Abstract
Management of the menopausal woman has become controversial since publication of the results of the Women's Health Initiative and the Million Women Study from 2002 onwards. This health-care pathway summarizes the role of hormone replacement therapy and non-estrogen-based treatments as well as alternative and complementary therapies. It is based on the fifth edition of Management of the Menopause and was updated on 5 April 2011.
Keywords
Introduction
The median age of the menopause is 51. Various definitions are in use:
Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity. Natural menopause is recognized to have occurred after 12 consecutive months of amenorrhoea, and is thus known with certainty only a year after the event.
Perimenopause includes the period beginning with the first features of the approaching menopause, such as vasomotor symptoms and menstrual irregularity, and ends 12 months after the last menstrual period.
Postmenopause should be defined as dating from the final menstrual period. However, it cannot be determined until after 12 months of spontaneous amenorrhoea.
Premature menopause ideally should be defined as menopause that occurs at an age less than two standard deviations below the mean estimated for the reference population. The age of 40 years is frequently used, arbitrarily, to define it.
Hormone replacement therapy
Hormone replacement therapy (HRT) consists of an estrogen, combined with a progestogen in non-hysterectomized women. Different routes of systemic estrogen administration are employed: oral, transdermal and subcutaneous. Progestogens can be administered orally, transdermally or directly into the uterus (levonorgestrel).
There is evidence from randomized controlled trials (including the Women's Health Initiative) that HRT reduces the risk of both spine and hip as well as other osteoporotic fractures. Epidemiological studies suggest that for HRT to be an effective method of preventing fracture, continuous and lifelong use is required. However, it has been shown that a few years of HRT given around the time of the menopause may have a long-term effect on fracture reduction. While alternatives to HRT use are available for the prevention and treatment of osteoporosis, estrogen may still remain the best option, particularly for young and/or symptomatic women.
Tibolone is a synthetic steroid compound that has mixed estrogenic, progestogenic and androgenic actions and is used in postmenopausal women who wish amenorrhoea. It conserves bone mass and reduces the risk of vertebral and non-vertebral (but not hip) fractures particularly in patients who have already had a vertebral fracture.
Testosterone patches and implants may be used to improve libido.
Duration of therapy
Menopausal symptoms. Treatment can be continued for up to five years and then stopped to evaluate whether symptoms recur with sufficient severity to warrant continuation. Since the duration of symptoms cannot be predicted, there are no arbitrary limits as to how long treatment for symptoms will be required, and treatment can be continued for as long as the individual feels that benefits outweigh risks.
Osteoporosis. Treatment may need to be lifelong. Bone mineral density falls when treatments are stopped. Younger women commencing treatment with HRT may wish to change to other agents, such as bisphosphonates or raloxifene, because of the increased risk of breast cancer with longer-term combined HRT. Bone mineral density estimation should be utilized to inform regimen change or cessation. A calcium-replete diet plus weight-bearing exercises should accompany HRT and all other regimens.
Premature menopause. Women are usually advised to continue with HRT until the median age of the natural menopause (i.e. 51). This advice remains unchanged by the Women's Health Initiative and Million Women Study, which were undertaken in women aged 50 and above.
Hysterectomized/non-hysterectomized women
Progestogens are added to reduce the increased risk of endometrial hyperplasia and carcinoma that occurs with unopposed estrogen. Oral or transdermal progestogen can be given ‘sequentially’ or 10–14 days every four weeks, for 14 days every 13 weeks (long cycle) or everyday – that is, ‘continuously’. The first leads to monthly bleeds, the second to bleeds every three months and the last aims to achieve amenorrhoea. Levonorgestrel can be delivered directly into the uterus with a device originally used to provide contraception and is the only way a ‘no-bleed’ regimen can be achieved in perimenopausal women.
Progestogens must be given to women who have undergone endometrial ablative techniques since it cannot be assumed that all the endometrium has been removed. In general, hysterectomized women should be given estrogen alone.
