT for more information.

Check blood pressure and body weight.

Stop HRT immediately if blood pressure is above systolic 160 mmHg or diastolic 95 mmHg.

Once each year, repeat the above checks and also:

Interrupt treatment with intravaginal oestrogen to re-assess the need for continued use.

Re-assess the need for continuing systemic HRT. Explain that some of the risks associated with HRT increase with longer duration of use. See Advice about the possible risks of HRT for more information.

Perform a breast examination if indicated by personal or family history. Encourage breast awareness and participation in the national breast screening programme as appropriate for their age.

Perform a pelvic examination if clinically indicated (for example if there is unscheduled bleeding, especially if heavy, prolonged, or recurrent). Encourage participation in the national cervical screening programme.

Measurement of oestrogen levels (estradiol) is rarely indicated.

However, if the clinical response to HRT is poor (that is, poor symptomatic relief), measurement of oestrogen levels may be used:

To establish whether absorption of transdermal HRT is adequate in women in whom poor absorption is suspected. If poor absorption is confirmed, prescribe oral HRT.

Rarely, in women with persisting symptoms where poor compliance is suspected.

Measurement of follicle stimulating hormone level is not indicated.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in review articles [RCPE, 2003; Roberts, 2007; Goodman et al, 2011; Menopause Matters, 2011b] and a textbook [Rees et al, 2009], the British National Formulary [BNF 65, 2013], and information published by the Commission on Human Medicines, formerly the Committee on Safety of Medicines [CSM, 2003a].

Initial and annual review

An initial review is recommended at 3 months, as most menopausal symptoms respond by then. When the woman is settled on treatment, an annual review is recommended because the risks and benefits of HRT for each woman change over time and need to be discussed regularly [Menopause Matters, 2011b].

Treatment should be interrupted at least annually to re-assess the need for continued treatment. If breakthrough bleeding or spotting appears at any time on therapy, the reason should be investigated and may include endometrial biopsy to exclude endometrial malignancy [CSM, 2003a].

Rarely, conjugated equine oestrogens may cause severe hypertension that returns to normal when treatment is stopped [Rees et al, 2009]. The British National Formulary lists blood pressure above systolic 160 mmHg or diastolic 95 mmHg as one of several reasons to stop HRT immediately [BNF 65, 2013].

Measurement of oestrogen

This recommendations is based on Best Practice in primary care pathology [Smellie et al, 2006].

Measurement of follicle-stimulating hormone (FSH)

FSH should not be measured because it does not reflect the adequacy of the oestrogen dose and levels may remain increased despite an adequate oestrogen effect [Goodman et al, 2011].

Referring a woman who has started HRT

When should I refer a women with premature menopause who has started hormone replacement therapy?

For women taking cyclical hormone replacement therapy (HRT), refer if:

There is a change in pattern of withdrawal bleeds or breakthrough bleeding.

For women taking long cycle regimens, refer if:

Breakthrough bleeding persists for more than 4–6 months after starting therapy.

A bleed occurs after amenorrhoea.

Refer if there is multiple treatment failure, for example three or more regimens have been tried.

Refer to a team specializing in the management of gynaecological cancer (depending on local arrangements), any persistent or unexplained bleeding after cessation of HRT for 6 weeks.

Basis for recommendation

Basis for recommendation

These recommendations are based on expert opinion in a textbook [Rees et al, 2009].

Abnormal bleeding requires investigation if [Rees et al, 2009]:

The pattern of withdrawal bleeding or breakthrough bleeding changes while taking monthly cyclical therapy.

There is breakthrough bleeding that persists for more than 4–6 months or does not lessen while taking a 3-monthly regimen.

Stopping HRT

When should I consider stopping hormone replacement therapy?

Women with premature menopause usually take hormone replacement therapy (HRT) up to the average age of the natural menopause (52 years); at that time, therapy is reassessed. Some women will still be symptomatic.

However, be aware that HRT may need to be stopped immediately (depending on clinical judgement and pending investigation and treatment) if any of the following occur:

Sudden severe chest pain (even if not radiating to left arm).

Sudden breathlessness (or cough with blood-stained sputum).

Unexplained swelling or severe pain in calf of one leg.

Severe stomach pain.

Serious neurological effects, including unusual severe, prolonged headache, especially:

If it is the first time, or getting progressively worse, or

There is sudden partial or complete loss of vision, or

Sudden disturbance of hearing or other perceptual disorders, or

Dysphasia, or

Bad fainting attack or collapse, or

First unexplained epileptic seizure, or

Weakness, motor disturbances, or very marked numbness suddenly affecting one side or one part of body.

Hepatitis, jaundice, or liver enlargement.

Blood pressure above systolic 160 mmHg or diastolic 95 mmHg.

Prolonged immobility after surgery or leg injury.

Detection of a risk factor which contra-indicates treatment (see Contraindications).

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on pragmatic advice and published expert opinion in a textbook [Rees et al, 2009]. The information on when to stop hormone replacement therapy immediately is based on the British National Formulary [BNF 65, 2013].

Scenario: Poor symptom control on HRT

Scenario: Poor symptom control on hormone replacement therapy for menopause

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Poor symptom control with HRT

What should I do if there is poor symptom control with hormone replacement therapy?

Review the woman:

Check that the hormone replacement therapy (HRT) has been used as recommended for at least 3 months to ensure full effect.

If applicable, check that patches are adherent.

Review the woman's expectations. HRT can help reduce symptoms due to oestrogen deficiency, but it is not an answer to all problems.

Consider an alternative diagnosis. See Differential diagnosis.

Treatment options include:

Increasing the oestrogen dose.

Adding vaginal oestrogen, if urogenital symptoms are not controlled.

Switching from oral to a non-oral route of administration (for example if absorption is poor owing to a bowel disorder, or if a drug interaction is present).

Switching delivery system, if patch adhesion is poor.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009].

Scenario: Managing adverse effects of HRT

Scenario: Managing adverse effects of hormone replacement therapy for menopause

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Oestrogen-related adverse effects

How do I manage oestrogen-related adverse effects?

Oestrogen-related adverse effects (such as fluid retention, bloating, breast tenderness or enlargement, nausea, headaches, leg cramps, and dyspepsia) may occur continuously or randomly throughout the cycle.

Encourage the woman to persist with treatment for 3 months (as adverse effects may resolve):

Leg cramps can improve with lifestyle changes, including exercise and regular stretching of the calf muscles.

Nausea/gastric upset may be helped by adjusting the timing of the oestrogen dose or taking with food.

Breast tenderness may be alleviated by a low-fat, high-carbohydrate diet. Gamolenic acid (evening primrose oil) is no longer available as a licensed medicinal product because of lack of efficacy.

Migraine triggered by fluctuating oestrogen levels may respond to transdermal therapy, as this produces more stable oestrogen levels.

For persistent adverse effects, consider:

Reducing the dose of oestrogen or

Changing the oestrogen type (that is, swapping between the two main forms of oestrogen [estradiol and conjugated oestrogens]) or

Changing the route of delivery (for example tablets may cause nausea, but patches and gels generally do not).

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Goyal, 2011; Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009]. The recommended management strategies have not been assessed in clinical trials.

Progestogen related adverse effects

How do I manage progestogen-related adverse effects (other than bleeding)?

Progestogen-related adverse effects tend to occur in a cyclical pattern during the progestogen phase of cyclical hormone replacement therapy (HRT). They include fluid retention, breast tenderness, headaches or migraine, mood swings, depression, acne, lower abdominal pain, and backache.

Encourage the woman to persist with treatment for about 3 months to await possible resolution of adverse effects.

For persistent or troublesome symptoms, consider the following options (many of which are the opposite of what may be needed to better control bleeding):

Changing the progestogen type, for example from more androgenic ones (such as norethisterone and norgestrel) to less androgenic ones (such as medroxyprogesterone or dydrogesterone).

Changing the route of progestogen delivery, for example from oral to transdermal, vaginal, or intrauterine progestogen. This may be most beneficial for women who experience nausea with oral HRT.

Reducing the duration of progestogen administration. Progestogens can be taken for 10–14 days of each monthly sequential regimen, so swapping from a 14-day to a 10-day product may provide benefit.

Changing to a product with a lower dose of progestogen (doses are preparation dependent).

Reducing the frequency of progestogen dosing. This can be achieved by switching to a long-cycle regimen of administering progestogen for 14 days every 3 months (but this strategy is only suitable for women without natural regular periods).

Changing to continuous combined therapy or tibolone often reduces progestogenic adverse effects with established use, but these options are only suitable for postmenopausal women.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009].

Bleeding on monthly cyclical regimens

How do I manage bleeding on monthly cyclical regimens?

Monthly cyclical regimens should produce regular predictable bleeding starting towards or soon after the end of the progestogen phase.

It is mandatory to investigate unexplained bleeding before changing treatment, to exclude pelvic pathology. Before changing treatment:

Visualize the cervix, check smears are up to date, and refer for transvaginal ultrasound to exclude pelvic abnormalities.

Check for compliance with treatment, drug interactions (for example with anticonvulsants), or gastrointestinal upset (which can interfere with absorption).

Altering the progestogen part of the regimen may improve bleeding problems:

For heavy or prolonged bleeding: increase the duration or dose of the progestogen, or change the type of progestogen. Idiopathic menorrhagia may be helped by using the levonorgestrel-releasing intrauterine system (Mirena®) combined with an oestrogen delivered orally or transdermally.

For bleeding early in the progestogen phase: increase dose or change the type of progestogen.

For irregular bleeding: change the treatment regimen or increase the dose of progestogen.

The absence of bleeding whilst taking a cyclical regimen reflects an atrophic endometrium and occurs in 5% of women.

Exclude pregnancy in perimenopausal women or women with ovarian failure.

Check compliance if the progestogen component is taken separately.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009].

Monthly cyclical regimens should produce regular predictable bleeding starting towards or soon after the end of the progestogen phase. Unpredictable or unacceptable bleeding may be due to non-adherence to therapy, drug interactions, or gastrointestinal upset (or cancer, if not already excluded) [Rees et al, 2009].

Changing treatment before examination is unsafe practice and can lead to delayed diagnosis of endometrial cancer or other pelvic pathology [Rees et al, 2009].

Bleeding on continuous or long cycle HRT

How do I manage bleeding on continuous combined or during long cycle hormone replacement therapy regimens?

Irregular breakthrough bleeding or spotting is common in the first 4–6 months of continuous combined hormone replacement therapy.

Bleeding beyond 6 months or after a spell of amenorrhoea requires further investigation or referral.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion [Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009].

How to manage weight gain

How do I manage weight gain?

Reassure the woman that weight gain is very common around the time of the menopause and that hormone replacement therapy does not cause significant further weight gain.

Basis for recommendation

Basis for recommendation

This recommendation is based on published expert opinion [Kongnyuy et al, 1999; Menopause Matters, 2011a] and information in a textbook [Rees et al, 2009].

In addition, there is some evidence that the tendency towards central abdominal obesity is ameliorated by oestrogen therapy. Studies generally indicate a reduction in overall fat mass, improved insulin sensitivity, and a lower rate of development of type 2 diabetes with hormone replacement therapy (oestrogen only and combined) [Davis et al, 2012].

Scenario: Managing the menopause without HRT

Scenario: Managing the menopause without hormone replacement therapy

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Management without HRT

How can I manage menopausal symptoms without hormone replacement therapy?

Offer lifestyle advice to control symptoms. If this is not effective, consider other treatments.

For vasomotor symptoms, consider:

A 2 week trial of paroxetine (20 mg daily), fluoxetine (20 mg daily), citalopram (20 mg daily), or venlafaxine (37.5 mg twice a day).

Note that antidepressants are not licensed for treating menopausal symptoms.

A 2–4 week trial of clonidine (50 to 75 micrograms twice a day, licensed use).

A progestogen such as norethisterone or megestrol (both off-label use) — seek specialist advice if this option is being considered.

For vaginal dryness, prescribe a vaginal lubricant or moisturizer, such as Replens MD®.

Manage psychological symptoms, such as mood disturbances, anxiety, and depression, on an individual basis. They may be addressed by using self-help groups, psychotherapy, other forms of counselling; or antidepressants. For more information, see the CKS topics on Depression and Generalized anxiety disorder.

CKS does not recommend the use of herbal or complementary therapies (for example soy, red clover, and black cohosh). If complementary or herbal products are being used, advise the woman that:

The efficacy of these products has not yet been established.

There is very little control over the quality of the products available, which may vary considerably.

Some of these treatments (for example ginseng, black cohosh, and red clover) have oestrogenic properties and should not be used by women with contraindications to oestrogen (for example women who have had breast cancer).

