Menopause and Hormone Replacement - study group statement

Consensus views arising from the 47th Study Group: Menopause and Hormone Replacement

Clinical practice

1. Hormone replacement therapy (HRT) is effective for symptomatic relief of menopausal symptoms and its use for this is justified when symptoms adversely affect quality of life. The lowest effective dose for a particular woman should be used for the shortest period necessary and treatment reappraised at least annually. If menopausal symptoms return after stopping HRT, women may wish to consider restarting it and, provided they are fully informed of the risks, it should not be withheld.
2. 'Short-duration' HRT may be considered to be use of HRT for up to five years and is usually aimed at relief of menopausal symptoms in women in their early 50s. In some women, symptoms may persist considerably longer than this. If a decision is made to stop HRT, it should be phased out slowly in symptomatic women.
3. HRT can be used in younger women who have experienced a premature menopause (younger than 40 years), unless contraindicated, for treating menopausal symptoms and preventing osteoporosis until the age of normal menopause, when the therapy should be reviewed.
4. HRT can be used as 'add-back' therapy when gonadotrophin-releasing hormone (GnRH) agonists are administered to avoid menopausal symptoms.
5. Local oestrogen replacement may be required for the long term to reverse the symptoms of urogenital atrophy, which is a late manifestation of oestrogen deficiency. It appears to be more effective than systemic therapy. Low-dose vaginal oestrogens can also be used in the management of postmenopausal women with recurrent urinary tract infection once underlying pathology has been excluded. There is no evidence that local vaginal oestrogen treatment is associated with significant risks.
6. While irritative urinary symptoms such as urgency, urge incontinence and frequency and nocturia may be improved by oestrogens, stress incontinence cannot be treated effectively by oestrogens alone, although it may be a beneficial adjunct to surgery.
7. Women who have experienced a surgical menopause with bilateral oophorectomy may benefit from testosterone replacement in addition to oestrogen specifically to improve libido. The place of testosterone in ovary-intact women with low libido requires further evaluation. Testosterone replacement may be associated with adverse clinical and metabolic side effects and long-term consequences are unknown.
8. The overall risk--benefit balance for HRT in women without menopausal symptoms is not generally favourable.
9. HRT prevents osteoporotic fractures while it is taken although the benefit declines soon after stopping. Its use for this alone is, for most women, not recommended. However, its use in women at very high risk of osteoporosis could be carefully considered, particularly if other therapeutic agents are unsuitable.
10. Raloxifene, a selective oestrogen receptor modulator (SERM), reduces the incidence of vertebral fractures in women with osteoporosis. There is no current evidence of protection against fractures at the hip or at other sites. Use of raloxifene is associated with reduced risk of breast cancer but increased incidence of vasomotor symptoms.
11. Most randomised trials and observational studies have indicated that current or recent use of HRT increases risk of breast cancer. However, the risk returns to that of women who have never used HRT soon after it is discontinued. Women must be carefully counselled regarding this increased risk, which appears to be directly related to duration of therapy, not to dose. The evidence suggests that combined oestrogen and progestogen preparations increase the risk of breast cancer more than oestrogen alone. Women taking HRT should be advised to attend regularly for mammographic screening. HRT is contraindicated in women with previous breast cancer.
12. Women being prescribed, or already taking, combined oestrogen and progestogen preparations should be informed that this therapy may increase the likelihood of both false positive and false negative mammographic screening and that mammography may not detect breast cancer. Approximately one-quarter of women taking combined oestrogen and progestogen preparations will show a significant increase in mammographic density. This increase in density has been shown to reduce the sensitivity of screening mammography and to increase the likelihood that women are recalled for further investigations after mammography (even if they are not found to have breast cancer).
13. Tibolone has oestrogenic, progestogenic and androgenic properties. It appears to be effective in the treatment of vasomotor symptoms. Recent data suggest that tibolone may also be associated with an increased risk of breast cancer, but less than that associated with combined oestrogen and progestogen preparations.