Treatment of urogenital symptoms alone
The options available are vaginally administered low-dose natural estrogens, such as oestradiol by tablet or ring or oestriol by cream or pessary. With the recommended dose regimens, these low-dose preparations have not been shown to significantly elevate systemic estrogen levels. Long-term treatment is required since symptoms return on cessation of therapy. Oestradiol vaginal tablets can be prescribed indefinitely. With the recommended dose regimens, no adverse endometrial effects should be incurred and a progestogen need not be added for endometrial protection.
Non-estrogen-based therapy
These treatments should be considered for women who do not wish to take estrogen-based HRT or have a contraindication to therapy.
Hot flushes
Progestogens such as norethisterone and megestrol acetate can be effective in controlling hot flushes and night sweats.
Clonidine is a centrally acting alpha-adrenoceptor agonist originally developed as an antihypertensive. However, it has only limited value and effectiveness.
Selective serotonin re-uptake inhibitors and serotonin and noradrenalin re-uptake inhibitors, such as paroxetine, fluoxetine, citalopram and venlafaxine, are effective in treating hot flushes in short-term studies.
Gabapentin is used to treat epilepsy, neuropathic pain and migraine. Limited evidence shows that it may be effective.
Vaginal atrophy
Traditional lubricants and newer vaginal moisturizers are available with and without prescription. The integrity and efficacy of condoms may be compromised by lubricants such as petroleum-based products and baby oil.
Prevention and treatment of osteoporosis
Pharmacological interventions
Interventions for the prevention and treatment of osteoporosis
The levels of evidence for the various agents detailed below are:
A, meta-analysis of RCTs or from at least one RCT/from at least one well-designed controlled study without randomization; B, from at least one other type of well-designed quasi- experimental study/from well-designed non-experimental descriptive studies, e.g. comparative studies, correlation studies, case-control studies; ND, not demonstrated
Bisphosphonates, such as alendronate, risedronate, zoledronic acid and ibandronate, are used in the prevention and treatment of osteoporosis. All bisphosphonates are absorbed poorly from the gastrointestinal tract and must be given on an empty stomach. The principal side-effect of all oral bisphosphonates is irritation of the upper gastrointestinal tract. Symptoms resolve quickly after drug withdrawal and these adverse effects are much reduced by using weekly or monthly rather than daily administration. Zoledronic acid is administered intravenously.
Raloxifene, a selective estrogen receptor modulator, is licensed for the prevention of osteoporosis-related vertebral fracture. It reduces the incidence of vertebral fracture by 30–50%, depending on the dose, in women with established osteoporosis; however, there is as yet no evidence of efficacy in non-vertebral fracture, such as hip fracture.
Parathyroid hormone peptides are given as daily subcutaneous injections. They reduce the risk of vertebral but not hip fractures.
Strontium ranelate decreases the risk of vertebral and hip fractures. It is administered daily, dissolved in water; it should be taken at least two hours after food. The most common side-effects are mild and transient nausea and diarrhoea but these are rare in absolute terms.
Denosumab is a fully human monoclonal antibody to receptor activator of nuclear factor-κB ligand (RANKL), the principal regulator of osteoclastic bone resorption. By binding to RANKL, denosumab prevents RANKL from binding to its receptor, resulting in a decrease in bone resorption due to reduction in the formation, activity and survival of osteoclasts. In postmenopausal women with osteoporosis it increases bone mineral density and reduces the risk of vertebral, hip and non-vertebral fractures. It is given by subcutaneous injection.
Non-pharmacological interventions
Calcium and vitamin D supplementation may be relevant when much evidence of insufficiency exists, especially in the elderly. Most studies show that about 1.5 g per day of elemental calcium is necessary to preserve bone health in postmenopausal women and elderly women who are not taking HRT. In women who use HRT, 1 g per day is sufficient to maintain calcium balance. The effects on fracture of calcium and vitamin D supplements alone or in combination, however, are contradictory. They may depend on the study population. People in sheltered accommodation or residential care may be more frail, have lower dietary intakes of calcium and vitamin D and are at higher risk of fracture than those living in the community. However, in women whose diet is replete there are concerns about an increased risk of kidney stones and coronary heart disease.