The long-term safety of these products (for example their effects on the breast and endometrium) have not been assessed.

Some treatments may have serious adverse effects (for example liver toxicity has been reported with black cohosh and kava [which has been withdrawn from the UK market]).

Dong quai extracts and some species of red clover contain coumarins, which make them unsuitable for women taking anticoagulants.

Basis for recommendation

Basis for recommendation

These recommendations are based on information published by the Commission on Human Medicines, formerly known as the Committee on Safety of Medicines [CSM, 2003b; CSM, 2004], a guideline published by the Royal College of Obstetricians and Gynaecologists [RCOG, 2010], and a textbook [Rees et al, 2009].

Progestogens

There is evidence that progestogens are effective for treating hot flushes. However, the clinical usefulness of progestogens given alone for vasomotor symptoms is limited by the unwanted adverse effects of the relatively high doses needed to relief of menopausal symptoms, and long term safety data are lacking.

Antidepressants

Limited evidence indicates that venlafaxine, fluoxetine, citalopram, and paroxetine are effective for treating hot flushes. They are not licensed for this use, but may be considered for treating women who cannot or do not want to take hormone replacement therapy [RCOG, 2010; Rees, 2011].

When effective, antidepressants provide relief from hot flushes almost immediately. A one-week trial is generally sufficient to determine whether an antidepressant is going to be effective [UKMi, 2011].

Clonidine

Clonidine is licensed for the treatment of vasomotor symptoms. However, there is limited evidence of its efficacy, and it may cause unacceptable adverse effects (for example dry mouth, sedation, depression, and fluid retention) [Rees et al, 2009; BNF 65, 2013].

The manufacturer states that it may take 2 to 4 weeks for clonidine to be fully effective [ABPI Medicines Compendium, 2013a].

Complementary and herbal therapies

There is no convincing evidence that complementary therapies are effective for managing menopausal symptoms. Prospective randomized controlled trials are required to confirm the efficacy and long-term safety of these therapies.

The Medicines and Healthcare products Regulatory Agency (MHRA) warns that the phrases 'natural', 'herbal', and 'derived from plants' do not necessarily mean that the product is 'safe'. Herbal medicines, like other medicines, can have adverse effects. They can also interact with other medicines, resulting in reduced or enhanced effects. For further information, see www.mhra.gov.uk/safetyinformation [MHRA, 2012].

Other treatments

Gabapentin:

Limited evidence indicates that gabapentin is effective for reducing hot flushes; further work is being done to confirm this. The use of gabapentin for this indication is restricted to specialist centres [RCOG, 2010].

Beta-blockers:

Beta-blockers should not be used to treat menopausal symptoms because their effectiveness for this indication has not been established [Rees et al, 2009; RCOG, 2010].

Lifestyle advice for menopausal symptoms

What lifestyle advice can I give for menopausal symptoms?

Encourage all women to make lifestyle modifications to reduce menopausal symptoms:

For hot flushes and night sweats, advise:

Taking regular exercise.

Wearing lighter clothing and sleeping in a cooler room.

Reducing stress.

Avoiding possible triggers, such as spicy foods, caffeine, smoking, and alcohol.

For sleep disturbances:

Avoiding exercise late in the day and maintaining a regular bedtime may improve sleep.

For mood and anxiety disturbances:

Adequate sleep, regular physical activity, and relaxation exercises may help.

For cognitive symptoms:

Exercise and good sleep hygiene may improve subjective cognitive symptoms.

Basis for recommendation

Basis for recommendation

These recommendations are based mainly on expert opinion in a textbook [Rees et al, 2009].

There is evidence that smoking cigarettes and having a body mass index of more than 30 kg/m2 increases the likelihood of flushing.

The Royal College of Obstetricians and Gynaecologists has advised that women who are more active tend to suffer less from the symptoms of the menopause, and that the best type of exercise is aerobic, sustained, regular exercise such as swimming and running [RCOG, 2010]. However, a Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials (RCTs) on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011].

Follow up

What follow up is required?

Advise the woman to return if:

Lifestyle measures alone have been insufficient, or her symptoms have worsened.

She does not respond to antidepressant treatment within 2 weeks.

She does not respond to clonidine treatment within 4 weeks, or she is experiencing adverse effects such as dizziness or constipation.

Review all women at least annually.

Basis for recommendation

Basis for recommendation

There is no published guidance on when to follow up menopausal women who are being treated with alternatives to hormone replacement therapy. These recommendations are pragmatic advice based on the fact that:

Women who are going to respond to antidepressants generally do so within 1–2 weeks [UKMi, 2011].

It may take 2 to 4 weeks for clonidine to be fully effective [ABPI Medicines Compendium, 2013a].

When to consider stopping treatment

When should I consider stopping treatment?

Consider stopping treatment if a woman is symptom-free on treatment; a trial withdrawal can be done after 1–2 years of treatment.

Advise that symptoms sometimes recur once treatment is stopped.

Use of vaginal moisturizers and lubricants may be continued indefinitely.

Basis for recommendation

Basis for recommendation

There is no published guidance on the duration of therapy for alternatives to hormone replacement therapy, therefore these recommendations are pragmatic.

Vasomotor symptoms usually resolve within 2–5 years [Rees et al, 2009].

Scenario: Managing women with comorbidities

Scenario: Managing women with comorbidities in menopause

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Current or previous endometrial cancer

How should I manage a woman with current or previous endometrial cancer?

Initially, offer lifestyle advice or non-hormonal therapies (see Scenario: Managing the menopause without HRT).

If these are inadequate and the woman requires treatment, seek specialist advice from an oncologist or a specialist menopause clinic regarding the most appropriate treatment.

In secondary care, management usually depends on the stage of the cancer. Treatment with hormone replacement therapy is usually limited to women with stage I disease, although women with stage II disease are occasionally treated.

In stage I endometrial cancer, specialists may advise that oestrogens can sometimes be used. Progestogens (combined with oestrogen or alone) may also be used.

Basis for recommendation

Basis for recommendation

This recommendation is based on published expert opinion [Mueck and Seeger, 2003; SOGC, 2009].

Thromboembolic disease or known thrombophilia

How should I manage a woman with a personal or family history of thromboembolic disease or with a known thrombophilia disorder?

Initially, offer lifestyle advice or non-hormonal therapies (see Scenario: Managing the menopause without HRT).

If these measures are inadequate and the woman requires treatment, refer to a specialist in thrombophilia.

Basis for recommendation

Basis for recommendation

These recommendations are based on a guideline published by the Royal College of Obstetricians and Gynaecologists (RCOG) [RCOG, 2011].

Although the mechanism is unclear, it is thought that oral hormone replacement therapy (HRT) provokes an increased risk of venous thromboembolism (VTE).

Limited evidence suggests that a substantial risk of VTE may relate only to oral and not to transdermal preparations. This may be because oral preparations undergo first-pass hepatic metabolism and therefore have a greater effect on factors produced by the liver than transdermal preparations, which avoid the first-pass effect.

The available evidence suggests that the risks of VTE in association with HRT may be influenced by the type of preparation, dose, and the duration of its use:

There is a greater risk of VTE in the first year of use than in subsequent years, and a lack of continuing risk in those who have stopped HRT.

The RCOG advises that women with a personal or family history of thromboembolic disease should avoid oral HRT due to the relatively high risk of recurrent VTE.

Ideally, alternatives to oral HRT should be recommended; however, if HRT is desirable, transdermal therapy may be considered, but specialist advice should be sought.

Oral HRT may be considered if it is taken with anticoagulation therapy; however, the risk of haemorrhage must be considered in the risk–benefit analysis. On standard anticoagulant thromboprophylaxis, major haemorrhage occurs at a rate of around 1% per year of treatment and 25% of these bleeds are fatal.

Current or previous breast cancer

How should I manage a woman with current or previous breast cancer?

Initially, offer lifestyle advice or non-hormonal therapies (see Scenario: Managing the menopause without HRT).

If these measures are inadequate and the woman requires treatment with hormone replacement therapy:

For a woman with a significant family history of breast cancer, refer to a specialist breast clinic to determine her personal risk, without which an informed decision cannot be made.

For women with current or previous breast cancer, seek specialist advice from an oncologist or a specialist menopause clinic.

Basis for recommendation

Basis for recommendation

These recommendations are based on published expert opinion in a textbook [Rees et al, 2009] and a consensus document published by the Royal College of Physicians of Edinburgh [RCPE, 2003].

Hormone replacement therapy (HRT) remains contraindicated in women who have had breast cancer [Rees et al, 2009].

Troublesome symptoms of oestrogen deficiency are common in women receiving treatment for breast cancer. HRT has been given with tamoxifen but should be avoided in women taking aromatase inhibitors (such as anastrozole) [RCPE, 2003].

A Clinical Evidence review (search date: June 2010) found high-quality evidence which showed that compared with placebo, tibolone is associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer [Burbos and Morris, 2011].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Hormone replacement therapy (HRT)

Types available

What types of HRT are available?

Oestrogen-only preparations include:

Oral tablet (daily).

Transdermal patch (once weekly or twice weekly) or gel (daily).

Vaginal ring (Estring®), creams, and pessaries.

Combined oestrogen–progestogen preparations include:

Oral tablet (daily).

Transdermal patch (once weekly or twice weekly):

In transdermal combined hormone replacement therapy (cyclical or continuous) the progestogen is either combined into the patch or given separately as a tablet.

[BNF 65, 2013]

Type of product to offer

Which type of hormone replacement therapy product should I offer?

Choice of hormone

Which hormone should I use?

Choice of systemic oestrogen:

'Natural' oestrogens, such as conjugated oestrogen, estradiol, estrone, and estriol, are more suitable for use as systemic hormone replacement therapy (HRT) than the synthetic oestrogens ethinylestradiol and mestranol.

For the purposes of this guideline, 'natural oestrogen' is defined as one that is found in normal physiology, irrespective of whether it has been prepared by chemical synthesis or extraction from a plant or animal source.

Choice of vaginal oestrogen:

Low-dose natural oestrogens, such as estriol (cream or pessary) or estradiol (tablet or ring) preparations, are suitable for vaginal use. Endometrial effects should not be incurred. A progestogen is not needed with such low-dose preparations.

Synthetic or conjugated oestrogens should be avoided as they are well absorbed from the vagina and may potentially result in endometrial stimulation.

Choice of progestogen:

The progestogens most commonly used in HRT are almost all synthetic and include:

Dydrogesterone and medroxyprogesterone.

Norethisterone and levonorgestrel.

Drospirenone.

Women vary in their tolerance to progestogens.

Medroxyprogesterone and dydrogesterone are sometimes better tolerated than norethisterone or levonorgestrel because they are less androgenic.

Drospirenone is also considered to be less androgenic and has aldosterone antagonistic activities. It is useful for women who complain of fluid retention during the progestogen phase.

Combined HRT tablets contain medroxyprogesterone, dydrogesterone, or drospirenone (less androgenic); or norethisterone, or levonorgestrel (more androgenic).

Combined HRT patches only contain norethisterone or levonorgestrel (more androgenic). There are currently no patches containing less androgenic progestogens.

The levonorgestrel-releasing intrauterine system (IUS) (Mirena®) is an alternative route of delivery of progestogen to protect the endometrium. Since levonorgestrel is delivered locally to the uterus, a much lower daily dose is used, which also results in low systemic levels of levonorgestrel. See Route for more information on when to consider the levonorgestrel-releasing IUS.

Tibolone is a synthetic steroidal compound with oestrogenic, progestogenic, and androgenic activity. It may be used as an alternative to combined HRT for postmenopausal women who wish to have amenorrhoea.

Tibolone is not suitable for use in the perimenopause or within 12 months of the last menstrual period.

Testosterone supplementation (patches and implants) can improve loss of libido, particularly after surgical menopause. Treatment is not always successful, as other factors such as marital problems may be involved, and testosterone may cause potentially serious adverse effects.

Testosterone patches are licensed for women with surgically induced menopause (in women receiving concomitant oestrogen therapy), but they are not recommended for women naturally menopausal or those taking conjugated oestrogens. Safety and efficacy of testosterone patches have not been established beyond 1 year of treatment.

Basis for recommendation

These recommendations are based on the British National Formulary [BNF 65, 2013] and on expert opinion in a textbook [Rees et al, 2009].

Synthetic oestrogens, such as mestranol or ethinylestradiol, are generally considered not to be suitable for hormone replacement therapy (HRT), except in women with early ovarian failure, because of their greater metabolic impact [Rees et al, 2009].