14. HRT has been demonstrated in randomised trials not to confer either primary or secondary prevention against ischaemic heart disease or stroke. There is increased risk of stroke and an early excess risk of myocardial infarction in HRT users. The absolute risk of these conditions increases with age. HRT is contraindicated in women with clinical evidence of ischaemic heart disease, cerebrovascular disease or peripheral arterial disease.
15. The metabolic effect of oestrogen can be influenced by the route of administration.
16. All women commencing HRT should be counselled about the risk of venous thromboembolism (VTE), should be aware of the signs and symptoms of VTE, and should be able to access medical help rapidly if they suspect that they have developed a thrombus. Prior to commencing HRT, a personal history and a family history assessing the presence of VTE in a first- or second-degree relative should be obtained. HRT should be avoided in women with multiple pre-existing risk factors for VTE. Non-oral oestrogen may be associated with lower risk of VTE, compared with oral oestrogen therapy.
17. Testing for thrombophilia should be discussed with and be available for women with a personal or family history of VTE. It is recommended that, in women with a previous VTE, with or without an underlying heritable thrombophilia, oral HRT should usually be avoided in view of the relatively high risk of recurrent VTE. Universal screening of women for thrombophilic defects prior to or continuing the prescription of HRT is inappropriate. In women without a personal history of VTE but with an underlying thrombophilic trait that is identified through screening, HRT is not recommended in high-risk situations such as type 1 antithrombin deficiency or with combinations of defects or additional risk factors for VTE, and specialist advice should be sought.
18. It is recommended that, when a woman who is on HRT develops a VTE, HRT should be discontinued. It is recommended that, if a woman requires to continue on HRT after a VTE, long-term anticoagulation should be considered.
19. HRT should be considered a risk factor for VTE when assessing women preoperatively. However, HRT does not require to be routinely stopped prior to surgery provided that appropriate thromboprophylaxis, such as low-dose unfractionated or low-molecular-weight heparin, with or without thromboembolic deterrent stockings, is used.
20. Recent randomised controlled trials in women of 65 years or older reported that HRT does not have a beneficial effect on cognitive function. Also, HRT does not appear to be an effective treatment of established Alzheimer's disease. There is some evidence that use of HRT in women older than 75 years may increase the risk of developing dementia.
21. HRT should not be used, and is not licensed, as a primary treatment for clinically significant depression or dementia. Some, but not all, studies have shown that HRT appears to improve depressed mood in women with menopausal symptoms.
22. In women with a uterus, oestrogen-only therapy is associated with a significantly increased risk of developing endometrial hyperplasia and, with continued use, of endometrial carcinoma. This risk remains beyond cessation of therapy.
23. The addition of progestogen to oestrogen therapy reduces the risk of endometrial disease, but regimens should usually include at least 10 days in each monthly cycle. Postmenopausal women who have been taking sequential oestrogen-progestogen therapy for more than five years and wish to continue are at increased risk of endometrial carcinoma. They should consider changing to a continuous combined regimen, which appears to confer no increased risk.
24. Progestogens* alone may be effective in treating hot flushes and may be considered a therapeutic option for women who do not want to take, or cannot take, oestrogen. However some evidence suggests that progestogens might increase breast cancer risk even when prescribed without oestrogen. In addition, high-dose progestogens may be associated with increased risk of VTE.
25. There are differences between the progestogens in their metabolic and physiological effects but it is not known if these differences are clinically significant.
26. Small research studies suggest that the antidepressants venlafaxine*, paroxetine* and fluoxetine* are options for women with hot flushes who are not candidates for oestrogen therapy. These are not contraindicated in women with breast cancer. The additional antidepressant effect of these agents may be beneficial in women who also suffer from mood disorders although they may be associated with loss of libido.
27. A benefit of up to 50% is seen in trials of many 'alternative' preparations prescribed for vasomotor symptoms, even in placebo groups. Data are lacking regarding the efficacy and safety of topical natural progesterone cream and it cannot be recommended at present for the treatment of hot flushes. Similarly, there is no convincing evidence to support the use of food supplements and herbs.