Hip protectors are used to reduce the impact of falling directly on the hip. Accumulating evidence indicates that hip protectors are an ineffective intervention for both those living at home and within an institution.
Alternative and complementary therapies
Evidence from randomized trials that alternative and complementary therapies improve menopausal symptoms or have the same benefits as HRT or non-estrogen-based treatments is poor. Many women, however, use them in the belief that they are safer and ‘more natural’. A major concern is interaction with other treatments, which can have potentially fatal consequences. Some herbal preparations may contain estrogenic compounds, and this is a concern for women with hormone-dependent diseases, such as breast cancer. Concern also exists about the quality control of production.
Phytoestrogens are plant substances that have effects similar to those of estrogens. The most important groups are called isoflavones and lignans. The major isoflavones are genistein and daidzein. The major lignans are enterolactone and enterodiol. Isoflavones are found in soybeans, chickpeas, red clover and probably other legumes (beans and peas). Oilseeds such as flaxseed are rich in lignans, and they also are found in cereal bran, whole cereals, vegetables, legumes and fruit.
Herbal remedies used by menopausal women include black cohosh, kava kava, evening primrose, dong quai, gingko, ginseng and wild yam cream.
Progesterone transdermal creams have been advocated for the treatment of menopausal symptoms and skeletal protection. At present, there are insufficient published data showing that transdermal progesterone has a positive effect on vasomotor symptoms or the skeleton; they do not have a protective effect on the endometrium.
Whom to refer for specialist advice
While the majority of women can be managed in primary care, in the situations shown in Table 1, referral may be necessary for investigation and specialist advice about the use of HRT.
Patient assessment
FSH, follicle-stimulating hormone; HRT, hormone replacement therapy; DXA, dual energy X-ray absorptiometry; V/Q scan, ventilation/perfusion scan; TFT, thyroid function test
Taking a patient history
Periods, symptoms and contraception
Date of last menstrual period (could she be pregnant?)
Frequency, heaviness and duration of periods
Hot flushes and night sweats
Vaginal dryness
Other symptoms
Contraception.
Personal or family medical problems
1. Breast, ovarian or bowel cancer in close family members
Have any parents, sisters or brothers or the patient had such cancers? If so, at what age did they develop it? Have any parents, brothers or sisters or the patient had such conditions? If so, when and why did this happen? Was it after a hip or knee replacement? Were they on the ‘pill’ or pregnant? Did they have any test to confirm the clot? Was the clinical suspicion confirmed? Were they treated with anticoagulants such as heparin or warfarin? Has the patient already had a heart attack or stroke? Have her parents, brothers or sisters had a myocardial infarction or stroke, and, if so, at what age? Does the patient smoke, and, if so, how many cigarettes a day? Does the patient have hypertension or diabetes? Does the patient have a high cholesterol level? Was the menopause before the age of 45 years? Has the patient taken systemic corticosteroids for six months or longer? Has the patient had anorexia or significant weight loss? Does the patient have a family history of osteoporosis (especially in her mother, grandmother or sister)? Has the patient had low calcium or vitamin D intake or deficiency or malabsorption disorders? Has the patient already had a fracture? If so, how did it happen and where was it? If from a fall, was it from standing height? Has the patient had migraines? What medicines are being taken, including herbal remedies and vitamin supplements? Is the patient at risk of pregnancy? Does she want to take HRT? If yes, what preparation would she prefer – and by what route? If not, what are her most important treatment endpoints?
2. Deep vein thrombosis or pulmonary embolism
3. Risk factors for heart disease and stroke
4. Risk factors for osteoporosis
5. Other
6. What does the patient want?