The levonorgestrel-releasing intrauterine system (Mirena®) provides adequate endometrial protection (delivers 20 micrograms of levonorgestrel daily to the endometrium). Oestrogen can then be given orally or transdermally [Rees et al, 2009].

Regimen

Which regimen should I use?

Offer oestrogen-only hormone replacement therapy (HRT) to women who do not have a uterus (usually taken continuously).

Offer combined (oestrogen and progestogen) HRT to women with an intact uterus:

Combined hormone replacement therapy can be prescribed as:

Monthly cyclical regimens — oestrogen is taken daily and progestogen is given at the end of the cycle for 10–14 days.

Three-monthly cyclical regimens — oestrogen is taken every day and progestogen is given for 14 days every 13 weeks.

Continuous combined regimens — oestrogen and progestogen are taken every day.

For perimenopausal women, monthly or 3-monthly cyclical regimens may be used:

A 3-monthly regimen may be more suitable for women with infrequent periods or who are intolerant to progestogens.

A monthly regimen produces monthly bleeding whilst a 3-monthly regimen produces a bleed every three months.

For postmenopausal women, monthly or 3-monthly cyclical regimens, or continuous combined regimens may be used. Continuous combined regimens may be preferred because they do not produce withdrawal bleeding:

Continuous combined HRT may produce irregular bleeding or spotting for the first 4–6 months of treatment. Bleeding should be investigated if it persists beyond 6 months, becomes heavier rather than less, or occurs after amenorrhoea.

It is preferable for the oestrogen and progestogen to be in combined form (for example in one tablet), because the adverse effects of the progestogen may lead to poor compliance if given separately. If oestrogen and progestogen are given separately, an explanation about the endometrial protective effect of progestogens is important, to ensure compliance.

Tibolone is an alternative no-bleed regimen for postmenopausal women.

Basis for recommendation

These recommendations are based on expert opinion published in a textbook [Rees et al, 2009].

Women who have had a hysterectomy do not usually require the addition of progestogen. Progestogens are added to hormone replacement therapy regimens to reduce the increased risk of endometrial hyperplasia and cancer which occurs with unopposed oestrogen.

Continuous regimens are not recommended in perimenopausal women because they often cause unpredictable bleeding in this group of women.

Route

Which route should I use?

Oral or transdermal preparations may be used to treat urogenital symptoms or vasomotor symptoms (for example flushes or sweats) with or without urogenital symptoms.

Transdermal preparations may be appropriate if:

The woman prefers this route.

Symptom control is poor with oral treatment.

Oral treatment causes adverse effects (such as nausea).

The woman has a history or risk of venous thromboembolism (in this situation, consider hormone replacement therapy [HRT] only after full discussion and appropriate investigation. See Thromboembolic disease or known thrombophilia).

The woman is taking a hepatic enzyme–inducing drug (for example an anticonvulsant drug).

The woman has a bowel disorder which may affect absorption of oral treatment.

The woman has a history of migraine (when steadier hormone levels may be beneficial).

The woman has lactose sensitivity (most HRT tablets contain lactose).

Low-dose vaginal oestrogen (tablet, cream, pessary, or vaginal ring) may be used for urogenital symptoms alone.

The levonorgestrel-releasing intrauterine system (IUS) (Mirena®) is an alternative route of delivery of progestogen to protect the endometrium. Since levonorgestrel is delivered locally to the uterus, a much lower daily dose is used, which also results in low systemic levels of levonorgestrel.

Offer the levonorgestrel-releasing IUS when:

The woman is experiencing persistent progestogenic adverse effects from systemic HRT, despite changes in type and route of progestogen.

Contraception is required along with HRT in the perimenopause.

Withdrawal bleeds on sequential HRT are heavy, after investigation if indicated.

The licence for use of the levonorgestrel-releasing IUS for the progestogen part of HRT is currently 4 years, as opposed to 5 years when used solely for contraception.

Basis for recommendation

These recommendations are based on the British National Formulary [BNF 65, 2013] and expert opinion in a textbook [Rees et al, 2009].

Oral oestrogens are more likely to cause nausea than other forms of oestrogen.

Systemic absorption of low-dose vaginal oestrogen is very low and does not relieve other menopausal symptoms, such as hot flushes.

Hormone levels delivered by patch are more constant than if given orally; oestrogen is absorbed directly through the skin into the systemic circulation, bypassing the liver. Some patches come in four strengths of oestrogen, allowing titration to the optimal dose.

Levonorgestrel-releasing intrauterine system (Mirena®):

The levonorgestrel-releasing intrauterine system provides adequate endometrial protection. The oestrogen dose and route can be tailored to meet individual needs.

Progestogenic systemic absorption is minimal, reducing systemic progestogenic side effects. The endometrial effect of the levonorgestrel-releasing intrauterine system can significantly reduce bleeding when used as part of a hormone replacement therapy regimen; 30–60% of women become amenorrhoeic.

Dose

Which dose should I use?

Prescribe the lowest effective dose of hormone replacement therapy (HRT) for the shortest time possible.

Oestrogen dose for symptom control:

Older women may be less tolerant of oestrogen and need to start (and are usually maintained) on a lower dose (for example 1 mg of oral estradiol or 25–50 micrograms of transdermal estradiol).

Younger women may require higher doses (for example 2–4 mg of oral estradiol or 100 micrograms of transdermal estradiol) to remain symptom-free.

Tailor the dose to the symptoms, as the ingested or applied dose may not be well absorbed.

The 'standard' bone-conserving doses of oestrogen are considered to be estradiol 2 mg, conjugated equine oestrogens 0.625 mg, or transdermal 50 microgram patch. However, it is now evident that lower doses also conserve bone mass.

Progestogens for endometrial protection: different progestogens used in combined HRT provide adequate endometrial protection. See Table 1 for information on the accepted doses of progestogens for endometrial protection.

Tibolone: the standard dose is 2.5 mg daily.

Table 1 . Accepted doses of progestogen for endometrial protection.
Progestogen type and route Accepted endometrial protection dosage
Cyclical preparations
Norethisterone oral 1 mg for last 12–14 days of 28-day cycle
Norethisterone patch 170–250 micrograms for last 14 days of a 28-day cycle
Levonorgestrel oral 75–250 micrograms for last 12 days of 28-day cycle
Levonorgestrel patch 10 micrograms for last 14 days of 28-day cycle
Norgestrel oral 150–500 micrograms for last 12 days of 28-day cycle
Medroxyprogesterone acetate oral 10 mg for last 14 days of 28-day cycle 20 mg for last 14 days of 3-month cycle
Dydrogesterone oral 10–20 mg for last 14 days of 28-day cycle
Continuous regimens
Norethisterone oral 0.5–1 mg
Norethisterone patch 170 micrograms
Levonorgestrel patch 7 micrograms
Medroxyprogesterone acetate oral 2.5–5 mg
Dydrogesterone 5 mg
Data from: [BNF 65, 2013]
Basis for recommendation

These recommendations are based on the Medicines and Healthcare products Regulatory Agency (MHRA) [MHRA and CHM, 2007b] and on expert opinion in a textbook [Rees et al, 2009].

Contraindications

What are the contraindications to HRT?

Contraindications to hormone replacement therapy are:

Current, past, or suspected breast cancer.

Known or suspected oestrogen-sensitive cancer.

Undiagnosed genital bleeding.

Untreated endometrial hyperplasia.

Previous idiopathic or current venous thromboembolism (deep vein thrombosis or pulmonary embolism).

Active or recent arterial thromboembolic disease (for example angina or myocardial infarction).

Untreated hypertension.

Active liver disease.

Porphyria cutanea tarda (absolute contraindication).

Basis for recommendation

This information is based on the British National Formulary [BNF 65, 2013] and an American guideline on the diagnosis and management of menopause [Goodman et al, 2011].

How to stop

How should HRT be stopped?

Some women do not notice any symptoms even with abrupt cessation of hormone replacement therapy (HRT), while others may experience a recurrence of hot flushes and sweats.

Some experts suggest that HRT should be gradually reduced rather than stopped abruptly. Suggested strategies are:

For oestrogen-only tablets: reduce from a 2 mg to a 1 mg tablet for 1–2 months, then use 1 mg on alternate days for a further 1–2 months.

For oestrogen-only patches: reduce the dose gradually to 25 micrograms daily (for example step the dose down a patch strength each month). Half a matrix-type patch (12.5 micrograms daily) can be used for a further 1–2 months.

For cyclical combined HRT tablets: reduce to a cyclical HRT pack containing 1 mg estradiol for 1–2 months. Cut the tablet in half for the next 1–2 months; this will ensure that the woman still receives oestrogen combined with a progestogen.

For cyclical combined HRT patches: reduce the dose as for oestrogen-only patches, but ensure that the woman still uses the oestrogen-only patches for 2 weeks of the cycle followed by the combined patches for a further 2 weeks, to ensure endometrial protection.

For continuous combined HRT tablets or patches: reduce the dose gradually every 1–2 months to the lowest strength tablet or patch. Then, take half a tablet or patch daily for a further 1–2 months.

If symptoms are severe after HRT is stopped, or persist for several months after stopping, the woman may wish to restart HRT after reassessment and counselling. Often a lower dose of HRT can be used (for example estradiol 1 mg) if HRT is restarted.

Basis for recommendation

This recommendation is based on published expert opinion [ICSI, 2006].

Antidepressants

Which one to use

Which antidepressant should I use?

Offer a selective serotonin reuptake inhibitor (SSRI), such as paroxetine, fluoxetine, or citalopram, or a serotonin–norepinephrine reuptake inhibitor (SNRI), such as venlafaxine.

There is evidence that paroxetine, fluoxetine, citalopram, and venlafaxine are effective for treating hot flushes, but no evidence that one is more effective than the other.

Neither SSRIs nor SNRIs are licensed for treating hot flushes.

Basis for recommendation

This recommendation is based on expert opinion in a textbook [Rees et al, 2009], and the British National Formulary [BNF 65, 2013].

Dose

What dose should I use?

Antidepressants are not licensed for treating menopausal symptoms. However, the following dosages have been assessed and found to be effective for hot flushes in short-term studies:

Citalopram 20 mg daily.

Paroxetine 20 mg daily.

Fluoxetine 20 mg daily.

Venlafaxine 37.5 mg twice daily (most convincing data).

Basis for recommendation

This information is based on published expert opinion [RCOG, 2010] and on a systematic review (search date: October 2005) that identified 43 randomized controlled trials (n = 4249) that compared the efficacy of non-hormonal therapies for the management of hot flushes [Nelson et al, 2006].

Prescribing issues: SSRI

What issues do I need to consider before prescribing a selective serotonin reuptake inhibitor?

For information on prescribing citalopram, paroxetine, or fluoxetine, including adverse effects, contraindications, cautions, and how to start and stop treatment, see the section on Prescribing information in the CKS topic on Depression.

Prescribing issues: venlafaxine

What issues do I need to consider before prescribing venlafaxine?

For information on prescribing venlafaxine, including adverse effects, contraindications, cautions, and how to start and stop treatment, see the section on Prescribing information in the CKS topic on Depression.

Clonidine

Dose

What dose of clonidine should I use?

For vasomotor symptoms, prescribe 50 micrograms twice daily and increase to 75 micrograms twice daily after 2 weeks, if necessary (licensed use).

Basis for recommendation

This recommendation is based on the British National Formulary [BNF 65, 2013] and the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2013a].

Prescribing issues

What issues should I consider before prescribing clonidine?

Clonidine is licensed for the management of vasomotor conditions commonly associated with the menopause and characterized by flushing.

Contraindications and cautions

Clonidine should not be used by women with sinus bradycardia or atrioventricular block.

Clonidine should be used with caution in women with cerebrovascular disease, coronary insufficiency, heart failure, renal failure (extreme care required), occlusive peripheral vascular disorders (such as Raynaud's disease), polyneuropathy, constipation, or a history of depression.

Adverse effects

Most adverse effects of clonidine are mild and tend to diminish with continued treatment. Hypotension, dizziness, sedation, dry mouth, decreased lacrimation, fluid retention, and nausea are the most common adverse effects. However:

Depending on the dose given, clonidine can cause bradycardia. Arrhythmias have been observed after high doses of clonidine in people with pre-existing cardiac conduction abnormalities.

The ability to drive or operate machinery may be impaired, especially in the initial phase of treatment with clonidine.

Clonidine may also aggravate depression or produce insomnia.

Drug interactions

Concurrent administration of clonidine with antihypertensive drugs, vasodilators, or diuretics may lead to an increased hypotensive effect.

