Menopause

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment is indicated if menopausal symptoms interfere with a woman's daily functioning and quality of life. The prevailing symptoms should be clarified, and lifestyle changes and drug therapy options (with benefits and risks) explained.

Hormone therapy should be given at the lowest dose and for the shortest time possible, while retaining the benefit of symptom relief. Since duration of symptoms cannot be predicted, there is no predetermined maximum duration of hormone therapy; all patients require individualised decision making. Reassessment should occur at least annually.

Management of hot flushes

Hot flushes can be treated pharmacologically (hormonal and non-hormonal), non-pharmacologically (lifestyle and alternative therapies), or with a combination of both.

Lifestyle changes

Despite limited evidence, certain lifestyle changes can improve symptom tolerance. Women should be encouraged to lose weight (where appropriate) and to exercise more.[11] Both have cardiovascular and bone health benefits and can improve overall wellbeing, but may not have a specifically identifiable impact on hot flushes and cannot improve bone density.[8]

Other self-care measures include avoidance of spicy foods, alcohol, caffeine, warm environments, and stress. Alcohol and caffeine intake are associated with worsening vasomotor symptoms (VMS). Wearing layered clothing and use of hand-held fans, drinking cold water, and mist bottles may be helpful. One qualitative review of randomised controlled trials (RCTs) and meta-analyses found that yoga is moderately effective in the short term for psychological symptoms, but has no impact on somatic, vasomotor, or urogenital symptoms.[33]

Oral combination oestrogen/progestin therapy

Hormonal therapy for a woman with a uterus comprises an oestrogen, and a progestin to protect against endometrial hyperplasia and cancer.[17] Oestrogens are the most effective treatment for VMS, reducing hot flushes by 80% to 90%.[34]

Combination regimens include:

Continuous combined regimens: an oestrogen and a progestin are taken daily
Sequential regimens: a progestin is added cyclically for 10 to 14 days each month.

The continuous combined regimen is indicated in women who have had amenorrhoea for more than 12 months. It is easy to follow and continues the amenorrhoea of the menopause. If the woman has breakthrough bleeding after the first 6 months on the continuous combined regimen, endometrial assessment (pelvic ultrasound ± endometrial biopsy) is required and consideration should be given to switching to a sequential regimen so that she can have a predictable bleeding pattern.

In a sequential regimen, a progestin is added to an oestrogen for the last 10 to 14 days of the cycle. Sequential hormone therapy (HT) may be preferred by perimenopausal women, but may also be indicated in postmenopausal women.[35][36]

Hormone therapy with an oestrogen alone

Women without a uterus can take an oestrogen alone if they do not have contraindications for systemic oestrogen therapy.[17] [ ]

Transdermal administration of an oestrogen

A transdermal formulation of oestrogen (usually estradiol) is preferable to an oral oestrogen in women who have a higher thrombotic risk (including body mass index >30), are taking other medications, have borderline triglyceride levels, are at risk for gallstones, or have difficulty adhering to a daily pill-taking regimen. Because there is no first-pass effect, a transdermal oestrogen formulation may reduce the risk of thromboembolism compared with an oral oestrogen, but this has not been studied in an RCT.[22][23] It might also have a lower incidence of nausea. Long-term complications of transdermal oestrogen formulations are probably the same as those of oral oestrogens, although these were not specifically studied in the Women's Health Initiative. According to UK National Institute for Health and Care Excellence recommendations, a transdermal oestrogen formulation at standard therapeutic doses does not increase the risk of venous thromboembolism compared with baseline population risk, nor is it likely to increase the risk of stroke.[1]

Transdermal estradiol is available in patch, metered-dose spray, or gel formulations, all of which are applied to the skin. One 12-week, multi-centre RCT found that, compared with placebo, transdermal estradiol gel significantly reduced the frequency and severity of hot flushes at weeks 4 and 12 in healthy menopausal women who had moderate to severe hot flushes.[37] Headache, infection, breast pain, nausea, and insomnia were the most frequently reported side effects. A network meta-analysis found no difference in efficacy between an estradiol transdermal patch and an estradiol transdermal spray for vasomotor symptoms.[38]

Women with an intact uterus require protection with a progestin. A combination of an oestrogen and a progestin is available in a single transdermal patch in most countries. Transdermal combined sequential HT preparations are also usually available.

Stopping oestrogen therapy

There is insufficient evidence to recommend one method of stopping oestrogen therapy over another. There is no standard age for discontinuation of HT. Each individual should be assessed on a regular basis (e.g., annually) to determine the extent of benefit from HT. For women who derive minimal benefit from HT, a reasonable discussion of treatment cessation may take place at any age.

Conjugated oestrogens with bazedoxifene

Conjugated oestrogens/bazedoxifene (a selective oestrogen receptor modulator) has been approved in some countries for the treatment of VMS and osteoporosis prevention in women with an intact uterus.[8][39] Compared with conjugated oestrogens/medroxyprogesterone, women treated with conjugated oestrogens/bazedoxifene experienced significantly fewer adverse events. Women taking conjugated oestrogens/bazedoxifene should not take a progestin.