* indicates an unlicensed indication

Education

1. The distinction between short-term HRT use for acute relief of menopausal symptoms and the risks and benefits of long-term use should be clarified.
2. Where appropriate, women should be advised in terms of absolute risks of the known adverse and beneficial effects of HRT, rather than relative risks.
3. With HRT use, women should appreciate the concept of individual needs and risk assessment coupled with population-based evidence.
4. Balanced information on HRT should be readily available to both clinicians and the public. Women with menopausal symptoms who choose to take HRT should be supported by well-informed healthcare professionals.
5. Accurate information should be available for women and primary care staff on the management of premature menopause.
6. The terminology for HRT preparations should be clarified and universally adopted.
7. Education at undergraduate level should introduce the communication skills necessary to enable doctors to deal with areas of medicine that are not disease-related, such as menopausal problems.
8. The primary care team should be able to respond to the challenge of evaluating and treating menopausal women. There are a number of GPs who have extended their knowledge and skills in the area of women's health and should be considered GP specialists. Further expansion of the GP specialist concept is important and should be supported by the academic colleges and central government.
9. Information technology offers enormous potential benefit for service delivery and communication. Investment in this field could assist information flow and decision support and provide for much-needed population-based research in areas such as menopausal medicine.
10. The media should make efforts to convey the key messages of the new results from research on HRT accurately.
11. New information regarding HRT should be released to experts sufficiently early so that findings can be put into context and cascaded down in sufficient time to allow clinicians to respond appropriately.
12. Editors of major medical journals should commission balanced editorials to accompany new research findings.

Research is recommended in the following areas:

1. To study the natural history of menopausal symptoms.
2. To ascertain more precisely the relationship between declining steroid hormone levels accompanying the menopause and menopausal symptoms and quality of life issues.
3. To clarify further the mechanisms that lead to menstrual cycle disturbance during the menopausal transition and the cessation of menstruation at the end of the transition.
4. To formulate internationally acceptable definitions for the onset of the menopausal transition, with a precise definition of menstrual irregularity.
5. To develop and assess treatment strategies in women with premature menopause.
6. To investigate the link between sex hormones, mental health and cognitive function.
7. To look at the effect of oestrogen on mood disorders as distinct from vasomotor symptoms and insomnia.
8. To define quality of life issues in menopausal women using appropriately validated quality of life tools.
9. To consider the holistic needs of women and their expectations and goals, including lifestyle and impact of symptoms on ability to function normally.
10. To identify further areas where HRT may have an impact on quality of life, e.g. urogenital prolapse, urinary incontinence and sexual dysfunction.
11. To identify the optimum regimen of HRT for women with endometriosis following hysterectomy and bilateral oophorectomy.
12. To study the benefit and optimum type of 'add-back' hormone therapy in women receiving long-term (more than six months) GnRH regimens.
13. To evaluate the role of intrauterine delivery of progestogen for providing long-term protection of the endometrium in an HRT regimen and its effect on breast cancer risk.
14. To evaluate the long-term effects of treatments for osteoporosis other than HRT, so that the benefits and any associated risks can be compared.
15. To ascertain what the optimum treatment is for women in their 50s with osteopaenia and a family history of osteoporotic fracture in a first-degree relative. In particular, to identify agents other than HRT that can be used by women before they actually sustain an osteoporotic fracture.
16. To identify dosages and routes of administration of oestrogen alone or combined oestrogen plus progestogen preparations that do not increase breast cancer risk, while still retaining fracture benefit.
17. To identify novel oestrogenic agents that do not bind oestrogen receptors in breast and endometrium, while maintaining bone protection.
18. To examine the effects of progesterone and synthetic progestogens on the breast.
19. To define factors and mechanisms that control proliferation and involution of terminal ductal-alveolar units within the breast.
20. To develop model systems that more accurately reflect the structure, activity, sensitivity and hormonal environment of postmenopausal breast, recognising that risk of breast cancer may be more dependent upon local influences within the breast than factors circulating in blood.
21. To examine whether women shown to have increased mammographic density as a result of HRT should consider temporarily stopping treatment for a period of time before attending for mammographic screening.
22. To ascertain whether cessation of a selective oestrogen receptor modulator (SERM) such as raloxifene, which reduces breast cancer risk in healthy but 'high-risk' women, is followed by a 'rebound' increase in risk.
23. To examine the effects of oestrogen alone and oestrogen plus progestogen in relation to cardiovascular disease risk, with emphasis on preparation, dosage and route of administration among younger, recently postmenopausal women.
24. To identify alternative agents and non-hormonal ways of alleviating menopausal symptoms. In particular, the potential roles of phyto-oestrogens and black cohosh need careful evaluation and the quality assurance of these agents during manufacture should be assessed.