Concurrent use of clonidine with beta-blockers and/or cardiac glycosides can cause bradycardia or dysrhythmia (AV-block) in isolated cases. Concurrent use with beta-blockers may also cause or potentiate peripheral vascular disorders.

Tricyclic antidepressants (TCAs) can antagonize the effects of clonidine, and a higher dose of clonidine (75 micrograms twice daily) may be required during concurrent use.

There is a risk of rebound hypertension when a beta-blocker or a TCA is stopped in a person taking clonidine. The beta-blocker or TCA should be withdrawn slowly over a few days to avoid this. Clonidine should also be reduced gradually over a few days if a high dose is used.

Basis for recommendation

This recommendation is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2013a].

Evidence

Evidence

Supporting evidence

Diagnosing the menopause

Evidence on diagnosis of menopause

A systematic review of 16 cross-sectional or longitudinal studies on women 40 years of age or older aimed to study the accuracy of self-assessed symptoms, signs, and laboratory tests in diagnosing the perimenopause. All studies defined perimenopause as 3–11 months of amenorrhoea or irregular periods, included a premenopausal control group, and reported a clinical examination finding. The review found that [Bastian et al, 2003]:

No single symptom or laboratory test could either rule in or rule out the perimenopause.

The prior probability of perimenopause is directly related to a woman's age.

After considering age, the following yielded the greatest positive likelihood ratios (LRs+):

Self assessment of going through the transition (LR+ range 1.53 to 2.13).

Hot flushes (LR+ range 2.15 to 4.06).

Night sweats (LR+ 1.90, 95% CI 1.63 to 2.21).

Vaginal dryness (LR+ range 1.48 to 3.79).

High follicle-stimulating hormone (FSH) levels (LR+ 3.06, 95% CI 2.06 to 4.54) and low inhibin B levels (LR+ 2.05, 95% CI 0.96 to 4.39) provided weak evidence to rule in the perimenopause. However, neither normal FSH level (LR 0.45, 95% CI 0.36 to 0.56) nor normal inhibin B level (LR 0.70, 95% CI 0.51 to 0.96) could rule out the perimenopause.

Modifiable risk factors

Evidence on modifiable risk factors for menopausal symptoms

Smoking and vasomotor symptoms:

A cross-sectional study of women (n = 1087) aged 40–60 years in the US, of whom 56% reported having hot flushes, found that [Whiteman et al, 2003]:

Compared with women who had never smoked, current smokers were at increased risk for:

Daily hot flushes (adjusted odds ratio [OR] 2.2, 95% CI 1.4 to 3.7); the risk increased with the amount smoked.

Moderate-to-severe hot flushes (adjusted OR 1.9, 95% CI 1.3 to 2.9).

A high body mass index (BMI) was associated with:

Daily hot flushes in premenopausal or perimenopausal women only.

An increased risk for moderate-to-severe hot flushes compared with a low BMI (less than 24.9 kg/m2) (adjusted OR 2.1, 95% CI 1.5 to 3.0).

Exercise and vasomotor symptoms:

A Cochrane systematic review (search date: March 2010) found no evidence from randomized controlled trials (RCTs) on the effectiveness of exercise for reducing hot flushes and night sweats in perimenopausal and postmenopausal women [Daley et al, 2011]:

Two (out of three) studies that compared exercise with no treatment seemed to produce small effect sizes in favour of exercise, but these studies were small.

A large, good-quality trial found no significant difference between exercise and control; however, vasomotor menopausal symptoms was not the primary outcome in the trial and so it was not powered to detect a difference in this outcome.

The authors of the Cochrane systematic review concluded that a large, high-quality RCT is required before any conclusion can be made about the effectiveness of exercise in this group of women.

Benefits of HRT

Evidence on the benefits of HRT

Vasomotor symptoms

Evidence on vasomotor symptoms

Oral and transdermal hormone replacement therapy (HRT), as oestrogen alone or oestrogen plus progestogen, are highly effective for reducing the frequency and severity of hot flushes and night sweats caused by the menopause.

Oral HRT:

A large randomized controlled trial (RCT) (n = 16,608) assessed postmenopausal women with an intact uterus who were 50–79 years of age. Compared with placebo, more women assigned to conjugated equine oestrogens 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily reported relief of hot flushes (86% with oestrogen plus progesterone compared with 58% with placebo; odds ratio [OR] 4.40, 95% CI 3.40 to 5.71) and night sweats (78% with oestrogen plus progesterone compared with 57% with placebo; OR 2.58, 95% CI 2.04 to 3.26) [Barnabei et al, 2005].

A Cochrane systematic review (search date: May 2002) identified 24 RCTs (n = 3329) that assessed the effectiveness of oral HRT (containing oestrogen alone or oestrogens together with progestogens in a cyclic or continuous regimen) compared with placebo for hot flushes and night sweats in menopausal women [MacLennan et al, 2004]:

The quality of the included studies was generally high in terms of concealment of treatment allocation, outcome assessment, and baseline equality. However, several studies had a greater than 10% loss to follow up, and majority of the studies did not analyse the data on an intention-to-treat basis.

This review did not differentiate between oral HRT products, combinations, doses, or regimens.

Trial duration ranged from 3 months to 3 years.

The main results were as follows:

In combined results for nine RCTs (n = 1104), oral HRT (oestrogen alone or oestrogens together with progestogens in a cyclic or continuous regimen) significantly reduced weekly hot flush frequency by 75% compared with placebo (95% CI 64.3 to 82.3; p < 0.0001).

In combined results for eight RCTs (n = 1238), oral HRT (oestrogen alone or oestrogens together with progestogens in a cyclic or continuous regimen) significantly reduced symptom severity compared with placebo (OR 0.13, 95% CI 0.07 to 0.23; p < 0.0001).

Withdrawal for lack of efficacy occurred significantly more often with placebo (OR 10.51, 95% CI 5.00 to 22.09; p < 0.0001).

Withdrawal for adverse events (commonly breast tenderness, oedema, joint pain, and psychological symptoms) was not significantly increased (OR 1.25, 95% CI 0.83 to 1.90; p = 0.3), although the occurrence of any adverse events was significantly increased for HRT (OR 1.41, 95% CI 1.00 to 1.99; p = 0.05).

Transdermal HRT:

A systematic review of 32 randomized trials (including four head-to-head comparisons) of oral conjugated equine oestrogen, or oral or transdermal 17-beta-estradiol, for menopausal hot flushes, found that all oestrogens significantly reduced the weekly number of hot flushes compared with placebo (weighted mean decrease –19.1 for oral conjugated equine oestrogen [1 trial], –16.8 for oral 17-beta-estradiol [5 trials], and –22.4 for transdermal 17-beta-estradiol [6 trials]). There were no significant differences between treatments [Nelson, 2004].

Urogenital symptoms

Evidence on urogenital symptoms

Hormone replacement therapy (HRT) with oral or intravaginal preparations is highly effective for treating vaginal atrophy (dryness, burning and itching, and dyspareunia). HRT is also effective for preventing urinary tract infections (UTIs).

Vaginal atrophy

Oral combined oestrogen and progestogen:

A large randomized controlled trial (RCT) (n = 16,608) that assessed postmenopausal women with an intact uterus who were 50–79 years of age compared oral conjugated equine oestrogens 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily with placebo. Compared with placebo, more women assigned to oestrogen combined with medroxyprogesterone reported relief of vaginal or genital dryness (74% with oestrogen plus progesterone and 55% with placebo: OR 2.40, 95% CI 1.90 to 3.02) [Barnabei et al, 2005].

Intravaginal oestrogens:

A Cochrane systematic review (search date: January 2006) identified 19 RCTs (n = 4162) that assessed the effectiveness of intravaginal oestrogen preparations (creams, pessaries, intravaginal tablets, and the estradiol-releasing vaginal ring) for women with vaginal atrophy associated with the menopause [Suckling et al, 2006]. It found intravaginal creams, pessaries, tablets, and the estradiol vaginal ring to be equally effective for the symptoms of vaginal atrophy.

The overall quality of the studies was good. All trials measured efficacy, but with various outcome measures.

The main results were as follows:

One small RCT (n = 67) found that the estradiol ring significantly reduced symptoms of dyspareunia compared with a placebo ring (odds ratio [OR] 12.67, 95% CI 3.23 to 49.67; p = 0.0003).

In combined results for two RCTs (n = 341), the estradiol ring significantly improved symptoms of pruritus compared with oestrogen cream (OR 2.71, 95% CI 1.66 to 4.43; p < 0.0001).

In combined results for two trials (n = 397), intravaginal oestrogen tablets significantly improved vaginal dryness compared with the estradiol ring (OR 0.40, 95% CI 0.24 to 0.64; p = 0.0002),

In combined results of three RCTs (n = 567), intravaginal oestrogen tablets significantly improved dyspareunia (OR 0.53, 95% CI 0.36 to 0.78; p = 0.001).

One small RCT (n = 48) found that intravaginal oestrogen tablets significantly improved vaginal dryness compared with intravaginal oestrogen cream (OR 7.00, 95% CI 1.64 to 29.85; p = 0.009).

In combined results for two RCTs (n = 716), intravaginal oestrogen tablets significantly improved burning and itching (OR 0.15, 95% CI 0.10 to 0.20; p < 0.0001) and dyspareunia (OR 0.17, 95% CI 0.0.12 to 0.23; p < 0.0001) compared with placebo.

In combined results for three RCTs (n = 1140), vaginal dryness differed significantly between the two groups, in favour of the intravaginal oestrogen tablet compared with placebo (OR 0.08, 95% CI 0.06 to 0.10; p < 0.0001).

One RCT (n = 150) found a significant increase in uterine bleeding, breast pain, and perineal pain associated with conjugated equine oestrogen cream compared with intravaginal tablets (OR 0.18, 95% CI 0.07 to 0.50; no p-value given).

UTIs

One systematic review (search date: December 1998) identified five RCTs (n = 334) that assessed the effectiveness of oral and topical oestrogen for preventing recurring UTIs in postmenopausal women [Cardozo et al, 2001]:

All the RCTs used different treatment periods, which ranged from 3–8 months.

Oral or vaginal oestrogen HRT significantly reduced the incidence of UTIs compared with placebo or no treatment (OR 2.51, 95% CI 1.48 to 4.25; no p-value given).

Incontinence

Evidence on incontinence

Urinary incontinence may be improved with the use of local oestrogen treatment. However, there is little evidence on the period after oestrogen treatment had finished, and no information on the long-term effects of local oestrogen. Conversely, systemic hormone replacement therapy (HRT) using conjugated equine oestrogen may worsen incontinence.

A Cochrane systematic review (search date: June 2012) identified thirty-four randomized controlled trials (RCTs) which assessed the effects of local and systemic oestrogen therapy for the treatment of urinary incontinence in post-menopausal women [Cody et al, 2012].

The RCTs included approximately 19,676 incontinent women of whom 9599 received oestrogen therapy (1464 received vaginal oestrogen).

Varying combinations of type of oestrogen, dose, duration of treatment, and length of follow up were used. Outcome data were not reported consistently and were available for only a minority of trials.

Systemic oestrogens

Combined results from six RCTs showed worse incontinence in women taking systemic oestrogens than in women on placebo (risk ratio (RR) 1.32, 95% CI 1.17 to 1.48). This result was heavily weighted by a subgroup of women from a large trial [Hendrix et al, 2005], which had large numbers of participants and a longer follow up of one year.

The result for women with an intact uterus where oestrogen and progestogen were combined also showed a statistically significant worsening of incontinence (RR 1.11, 95% CI 1.04 to 1.18) compared with placebo.

In one large RCT, women who were continent and received systemic oestrogen replacement, with or without progestogens, for reasons other than urinary incontinence were more likely to report the development of new urinary incontinence.

Topical oestrogens

There was some evidence that oestrogens used locally (for example vaginal creams or pessaries) may improve incontinence (RR 0.74, 95% CI 0.64 to 0.86).

Overall, there were around one to two fewer voids in 24 hours amongst women treated with local oestrogen, and there was less frequency and urgency. No serious adverse events were reported although some women experienced vaginal spotting, breast tenderness, or nausea.

One small RCT showed that women were more likely to have an improvement in incontinence after pelvic floor muscle training than with local oestrogen therapy (RR 2.30, 95% CI 1.50 to 3.52).

The data were too few to address questions about oestrogens compared with or in combination with other treatments, different types of oestrogen, and different modes of delivery.

The authors of this Cochrane systematic review advised that due to the risks associated with long-term use of systemic oestrogen, treatment should be for limited periods, especially in women with an intact uterus.