Bazedoxifene has a favourable (anti-oestrogenic) effect on breast tissue.[40] Further research is required.

Bioidentical hormones

Bioidentical hormone therapy (BHT) preparations are simply an oestrogen (with or without a progestin) in a custom compounded base. Unregulated compounded BHT has been touted as 'natural' and safer than conventional HT, but these claims are unsubstantiated.

One systematic review concluded that BHT is more effective than placebo for treating moderate to severe menopausal hot flushes (low to moderate quality evidence), but with higher rates of adverse effects.[41] There is no long-term safety data relating to outcomes such as myocardial infarction, stroke, and breast cancer.[41]

Advisory bodies such as the North American Menopause Society, the American College of Obstetricians and Gynecologists, the US National Academies of Sciences, Engineering, and Medicine, and the British Menopause Society do not generally recommend compounded oestrogen/progestin therapy due to the lack of standardised purity and potency with the attendant risks of over- or under-dosing.[17][35][42][43] Similarly, the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) do not recommend BHT due to the lack of proven benefit and the potential for poor quality control.[23] For most women, licensed (regulated) HT provides appropriate therapy without the risks of custom preparations.

Regulated preparations containing estradiol and micronised progesterone (an oestrogen similar to, and a progestogen equivalent to, those produced by the ovaries) should be used in preference to compounded preparations by women considering more natural preparations. The 2017 AACE/ACE position statement recommends that when the use of progesterone is necessary, micronised progesterone is considered the safer alternative to a synthetic progestin.[23] Micronised progesterone may be taken by the oral or vaginal route, but transdermal micronised progesterone does not protect the endometrium.[44]

Bioidentical progesterone cream is available over the counter, but only one of three published RCTs showed some efficacy compared with placebo in reducing VMS.[45]

Risks of hormone therapy

It is important to provide information on the benefits and risks of HT, to help women make an informed choice about which, if any, treatment to use for menopausal symptoms. [ ] [ ]

Risk associated with HT use varies between women depending upon dose, duration, route of administration, age at initiation of therapy, and whether a progestogen is included in the regimen. The benefit-risk ratio of HT appears favourable for the management of VMS and the prevention of bone loss or fracture among women (without contraindications) who are aged under 60 years or are within 10 years of the menopause onset.[8][17]

During 18 years of follow-up, all-cause mortality among the pooled cohort of postmenopausal women who received 5 to 7 years of HT in the two Women's Health Initiative trials did not differ between the HT and placebo groups (27.1% versus 27.6%, respectively; hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.94 to 1.03]).[46] Neither oestrogen alone (HR 0.94, 95% CI 0.88 to 1.01) nor oestrogen plus progestin (HR 1.02, 95% CI 0.96 to 1.08) were associated with increased risk of all-cause mortality.[46]

Heart disease, stroke, and venous thromboembolism

HT is not currently recommended for the primary prevention of cardiovascular disease.[17][18][19][20] Further research is required to evaluate the impact of timing of HT initiation on coronary heart disease risk and mortality.
[Figure caption and citation for the preceding image starts]: Absolute rates of coronary heart disease for different types of hormone therapy (HT) compared with no HT (or placebo), different durations of HT use, and time since stopping HT for menopausal women.National Institute for Health and Care Excellence. Menopause: diagnosis and management. Dec 2019 [Citation ends].
The risk of venous thromboembolism and ischaemic stroke increases with oral HT, but the absolute risk of stroke in women under 60 years of age is very low.[1][47][48] Observational studies and a meta-analysis indicate that transdermal oestrogens are associated with a lower risk of venous thromboembolism and stroke than oral oestrogens.[1][17][47][48] Patients at high risk for cardiovascular complications should have a careful assessment of the risks and benefits of HT, and may be candidates for a trial of non-HT.[11]
[Figure caption and citation for the preceding image starts]: Absolute rates of stroke for different types of hormone therapy (HT) compared with no HT (or placebo), different durations of HT use, and time since stopping HT for menopausal women.National Institute for Health and Care Excellence. Menopause: diagnosis and management. Dec 2019 [Citation ends].