Controversial benefits of HRT

Evidence on controversial benefits of HRT

There is no good evidence that hormone replacement therapy (HRT) improves sleep disturbances, depression, or cognitive function:

Sleep disturbance and depression

One large randomized controlled trial (RCT) (n = 16,608) of postmenopausal women with an intact uterus who were 50–79 years of age compared conjugated equine oestrogen 0.625 mg daily plus medroxyprogesterone acetate 2.5 mg daily versus placebo [Hays et al, 2003]:

Sleep disturbance — oestrogen plus medroxyprogesterone was associated with a statistically significant but small and not clinically meaningful benefit in terms of sleep disturbance after 1 year (0.4 point on a 20-point scale).

Depression — oestrogen plus medroxyprogesterone did not significantly improve mental health or depressive symptoms (assessed using the RAND 36-Item Health Survey) compared with placebo after 1 year (range in mean change of scores from baseline –0.1 to +0.6 with oestrogen plus progestin versus –0.1 to +0.7 with placebo; p = 0.40 to 0.81).

Cognitive function

A systematic review (search date: 1996) assessed the effects of oestrogen on cognitive function in postmenopausal women. This review included ten RCTs and nine observational studies [Haskell et al, 1997]. Evidence was insufficient for the clinical trials to suggest that oestrogen improves cognitive function.

The Women's Health Initiative Memory Study assessed the effects of conjugated equine oestrogen, alone and in combined HRT (conjugated equine oestrogen plus medroxyprogesterone acetate), on the incidence of probable dementia and mild cognitive impairment in women 65–79 years of age (n = 7506) [Shumaker et al, 2004]. When results from the oestrogen-alone and combined HRT arms were combined, the risk of probable dementia increased, from 23 cases per 10,000 women per year taking placebo to 41 cases per 10,000 women per year taking HRT (hazard ratio 1.76, 95% CI 1.19 to 2.60). Evidence of an increased risk began to appear after 1 year.

Osteoporosis

Evidence on the risk of osteoporosis with long-term HRT

Hormone replacement therapy (HRT) (both oestrogen-only and combined HRT) is considered effective for the prevention of postmenopausal osteoporosis; however, it is generally recommended as an option only for women at significant risk, for whom non-oestrogen treatments are unsuitable.

A large Cochrane systematic review (search date: February 2012; n = 42,830) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012].

Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), which were both reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2007 (see Hormone replacement therapy: safety update - UK public Assessment Report).

The results of this study are summarized below. For a full discussion of this study, see Long term hormone therapy for perimenopausal and postmenopausal women (Review), published in the Cochrane Library (www.thecochranelibrary.com).

Hip fractures

The WHI trial found a statistically significant reduction in the risk of hip fracture for women taking combined continuous HRT and oestrogen-only HRT.

In women taking oestrogen-only HRT, there was a statistically significant reduction at 7.1 years’ mean follow-up (RR 0.64, 95% CI 0.45 to 0.93). The absolute risk (AR) of a hip fracture decreased from 14 per 1000 in the control group to 9 per 1000 (95% CI 6 to 13) in the HRT group. However, the benefit from HRT was not maintained during extended follow-up (to 10.7 years).

In women taking combined continuous HRT, there was no statistically significant difference in the incidence of hip fractures during the first four years of follow-up, but at 5.6 years’ mean follow-up there was a statistically significant reduction in the risk of hip fracture (RR 0.68, 95% CI 0.48 to 0.97). The AR of a hip fracture decreased from 9 per 1000 in the control group to 6 per 1000 (95% CI 4 to 9) in the HRT group. The risk remained significantly lower in the HRT group at a mean follow-up of 7.9 years (RR 0.77, 95% CI 0.60 to 0.99).

The HERS trial found no statistically significant difference between combined continuous HRT and placebo for this outcome, and the unblinded extension of this study found a statistically significant increased risk in the group taking HRT from years 4.1 to 6.8 (post-randomisation) (RR 2.10, 95% CI 1.06 to 4.16).

Other studies found no statistically significant difference between the groups for this outcome.

Clinical vertebral fractures

The WHI trial reported:

Significantly fewer fractures in the oestrogen-only HRT group than in the placebo group (RR 0.64, 95% CI 0.44 to 0.93) at a mean of 7.1 years’ follow-up. The AR of a clinical vertebral fracture decreased from 13 per 1000 in the control group to 8 per 1000 (95% CI 6 to 12) in the HRT group.

Significantly fewer fractures in the combined continuous HRT group than in placebo (RR 0.68, 95% CI 0.48 to 0.97) at a mean of 5.6 years’ follow-up. The AR of a clinical vertebral fracture decreased from 10 per 1000 in the control group to 7 per 1000 (95% CI 5 to 10) in the HRT group. At a mean of 7.9 years’ follow up in there was no longer any significant difference between the groups.

The HERS trial found no statistically significant difference between the groups during follow-up for this outcome.

Any fractures

The WHI trial reported:

Statistically significant reduction in the risk of any fracture for women taking combined continuous HRT at mean follow-up of 5.6 years (RR 0.78, 95% CI 0.71 to 0.86) and at 7.9 years (RR 0.82, 95% CI 0.76 to 0.89). At 5.6 years the AR of any fracture decreased from 111 per 1000 in the control group to 86 per 1000 (95% CI 79 to 94) in the HRT group.

Statistically significant reduction in the risk of any fracture for women taking oestrogen-only HRT at mean follow-up of 7.1 years (RR 0.73, 95% CI 0.65 to 0.80). At 7.1 years the AR of any fracture decreased from 140 per 1000 in the control group to 102 per 1000 (95% CI 91 to 112) in the HT group.

None of the other studies found any statistically significant difference between HRT and placebo for this outcome.

Colorectal cancer

Evidence on the risk of colorectal cancer with long-term HRT

A large Cochrane systematic review (search date: February 2012) found no strong evidence that combined continuous hormone replacement therapy (HRT) has a clinically meaningful impact on the incidence of colorectal cancer in relatively healthy women.

A large Cochrane systematic review (search date: February 2012; n = 42,830) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012].

Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), which were both reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2007 (see Hormone replacement therapy: safety update - UK public Assessment Report).

The results of the Cochrane systematic review are summarized below. For a full discussion, see Long term hormone therapy for perimenopausal and postmenopausal women (Review), published in the Cochrane Library (www.thecochranelibrary.com).

The WHI trial reported that:

At one to four years’ follow up there was no statistically significant difference in the incidence of colorectal cancer in women taking combined HRT compared with women taking placebo. However, women taking combined HRT had a significantly lower incidence of colon cancer at a mean follow up of 5.6 years (risk ratio [RR] 0.64, 95% CI 0.44 to 0.91), but the rates were no longer significantly different at a mean of 7.1 years’ follow up (RR 0.76, 95% CI 0.57 to 1.01).

No statistically significant difference was shown between any other type of HRT and placebo for this outcome.

There were insufficient evidence to assess the risk of long-term HRT use in perimenopausal women or postmenopausal women younger than 50 years of age. However, a subsequent open label randomized controlled trial investigated the long term effect of HRT on cardiovascular outcomes in recently postmenopausal women (aged 45–58 years) [Schierbeck et al, 2012]:

The evidence showed that, after 10 years of randomized treatment, women receiving HRT early after menopause had a significantly reduced risk of mortality, heart failure, or myocardial infarction, without any apparent increase in the risk of cancer, VTE, or stroke, compared with women receiving placebo.

The findings suggest that starting HRT early in menopause may reduce the risk of vascular events and death.

Risks of HRT

Evidence on the risks of HRT

There is evidence that in relatively healthy postmenopausal women, combined continuous hormone replacement therapy (HRT) significantly increases the risk of a coronary event, venous thromboembolism (VTE), stroke, breast cancer, gallbladder disease, and death from lung cancer. Oestrogen-only HRT significantly increases the risk of VTE, stroke, and gallbladder disease, but does not significantly increase the risk of breast cancer. Among women aged over 65 years who are relatively healthy and taking continuous combined HRT, there is a statistically significant increase in the incidence of dementia (after 4 years' use). Among women with cardiovascular disease, long-term use of combined continuous HRT significantly increases the risk of VTE. Women taking HRT have a significantly decreased incidence of fractures with long-term use (see Osteoporosis). There is no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer (see Colorectal cancer).

A Cochrane systematic review (search date: February 2012) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012].

Twenty-three randomized double-blind studies (n = 42,830) compared HRT with placebo when taken for at least one year. HRT (oestrogen-only or combined oestrogen and progestogen) was given by oral, transdermal, subcutaneous, or intranasal routes, and a total of 14 outcomes were assessed.

Most participants were postmenopausal, either spontaneously or surgically, with some degree of co-morbidity. The women were aged 26 to 91 years; the average age of the women in most studies was 60 years.

None of the studies focused on peri-menopausal women, but one trial analyzed subgroups of relatively healthy 50 to 59 year old women taking combined continuous HRT (n = 2839) and oestrogen-only HRT (n = 1637) compared with similar-sized placebo groups:

The only significantly increased risk reported was for VTE in women taking combined continuous HRT; however, the absolute risk was low (0.5% overall for a woman taking HRT for five years). Women without a uterus, taking HRT for five to six years appear relatively safe and there may even be some health benefits. However, other differences in risk cannot be excluded as this study was not designed to have the power to detect differences between groups of women within 10 years of the menopause.

A subsequent open label randomized controlled trial investigated the long term effect of HRT on cardiovascular outcomes in recently postmenopausal women (aged 45–58 years) [Schierbeck et al, 2012]. See Long term CV effect of HRT in recently postmenopausal women for more information.

Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), which were both reviewed by the Medicines and Healthcare Products Regulatory Agency (MHRA) in 2007 (see Hormone replacement therapy: safety update - UK public Assessment Report).

See Risk with combined HRT for a detailed summary of the results for combined HRT, and Risk with oestrogen-only HRT for a summary of the results for oestrogen-only HRT. For a full discussion of the Cochrane systematic review, see Long term hormone therapy for perimenopausal and postmenopausal women (Review), published in the Cochrane Library (www.thecochranelibrary.com).

Risk with combined HRT

Combined hormone replacement therapy

There is evidence that in relatively healthy postmenopausal women, combined continuous hormone replacement therapy (HRT) significantly increases the risk of a coronary event, venous thromboembolism (VTE), stroke, breast cancer, gallbladder disease, and death from lung cancer. Among women with cardiovascular disease, long-term use of combined continuous HRT significantly increases the risk of VTE.

A Cochrane systematic review (search date: February 2012) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012]. Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS); the authors of the Cochrane systematic review considered the evidence from the WHI trial and the HERS trial (where available), both individually and pooled with other relevant trials.

Coronary event (myocardial infarction or cardiac death)

The WHI trial reported that compared with placebo, women taking combined continuous HRT were at a significantly higher risk of a coronary event after taking HRT for one year (RR 1.74, 95% CI 1.05 to 2.89), two years (RR 1.49, 95% CI 1.05 to 2.12), and three years (RR 1.43, 95% CI 1.05 to 1.95). However, at a mean follow-up of 5.6 years there was no statistically significant difference between the groups (RR 1.22, 95% CI 0.98 to 1.52).

The authors of the Cochrane review pooled the results of the WHI study with the results of other relevant studies and found:

At follow up of 1 year, the absolute risk (AR) of an event increased from 2 per 1000 in the control group to 4 per 1000 (95% CI 3 to 7) in the HRT group.

At follow up of 2 years, AR of an event increased from 6 per 1000 in the control group to 9 per 1000 (95% CI 7 to 13) in the HRT group.

At follow up of 4 years, AR of an event increased from 8 per 1000 in the control group to 11 per 1000 (95% CI 8 to 13) in the HRT group.

The HERS trial assessed this outcome in women with pre-existing cardiovascular disease taking combined continuous HRT, and reported results of borderline statistical significance at one year, suggesting increased risk for this group of women (RR 1.5, 95% CI 1.00 to 2.25). Subsequent analysis based on the entire 6.8 years of follow-up (blinded and unblinded) showed no statistically significant variation in risk over time.

Venous thromboembolism (VTE) (pulmonary embolus or deep vein thrombosis)

The WHI trial reported that compared with placebo, women taking combined continuous HRT were at a significantly higher risk of a thromboembolic event at one year (RR 3.59, 95% CI 1.95 to 6.61), two years (RR 2.98, 95% CI 1.88 to 4.71), three years (RR 2.54; 95% CI 1.73 to 3.72), at a mean of 5.6 years (RR 2.03, 95% CI 1.55 to 2.64), and at a mean of 7.9 years (RR 1.65, 95% CI 1.32 to 2.05). Analysis of time trends in this comparison found a statistically significant time trend for a diminishing risk of venous thromboembolism over time.

The authors pooled the results of the WHI study with the results of one relevant study and:

At follow up of 1 year, the AR of an event increased from 2 per 1000 in the control group to 7 per 1000 (95% CI 4 to 11) in the HRT group.

At follow up of 2 years, the AR of an event increased from 3 per 1000 in the control group to 9 per 1000 (95% CI 6 to 14) in the HRT group.

At follow up of 5.6 years, the AR of an event increased from 10 per 1000 in the control group to 20 per 1000 (95% CI 15 to 26) in the HRT group.

One study assessed this outcome in women with pre-existing cardiovascular disease taking combined continuous HRT for one to four years. The results showed that these women were more likely to experience a VTE compared with women taking placebo.

At follow up of 1 year, the AR of an event increased from 3 per 1000 in the control group to 9 per 1000 (95% CI 3 to 29) in the HRT group.

At follow up of 2 years, the AR of an event increased from 4 per 1000 in the control group to 15 per 1000 (95% CI 6 to 38) in the HRT group.

At follow up of 4.1 years, the AR of an event increased from 9 per 1000 in the control group to 13 per 1000 (95% CI 6 to 28) in the HRT group.

Stroke

The WHI trial reported that there was no statistically significant difference between the control and HRT groups for the incidence of stroke during the first two years of the study; however, women taking combined continuous HRT were at a significantly higher risk of stroke after taking it for three or more years:

At three years (RR 1.47, 95% CI 1.02 to 2.11), at a mean of 5.6 years (RR 1.38, 95% CI 1.08 to 1.75), at a mean of 7.9 years (RR 1.29, 95% CI 1.06 to 1.56).

The authors pooled the results of the WHI study with one relevant study and:

At follow up of 3 years, the AR of an event increased from 6 per 1000 in the control group to 8 per 1000 (95% CI 6 to 12) in the HRT group.

At follow up of 5.6 years, the AR of an event increased from 14 per 1000 in the control group to 19 per 1000 (95% CI 15 to 24) in the HRT group.

At follow up of 7.9 years, the AR of an event increased from 21 per 1000 in the control group to 28 per 1000 (95% CI 23 to 34) in the HRT group.

Breast cancer

The WHI trial reported that there was no statistically significant difference between the control and HRT groups for the incidence of breast cancer during the first four years of follow-up, but the HRT group were at a significantly higher risk of breast cancer after taking HRT for five or more years: at a mean of 5.6 years (RR 1.26, 95% CI 1.02 to 1.56), and at a mean of 7.9 years’ follow-up (RR 1.27, 95% CI 1.07 to 1.52). At a mean of 11 years’ follow-up the rate of invasive breast cancer was significantly higher in the HRT group (RR 1.25, 95% CI 1.08 to 1.45) compared with the control group. Breast cancers diagnosed in the HRT group were of similar histology and stage to those in the control group but were more likely to be node positive (P = 0.03).

At follow up of 5.6 years, the AR of breast cancer increased from 19 per 1000 in the control group to 23 per 1000 (95% CI 19 to 29) in the HRT group.

At follow up of 7.9 years, the AR of breast cancer increased from 26 per 1000 in the control group to 33 per 1000 (95% CI 28 to 40) in the HRT group.

Analysis of time trends found a statistically significant trend for increasing breast cancer risk over time in the group taking HRT.

The authors pooled the results of the WHI study with the results of one relevant study and the results showed a significantly reduced risk of breast cancer at one year in the HRT arm (RR 0.53, 95% CI 0.28 to 0.96).

Gallbladder disease

A meta-analysis of the four studies (including the WHI trial) comparing combined continuous HRT with placebo (mean follow-up ranging from 3 to 5.6 years) showed significantly increased risk of gallbladder disease in the HRT group (RR 1.55, 95% CI 1.29 to 1.86). The AR of an event increased from 27 per 1000 in the control group to 47 per 1000 (95% CI 38 to 60) in the HRT group.

Although these studies had differing lengths of follow-up, no statistical heterogeneity was observed in either meta-analysis.

Probable dementia in women aged over 65 years

The WHI trial reported that the incidence of probable dementia was significantly higher in the group taking combined continuous HRT than in the control group (RR 1.97, 95% CI 1.16 to 3.33).

At follow up of 4.2 years, the AR of probable dementia increased from 9 per 1000 in the control group to 18 per 1000 (95% CI 11 to 30) in the HRT group.

Death from lung cancer

In a post hoc analysis, one randomized controlled trial (RCT) compared placebo with combined continuous HRT after a mean follow-up of 8 years, and with oestrogen-only HRT after a mean follow-up of 7.9 years. Lung cancer overall, non-small cell lung cancer, and small cell lung cancer were reported separately.

Whilst there was no statistically significant difference between oestrogen-only HRT and placebo for any of these outcomes, women taking combined HRT were significantly more likely to die from lung cancer overall (risk ratio [RR] 1.74, 95% CI 1.19 to 2.57) or from non-small cell lung cancer (RR 1.91, 95% CI 1.24 to 2.95) compared with women in the placebo group. The absolute risk of death from lung cancer increased from 5 per 1000 in the control group to 9 per 1000 (95% CI 6 to 13) in the HRT group. This finding was independent of smoking status.

The mortality rate for small cell lung cancer did not differ significantly between the groups.

There was no strong evidence that HRT has a clinically meaningful impact on the incidence of colorectal cancer (see Colorectal cancer).

No statistically significant difference was found between combined HRT and placebo for the following outcomes:

Death from: any cause (total mortality), coronary heart disease (CHD), stroke, breast cancer, colon cancer, and any cancer.

Transient ischaemic attack (TIA), stroke and TIA (as a composite endpoint), lung cancer, endometrial cancer, mild cognitive impairment, and mild cognitive impairment or probable dementia (as a composite endpoint).

Ovarian cancer:

There was a trend towards an increased risk of ovarian cancer but it was not statistically significant. However, a systematic review of (mainly) observational studies (identified but not included in the Cochrane systematic review) [Greiser et al, 2007] suggests that both oestrogen-only and combined HRT may be associated with an increased risk of ovarian cancer.

Specific cognitive functions. However, compared with placebo:

Combined continuous HRT appeared to have a negative impact on verbal memory (p ≤ 0.01) and a non-significant trend to a positive impact on figural memory (p = 0.012) over time.

In one study, verbal recall declined significantly less (p = 0.01) over two years follow-up in a subgroup of women who scored at or above average at baseline and who were taking moderate-dose oestrogen with intermittent norethindrone.

Quality of life:

Although a subgroup analysis reported significantly improved severity of hot flushes and night sweats compared with placebo, results for general quality of life measured did not have a clinically significant effect on health-related quality of life in these group of women.

Conclusion

The authors of the Cochrane systematic review concluded that:

'Women who find menopausal symptoms intolerable and who are at low risk of cardiovascular disease, VTE, or breast cancer may wish to weigh the benefits of symptom relief against the small absolute risk of harm from short term use of HRT. Current recommendations favour the use of low-dose HRT for relief of vasomotor symptoms among women within 10 years of their last period, taken for the shortest possible time required to achieve treatment goals, with doses individually tailored and reviewed regularly'.

Although there are no specific contraindications to the use of HRT in women with cardiovascular disease, a history of VTE, or breast cancer, the use of HRT is not recommended in this group of women. Women at high risk of lung cancer (current smokers or long-term past smokers) should be made aware that combined HRT increases the risk of death from lung cancer.

Risk with oestrogen-only HRT

Oestrogen-only hormone replacement therapy

There is evidence that in relatively healthy postmenopausal women, oestrogen-only hormone replacement therapy (HRT) significantly increases the risk of venous thromboembolism (VTE), stroke, and gallbladder disease. Although the evidence showed no statistically significant difference between oestrogen-only HRT and placebo for endometrial cancer, endometrial cancer is a well documented adverse effect of unopposed oestrogen in women with a uterus. Oestrogen-only HRT does not appear to significantly increase the risk of breast cancer.

A Cochrane systematic review (search date: February 2012) assessed the effects of long-term HRT on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures, cognition, and quality of life in perimenopausal and postmenopausal women, both during HRT use and after stopping HRT [Marjoribanks et al, 2012]. Seventy percent of the data were derived from the Women's Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS); the authors of the Cochrane systematic review considered the evidence from the WHI trial and the HERS trial (where available), both individually and pooled with other relevant trials.

VTE (pulmonary embolus [PE] or deep vein thrombosis [DVT])

The WHI trial reported that women taking oestrogen-only HRT were at a higher risk of a thrombo-embolic event than women taking placebo.

The risk was highest within the first two years and was statistically significant in this time period (RR 2.22, 95% CI 1.12 to 4.39). The absolute risk (AR) of an event increased from 2 per 1000 in the control group to 5 per 1000 (95% CI 2 to 10) in the HRT group.

At a mean follow-up of seven years, the risk was lower but the HRT group was still at a higher risk (that bordered on statistical significance) compared with placebo (RR 1.32, 95% CI 1.00 to 1.74).

The increased risk disappeared during extended follow-up (overall 10.7 years’ follow-up: RR 1.05, 95% CI 0.84 to 1.31).

When DVT was considered as a single outcome (without pulmonary embolism), the rate was significantly lower in the HRT group during extended follow-up (RR 0.63, 95% CI 0.41 to 0.98) though the rate over the entire 10.7 years’ intervention and extended follow-up did not differ significantly between the two groups (RR 1.04, 95% CI 0.84 to 1.29).

Stroke

The WHI trial reported that there was a statistically significant increase in the incidence of stroke at 7.1 years’ follow-up (RR 1.34, 95% CI 1.07 to 1.68). The AR of a stroke increased from 23 per 1000 in the control group to 32 per 1000 (95% CI 25 to 40) in the HRT group. However, the increased risk was not maintained during an extended follow-up (overall 10.7 years): RR 1.17 (95% CI 0.97 to 1.40).

The authors noted that the excess in the HRT group was due to an increased risk of ischaemic rather than haemorrhagic stroke and that the excess risk became apparent after four years of follow-up. However, the increased risk was not maintained during extended

Gallbladder disease

A meta-analysis of the three studies (including the WHI trial) comparing oestrogen-only HRT with placebo (mean follow-up ranging from 3 to 7.1 years) for the outcome of gallbladder disease requiring surgery showed a statistically significant increase in risk in the HRT group (RR 1.75, 95% CI 1.40 to 2.19). The AR of an event increased from 26 per 1000 in the control group to 45 per 1000 (95% CI 36 to 57) in the HRT group.

No statistically significant difference was found between oestrogen-only HRT and placebo for the following outcomes:

Death from: any cause (total mortality), CHD, stroke, colon cancer, endometrial cancer, and lung cancer.

Coronary events (myocardial infarction or cardiac death), transient ischaemic attack (TIA) as a single outcome, stroke and TIA (as a combined outcome), breast cancer, colorectal cancer (see Colorectal cancer for more information), lung cancer, change in dementia status in women with mild to moderate Alzheimer's disease, and quality of life.

Specific cognitive functions.

However, at two years follow up, one study reported significantly higher scores for memory and concentration in women taking a low or moderate dose of intranasal oestrogen compared with women taking placebo (p ≤ 0.006).

Probable dementia and mild cognitive impairment alone.

However, when mild cognitive impairment or probable dementia was assessed as a composite endpoint, the incidence was significantly higher in the group taking oestrogen-only HRT than in the placebo group (RR 1.36, 95% CI 1.01 to 1.84).

Endometrial cancer. However, the women in the included studies were closely monitored for endometrial hyperplasia if they had a uterus, and endometrial cancer is well documented as an adverse effect of unopposed oestrogen in women with a uterus.

Conclusion

The authors of the Cochrane systematic review concluded that:

'Women who find menopausal symptoms intolerable and who are at low risk of cardiovascular disease, VTE, or breast cancer may wish to weigh the benefits of symptom relief against the small absolute risk of harm from short term use of HRT. Current recommendations favour the use of low-dose HRT for relief of vasomotor symptoms among women within 10 years of their last period, taken for the shortest possible time required to achieve treatment goals, with doses individually tailored and reviewed regularly'.

Although there are no specific contraindications to the use of HRT in women with cardiovascular disease, a history of VTE, or breast cancer, the use of HRT is not recommended in this group of women.

Transdermal HRT for VTE

Evidence on transdermal HRT for venous thromboembolism

Oral and not transdermal hormone replacement therapy (HRT) is associated with an increased risk of venous thromboembolism (VTE) in case-control studies.

A case-controlled study of women (n = 155) 45–70 years of age with a documented episode of VTE found that oral but not transdermal HRT is associated with risk of VTE in postmenopausal women [Scarabin et al, 2003].

Thirty-two (21%) cases and 27 (7%) controls were current users of oral HRT, whereas 30 (19%) cases and 93 (24%) controls were current users of transdermal oestrogen replacement therapy. The odds ratio for VTE was 3.5 (95% CI 1.8 to 6.8) in current users of oral HRT and 0.9 (95% CI 0.5 to 1.6) in current users of transdermal HRT compared with non-users.

A second case-controlled study of women (n = 235) 45–70 years of age with a first documented episode of idiopathic VTE and 554 controls found that oral but not transdermal oestrogen was associated with an increased risk of VTE [Straczek et al, 2005].

The odds ratio for oral oestrogen was 4.3 (95% CI 2.6 to 7.2) and 1.2 (95% CI 0.8 to 1.7) for transdermal oestrogen.

The risk for women with a prothrombotic mutation using transdermal oestrogen was similar to that of women with a mutation who were not using oestrogen (OR 4.4, 95% CI 2.0 to 9.9; and OR 4.1, 95% CI 2.3 to 7.4, respectively).

A third case-control study recruited 271 postmenopausal women with a first documented episode of idiopathic VTE and 610 controls; the women were aged between 45 and 70 years of age. Results showed that oral and not transdermal oestrogen were associated with an increased risk of VTE [Canonico et al, 2007].

After adjustment for potential confounding factors, the odds ratios for VTE were 4.2 (95% CI 1.5 to 11.6) in current users of oral HRT, and 0.9 (95% CI 0.4 to 2.1) for transdermal HRT compared with nonusers.

Long term CV effect of HRT in recently postmenopausal women

Long term effect of HRT on cardiovascular events in recently postmenopausal women.

There is some evidence that after 10 years of randomized treatment, women receiving hormone replacement therapy (HRT) early after menopause had a significantly reduced risk of mortality, heart failure, and myocardial infarction (MI), without any apparent increase in risk of cancer, venous thromboembolism (VTE), or stroke. However, further trials are needed.

An open label randomized controlled trial (RCT) investigated the long-term effect of HRT on cardiovascular outcomes in recently postmenopausal women [Schierbeck et al, 2012].

Healthy women who were recently postmenopausal or had perimenopausal symptoms in combination with recorded postmenopausal serum follicle stimulating hormone (FSH) values were randomly allocated to receive HRT (n = 502) or no treatment (n = 504); 1006 women aged 45–58 years were included. Women who had undergone hysterectomy were included if they were aged 45–52 and had recorded values for postmenopausal serum FSH.

Women with an intact uterus were treated with combined HRT (triphasic estradiol and norethisterone acetate) and women who had undergone hysterectomy received oestrogen-only HRT (2 mg estradiol a day).

Intervention was stopped after about 11 years due to adverse reports from other trials, but participants were followed for death, cardiovascular disease (CVD), and cancer for up to 16 years.

The primary endpoint was a composite of death, admission to hospital for MI, or heart failure.

Secondary endpoints were the individual components of the primary endpoint and admission to hospital for stroke. Safety endpoints included death or a diagnosis of breast cancer or other cancer grouped together, and admission to hospital for pulmonary embolism or deep venous thrombosis.

After 10 years of intervention:

The primary composite endpoint occurred in 49 women (33 in the control group and 16 in treated group; hazard ratio [HR] 0.48, 95% CI 0.26 to 0.87; p = 0.015).

Heart failure was diagnosed in eight participants (seven in the control group and one in the treatment group; HR 0.14, 0.02 to 1.16; p = 0.07).

MI was diagnosed in five participants (four in the control group and one in treatment group; HR 0.25, 0.03 to 2.21; p = 0.21).

The composite endpoint mortality or breast cancer applied to 40 women in the control group and 22 women in the treatment group (HR 0.54, 0.32 to 0.91, p = 0.020).

Deaths due to cardiovascular causes occurred in 18 women in the control group and five in the treatment group.

Deaths due to non-cardiovascular causes occurred in eight women in the control group and 10 in the treatment group.

There was no significant difference between HRT and placebo for the risk of stroke, VTE, or occurrence of any cancer.

After 16 years of total follow-up:

The composite primary trial endpoint of death, MI, or heart failure occurred in 86 women (53 in the control group and 33 in the treatment group; HR 0.61, 0.39 to 0.94; p = 0.02).

Heart failure was diagnosed in 11 women (8 in the control group and 3 in the treatment group; HR 0.37, 0.10 to 1.41; p = 0.15).

MI was diagnosed in 16 women (11 in the control group and 5 in the treatment group; HR 0.45, 0.16 to 1.31; p = 0.14).

A significant interaction was found between HRT and age at baseline for the composite endpoint mortality or breast cancer (p = 0.028) with the younger women (younger than 50 years) receiving HRT having a significantly reduced risk (0.49, 0.28 to 0.87, p = 0.015).

Women who had undergone hysterectomy (n = 192) and received oestrogen alone had a decreased risk of death or breast cancer compared with women in the control group (0.42, 0.18 to 0.97; p = 0.043).

Death due to cardiovascular causes occurred in 23 women in the control group and 6 women in the treatment group.

Death due to non-cardiovascular causes occurred in 17 women in the control group and 21 women in the treatment group.

There was no significant difference between HRT and placebo for stroke, VTE and PE, breast cancer, and other cancers.

Although a large population of Danish women were smokers in the 1990s, the hazard ratios were similar between smokers and non-smokers in this study and there was no interaction between smoking and treatment for the primary endpoint or for mortality alone.

HRT for the prevention of CV events

Evidence on HRT for the prevention of cardiovascular disease in post-menopausal women.

Hormone replacement therapy (HRT) has been used for the management and prevention of cardiovascular disease (CVD) in older post-menopausal women. However, recent evidence suggests that treatment with HRT has no role in the prevention or treatment of CVD in post-menopausal women. In fact, HRT causes an increase in the risk of stroke and venous thromboembolic events (VTE) with both oestrogen-only and combined HRT. Combination HRT is associated with an increased risk of non-fatal myocardial infarction (MI) in primary prevention trials. HRT should therefore only be considered for women seeking relief from menopausal symptoms. In women with predisposing risk factors for CVD events, short-term HRT treatment at the lowest effective dose should be used cautiously.

A Cochrane systematic review (search date: April 2010) assessed the effects of HRT for the prevention of cardiovascular disease in post-menopausal women, including whether there are differential effects between use of single therapy alone compared with combination HRT, and the use of HRT in primary or secondary prevention of cardiovascular disease [Main et al, 2013].

Thirteen randomized controlled trials (RCTs) (n = 38,171 post-menopausal women) compared oral HRT (oestrogen, with or without progestogen) with placebo. Five of the trials aimed to assess the effects of HRT in the primary prevention of CVD, and therefore included predominantly healthy women. The other eight trials aimed to assess the impact of HRT in secondary prevention of CVD, and therefore recruited women with established CVD or women who had had a designated specific CVD event of interest (namely coronary artery by-pass graft [CABG], angina, MI or transient ischaemic attack, or VTE (pulmonary embolism [PE] or deep vein thrombosis [DVT]).

Treatment length varied from 11.9 months to 7.1 years.

The primary outcomes were death from any cause, cardiovascular death, non-fatal acute MI, stroke, and angina. The secondary outcomes were PE, VTE (PE plus DVT), CABG, and angioplasty (with or without a stent).

When the results of the evidence were pooled:

Single and combination HRT in both primary and secondary prevention studies conferred no protective effects for:

All cause mortality, after a mean follow-up of 3.2 years — risk ratio (RR) 1.03 (95% CI 0.94 to 1.14); assumed risk (AR) 39 per 1000 in the control group compared with 40 per 1000 (95% CI 37 to 44) in the HRT group.

Death due to a cardiovascular cause, after a mean follow-up of 3.3 years — RR 1.03 (95% CI 0.86 to 1.23); AR 12 per 1000 in the control group compared with 12 per 1000 (95% CI 37 to 44) in the HRT group.

Non-fatal MI, after a mean follow-up of 3.1 years — RR 1.04 (95% CI 0.92 to 1.18); AR 24 per 1000 in the control group compared with 25 per 1000 (95% CI 22 to 28) in the HRT group.

Angina, after a mean follow-up of 3.7 years — RR 0.91 (95% CI 0.8 to 1.03); AR 26 per 1000 in the control group compared with 23 per 1000 (95% CI 21 to 27) in the HRT group.

There was an increased risk of:

Stroke, after a mean follow-up of 3.8 years — relative risk (RR) 1.26 (95% CI 1.11 to 1.43); number needed to harm (NNH) 164; absolute risk (AR) 25 per 1000 in the control group compared with 31 per 1000 (95% CI 27 to 35) in the HRT group.

VTE, after a mean follow-up of 4.1 years — RR 1.89 (95% CI 1.58 to 2.26); NNH 109; AR 10 per 1000 in the control group compared with 20 per 1000 (95% CI 16 to 23) in the HRT group.

PE, after a mean follow-up of 3.4 years — RR 1.84 (95% CI 1.42 to 2.37); NNH 243; AR 5 per 1000 in the control group compared with 9 per 1000 (95% CI 7 to 12) in the HRT group.

Benefits of tibolone

Evidence on the benefits of tibolone

Tibolone is effective for treating vasomotor symptoms and may improve sexual function. It is not known whether tibolone is more effective than oestrogen and progestogen combined treatment in reducing vasomotor symptoms; however, it may be more effective than oestrogen and progestogen combined treatment in improving sexual function.

A Clinical Evidence Review (search date: June 2010) assessed the effectiveness of tibolone for treating vasomotor symptoms and improving sexual function [Burbos and Morris, 2011].

For vasomotor symptoms, three randomized controlled trials (RCTs) were found comparing tibolone with placebo:

The first RCT (n = 82) found that tibolone significantly reduced vasomotor symptoms at 16 weeks compared with placebo (39% reduction in mean score, p = 0.001).

The second RCT (n = 775) compared four doses of tibolone (0.625 mg daily, 1.25 mg daily, 2.5 mg daily, and 5 mg daily) with placebo. It found that tibolone 1.25 mg, 2.5 mg, and 5 mg reduced the frequency of hot flushes and sweating episodes compared with placebo (assessed using symptom diaries, results presented graphically; p < 0.0001). It found no significant difference in frequency of hot flushes and sweating episodes between tibolone 0.625 mg and placebo.

The third RCT (n = 396) compared two doses of tibolone (1.25 mg daily and 2.5 mg daily) with placebo. At 12 weeks the mean change in daily hot flushes was higher with both doses of tibolone than with placebo (–8.3 with tibolone 1.25 mg and –5.5 with placebo, p = 0.003 or less; and –9.7 with tibolone 2.5 mg and –5.5 with placebo, p < 0.001).

The third RCT also assessed for the mean change in severity scores of flushes. At 12 weeks the mean change in severity scores of flushes was higher with both doses of tibolone than with placebo (–0.9 with tibolone 1.25 mg and –0.3 with placebo, p < 0.001; and –1.7 with tibolone 2.5 mg and –0.3 with placebo, p < 0.001).

For urogenital symptoms, one trial was found comparing tibolone with placebo:

The RCT (n = 38) found that tibolone significantly increased sexual fantasies (p < 0.03) and arousability over 3 months compared with placebo (p < 0.01).

For vasomotor symptoms, two trials were found comparing tibolone with combined oestrogen and progestogen:

One RCT (n = 437) compared combined oestrogen-progestogen with tibolone. It found that combined oestrogen-progestogen reduced hot flushes over 48 weeks compared with tibolone (1.56 with tibolone and 1.25 with combined oestrogen-progestogen [p < 0.001], using a 5-point scoring system, where 1 = none and 5 = very severe).

The second RCT (n = 235) found no significant difference in vasomotor symptoms between combined oestrogen-progestogen and tibolone at 52 weeks (figures not reported).

For urogenital symptoms, two trials were found comparing tibolone with combined oestrogen and progestogen:

One RCT (n = 437) found that tibolone significantly improved vaginal dryness from baseline compared with estradiol plus norethisterone after 48 weeks of treatment (assessed using a 5-point scoring system: 2.1 at baseline to 1.33 after treatment with tibolone versus 2.1 at baseline to 1.27 after treatment with estradiol plus norethisterone; p < 0.001). This RCT also found that tibolone improved sexual satisfaction as measured using McCoy's Sex Scale Questionnaire compared with estradiol plus norethisterone (p < 0.05).

The second RCT (n = 50) found that tibolone significantly improved sexual desire and coital frequency (as measured using a questionnaire) compared with conjugated oestrogen 0.625 mg plus medroxyprogesterone acetate 2.5 mg after 12 months (p < 0.05 for both outcomes).

Risks of tibolone

Risks of tibolone

Tibolone is associated with an increased risk of breast cancer recurrence in women previously treated surgically for breast cancer.

A Clinical Evidence review (search date: June 2010) found one randomized controlled trial (RCT) comparing tibolone with placebo in 3148 women who had previously been treated surgically for breast cancer [Burbos and Morris, 2011].

The rate of breast cancer recurrence at 3.1 years was 15% (237/1556) with tibolone and 11% (165/1542) with placebo (p = 0.001).

The RCT was stopped early.

The authors of the review advise that clinicians should avoid prescribing tibolone for women with known or suspected breast cancer, and those with a history of previous breast cancer. They state that it remains reasonable to prescribe tibolone for women with no history of breast cancer, although they found no data from RCTs on the effects of tibolone on breast cancer risk in this group.

Other treatments

Evidence on other treatments for menopausal symptoms

Complementary therapies

Evidence on complementary therapies

There is no good evidence that phytoestrogens, black cohosh, evening primrose oil, dong quai, ginkgo biloba, or ginseng are effective for treating menopausal symptoms.

A Cochrane systematic review (search date: March 2007) found no evidence that phytoestrogens were effective for alleviating menopausal symptoms [Lethaby et al, 2007]. The review identified 30 trials of the efficacy and safety of phytoestrogens. Studies were included if they were randomized, had peri- or postmenopausal participants with vasomotor symptoms, were at least 12 weeks in duration, and had an intervention that was a food or supplement with high levels of phytoestrogens (not combined with other herbal treatments). Trials of women with breast cancer or a history of breast cancer were excluded. Most of the trials were too dissimilar to combine in a meta-analysis. The main results were:

Of the five trials (n = 300) with data suitable for pooling that assessed daily frequency of hot flushes, the frequency of hot flushes did not significantly differ between Promensil (a red clover extract) and placebo (weighted mean difference –0.6, 95% CI –1.8 to +0.6).

There was no evidence of a difference in percentage reduction in hot flushes in two trials that compared Promensil with placebo (weighted mean difference 20.2, 95% CI –12.1 to +52.4).

Individual results from the remaining trials were compared. Some of the trials found that phytoestrogen treatments alleviated the frequency and severity of hot flushes and night sweats compared with placebo, but many of the trials were of low quality and were underpowered.

A strong placebo effect was observed in most trials, with a reduction in frequency ranging from 1% to 59% with placebo.

No evidence indicated that the treatments caused oestrogenic stimulation of the endometrium (a potential adverse effect) when used for up to 2 years.

One systematic review (search date: December 2002) identified 18 randomized controlled trials (RCTs) of herbal treatments for the menopause. This review found that black cohosh and red clover may be effective for menopausal symptoms, but evidence is insufficient that evening primrose oil, dong quai, gingko biloba, and ginseng are effective for menopausal symptoms [Huntley and Ernst, 2003]:

The quality of the trials assessed was generally good, and many reported improvement with respect to baseline. This is important because of the known significant placebo effect with menopause treatments.

Black cohosh:

A small RCT randomized 80 women to receive black cohosh (16 mg daily), low-dose oestrogen (0.625 mg), or placebo for 12 weeks. All groups improved (compared with baseline), but the greatest improvement was with black cohosh (p < 0.001).

A second RCT randomized 60 hysterectomized women to receive black cohosh (16 mg daily), estriol (1 mg daily), conjugated oestrogens (1.25 mg), or oestrogen plus progestogen therapy. All groups improved significantly compared with baseline (p = 0.01).

A third RCT randomized 85 women with previous breast cancer to receive black cohosh (dose not reported) or placebo for 60 days. There was no significant difference between groups.

Dong quai:

One small RCT (n = 71) randomized women to receive dong quai or placebo for 24 weeks. There was no significant difference between groups at 24 weeks.

Ginseng:

One study randomized 384 women to receive ginseng or placebo for 16 weeks. Compared with placebo, ginseng only produced significant improvement on the Psychological General Well-being Index.

Evening primrose oil:

A small RCT (n = 56) randomized women to receive 2 grams of evening primrose oil daily or placebo for 24 weeks. Evening primrose oil and placebo did not significantly differ for any outcome measured.

Antidepressants, clonidine, and gabapentin

Evidence on antidepressants, clonidine, and gabapentin

Limited evidence indicates that clonidine, gabapentin, paroxetine, fluoxetine, citalopram, and venlafaxine are effective for treating hot flushes:

A systematic review (search date: October 2005) identified 43 randomized controlled trials (RCTs) (n = 4249) that compared the efficacy of non-hormonal therapies to treat hot flushes [Nelson et al, 2006]:

The trials assessing clonidine were of poor quality. Treatment duration in most trials was short (only up to 4 weeks in some cases). One trial assessed longer-term efficacy of antidepressants, with follow up at 9 months. The main results were as follows:

Antidepressants:

Combined results from seven RCTs (n = 848) found that paroxetine (10 or 20 mg daily), fluoxetine (20 mg daily), citalopram (20 mg daily), and venlafaxine (75 mg daily) decreased the number of daily hot flushes compared with placebo (mean difference, –1.13, 95% CI –1.70 to –0.57). Treatment duration was short, with most trials assessing efficacy from 4–12 weeks.

One trial (n = 150), included in these combined results, assessed efficacy after 9 months of treatment. This study found that fluoxetine and citalopram did not significantly decrease hot flushes compared with placebo.

The authors of this systematic review also performed a sensitivity analysis. Compared with placebo, antidepressants significantly reduced the number of hot flushes in women who had breast cancer and were taking a selective oestrogen receptor modulator (mean difference, –1.40; 95% CI –1.97 to –0.82). In the other two RCTs which enrolled women without breast cancer who were taking a selective oestrogen receptor modulator, the number of hot flushes were not reduced (mean difference, –0.17, 95% CI –1.41 to –1.07).

Clonidine:

Combined results from four RCTs (n = 444) found that clonidine decreased the number of daily hot flushes compared with placebo (mean difference –0.95, 95% CI –1.44 to –0.47).

Treatment duration ranged from 4–8 weeks.

Gabapentin:

Combined results from two trials (n = 479) found that gabapentin decreased the number of daily hot flushes compared with placebo (mean difference, –2.05, 95% CI –2.80 to –1.30).

Treatment duration ranged from 8–12 weeks.

Progestogens

Evidence on progestogens

Progestogens used alone are effective for treating vasomotor symptoms. However, due to adverse effects from the relatively high doses needed to achieve relief of menopausal symptoms, the clinical usefulness of progestogens given alone is unclear.

A Clinical Evidence review (search date: June 2010) assessed the evidence for the effectiveness of progestogens alone for reducing vasomotor symptoms [Burbos and Morris, 2011].

Three randomized controlled trials (RCTs) were identified that compared oral progestogens with placebo. All three studies found that progestogens significantly reduced vasomotor symptoms.

The first RCT (n = 97) compared oral medroxyprogesterone 200 mg twice daily with placebo. At 4 weeks, the proportion of women with 50% reduction in the frequency of daily hot flushes was significantly higher in the progestogen group than placebo (relative risk [RR] 2.9, 95% CI 1.71 to 4.89).

The second RCT (n = 21) found that oral medroxyprogesterone 100 mg twice daily significantly reduced hot flushes compared with placebo at 24 weeks (RR 2.6, 95% CI 1.37 to 4.83), and increased the proportion of women free from sweating (RR 6.0, 95% CI 2.1 to 17.4).

The third study (n = 27) found that oral medroxyprogesterone 20 mg daily significantly reduced daily hot flushes compared with placebo. There was a 74% reduction in daily hot flushes for medroxyprogesterone and a 26% reduction for placebo (p < 0.05).

Testosterone

Evidence on testosterone

There is evidence that adding testosterone to a hormone replacement therapy (HRT) regimen has significant beneficial effects on sexual function in post-menopausal women. However, this combined treatment is associated with a high incidence of facial hair growth and acne, and a reduction in high density lipoprotein (HDL) cholesterol. These adverse events may differ by the different doses and route of testosterone administration. There is insufficient evidence to determine the effect of long-term use of testosterone for this indication.

A Cochrane systematic review (search date: October 2008) was done to determine the benefits and risks of testosterone therapy in postmenopausal women taking HRT [Somboonporn et al, 2005].

Thirty-five trials which involved a total of 4768 women were included in the review. The median study duration was six months (range 1.5 to 24 months). Studies included randomized comparisons of testosterone plus HRT compared with HRT alone in perimenopausal or postmenopausal women.

Most of the trials were of adequate quality with regard to randomization and concealment of allocation sequence. However, different numbers of trials and participants were analyzed for each outcome depending on which outcomes were reported and whether they were reported in a form suitable for inclusion. The major methodological limitations were attrition bias and lack of a washout period in the crossover studies.

The results showed that adding testosterone to an HRT regimen has significant beneficial effects on different aspects of sexual function, including number of satisfying sexual events (standardized mean difference [SMD] 0.29, 95% CI 0.20 to 0.38), the total number of sexual events (SMD 0.25, 95% CI 0.17 to 0.34), number of orgasms (SMD 0.30, 95% CI 0.21 to 0.39), degree of libido or desire (SMD 0.35, 95% CI 0.26 to 0.43), level of orgasm (SMD 0.28, 95% CI 0.19 to 0.37), arousal (SMD 0.36, 95% CI 0.27 to 0.45), pleasure or enjoyment of sex (SMD 0.33, 95% CI 0.22 to 0.43), sexual concerns (SMD 0.32, 95% CI 0.22 to 0.41), responsiveness (SMD 0.32, 95% CI 0.23 to 0.40), sexual self-image (SMD 0.26, 95% CI 0.16 to 0.35), and for the composite sexual function score (SMD 0.41, 95% CI 0.19 to 0.63).

Adverse effects of treatment with testosterone plus HRT were a reduction in HDL cholesterol, increased incidence of facial hair growth (Peto odds ratio [OR] 1.52, 95% CI 1.07 to 2.17), and acne (Peto OR 1.52, 95% CI 1.07 to 2.14).

A reduction in HDL cholesterol was consistently seen for all testosterone regimens over all study durations that were evaluated, but the magnitude and precision of this effect varied with the study duration and route of administration of testosterone.

In a subgroup analysis, HDL levels were markedly decreased in postmenopausal women who were treated with oral testosterone (weighted mean difference [WMD] -18.63, 95% CI -22.18 to -15.08) while the effect size was smaller in the women who were treated with a testosterone patch (WMD -1.09, 95% CI -1.98 to -0.91).

There was no convincing evidence for effects on sense of well-being, unexplained fatigue, bone health, body composition, menopausal symptoms, cognition, or hostility. However, the authors of the Cochrane review stated that the conclusions are limited by the paucity of studies that have included these outcomes.

Evidence for long-term effects on breast cancer and coronary heart disease is lacking.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of menopause, with additional searches for evidence in the following areas:

Antidepressants for hot flushes

Search dates

July 2007 - April 2013

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

exp Menopause/, exp Menopause, Premature/, menopaus$.tw.

exp Hormone Replacement Therapy/, hormone replacement therapy.tw., HRT.tw.

exp Antidepressive Agents/, anti-depress$.tw., antidepress$.tw.

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

Royal College of Physicians

Royal College of General Practitioners

Royal College of Nursing

NICE Evidence

Health Protection Agency

World Health Organization

National Guidelines Clearinghouse

Guidelines International Network

TRIP database

GAIN

NHS Scotland National Patient Pathways

New Zealand Guidelines Group

Agency for Healthcare Research and Quality

Institute for Clinical Systems Improvement

National Health and Medical Research Council (Australia)

Royal Australian College of General Practitioners

British Columbia Medical Association

Canadian Medical Association

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Singapore Ministry of Health

National Resource for Infection Control

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Driver and Vehicle Licensing Agency

NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Drug & Therapeutics Bulletin

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

Patient experiences

Healthtalkonline

BMJ - Patient Journeys

Patient.co.uk - Patient Support Groups

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

British National Formulary (BNF)

electronic Medicines Compendium (eMC)

European Medicines Agency (EMEA)

LactMed

Medicines and Healthcare products Regulatory Agency (MHRA)

REPROTOX

Scottish Medicines Consortium

Stockley's Drug Interactions

TERIS

TOXBASE

Micromedex

UK Medicines Information

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