Breast and ovarian cancer

HT with an oestrogen alone is associated with little or no change in the risk of breast cancer.[1] An oestrogen prescribed in combination with a progestin is associated with a small increase in the risk of breast cancer.[1][47][48][Evidence C] The increased risk is related to duration of treatment, and likely recedes after treatment is stopped.[1][47][48] The UK Medicines and Healthcare products Regulatory Agency has published a table summarising the risk of breast cancer for women currently receiving hormone therapy and post treatment from age of menopause up to age 69 years.[49]
[Figure caption and citation for the preceding image starts]: Summary of HRT risks and benefits* during current use and current use plus post-treatment from age of menopause up to age 69 years, per 1000 women with 5 years or 10 years use of HRT. Key: *Menopausal symptom relief is not included in this table, but is a key benefit of HRT and will play a major part in the decision to prescribe HRT. †Best estimates based on relative risks of HRT use from age 50. For breast cancer this includes cases diagnosed during current HRT use and diagnosed after HRT use until age 69 years; for other risks, this assumes no residual effects after stopping HRT use. § Latest evidence suggests that transdermal HRT products have a lower risk of VTE than oral preparationsMedicines and Healthcare products Regulatory Agency. Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping. Aug 2019 [internet publication]; used with permission [Citation ends].
There is evidence to suggest that HT increases breast tissue density.[1] This can make tumour detection more difficult, and may result in some women being recalled for repeat mammography and/or further evaluation.
A meta-analysis of 52 epidemiological studies analysed the risks of ovarian cancer in 12,110 postmenopausal women, 55% of whom had used HT for some period of time.[50] The meta-analysis suggested that 5 years of HT use, starting at age 50 years, would result in one extra ovarian cancer per 1000 users.[50]
One 2019 meta-analysis of prospective studies found HT use for more than 1 year in postmenopausal women to be associated with an increased risk of breast cancer.[51] Risk increased with longer duration of HT use, and persisted after HT was stopped. Risk was higher with combined oestrogen-progestogen compared with oestrogen-only preparations, but there was no increased risk with topical vaginal oestrogens. Current advice is unchanged - that HT should be used for the shortest time that it is needed, and patients should be vigilant for signs of breast cancer and encouraged to attend regular breast cancer screening.[49][52] The risks and benefits of HT should be discussed with patients during shared decision making before commencing HT.[1][53]

Non-hormonal medications for vasomotor symptoms

A systematic review and meta-analysis of 43 trials of non-hormonal therapies found that oestrogen replacement was significantly more effective than non-hormonal alternatives.[54] However, non-hormonal alternatives may benefit women who are unable to take an oestrogen because of risk factors or inability to tolerate HT.[55]

Selective serotonin-reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs)

SSRIs and SNRIs are effective for treating VMS in women unable to take HT.[56][57][58]
Some evidence suggests that escitalopram may be more effective than other SSRIs at reducing hot flushes.[58] Only paroxetine is approved for the treatment of moderate to severe VMS associated with the menopause.[34][59]
In an 8-week RCT of 339 perimenopausal and postmenopausal women with bothersome VMS, venlafaxine (an SNRI) reduced the frequency of symptoms by 1.8 more per day than placebo (P=0.005).[60] Low-dose estradiol appeared to be more effective (2.3 fewer VMS per day than placebo), but it was not compared directly with venlafaxine in this study.[60] Venlafaxine may be a reasonable alternative for women unable to take an oestrogen.
Compared with placebo, desvenlafaxine (an SNRI) reduced the frequency and severity of moderate to severe hot flushes over a 12-month period in an RCT of 365 postmenopausal women with bothersome VMS.[61] Subsequent to concerns regarding the safety of desvenlafaxine in this patient population, a discrete safety analysis found no evidence for an increased risk of cardiovascular, cerebrovascular, or hepatic events associated with desvenlafaxine (compared with placebo) for the treatment of menopausal VMS.[62]

Gabapentin

Studies indicate that gabapentin is moderately effective for the treatment of hot flushes.[36][63] However, drowsiness, dizziness, and unsteadiness are commonly reported adverse effects.[63] Gabapentin may result in intolerable lethargy when used during the day.[36] Side effects can be mitigated by dosing only at night, or by using a dose escalation regimen.

Clonidine

Clonidine, an antihypertensive agent, reduces hot flushes but may be less effective than SSRIs/SNRIs and gabapentin.[36] Hypotension may be a treatment-limiting adverse effect.[64] Blood pressure should be monitored during therapy and for rebound after discontinuation. Transdermal patches result in stable blood levels and are preferred to oral clonidine preparations.[36]

Symptoms of urogenital atrophy

Low-dose vaginal oestrogen preparations can be considered in women with symptoms of urogenital atrophy.[17]

A review of Medline and Cochrane databases showed that vaginal oestrogens are more effective than placebo for improving dryness and decreasing dyspareunia, urinary urgency, and urinary frequency.[65] Rates of urinary tract infections also declined with vaginal oestrogen use. Serum estradiol levels remained within postmenopausal norms, except for those who used high-dose vaginal oestrogen cream.[65]

In women without a history of hormone-dependent cancer, vaginal oestrogens can be continued for symptom relief, and there is no evidence to recommend endometrial surveillance.[30] In the Women's Health Initiative observational study, the risk of cardiovascular disease, invasive breast cancer, and endometrial cancer did not differ between women who were vaginal oestrogen users and those who were not.[66]

Vaginal oestrogens do not require progestin replacement.

Vaginal estradiol tablets do not result in significant systemic absorption and can be used long-term as required. However, in October 2019, the European Medicines Agency recommended limiting the use of high-strength estradiol vaginal creams (containing estradiol 100 micrograms/g or 0.01%) to a single treatment period of up to 4 weeks. This is because levels of estradiol in the blood were found to be higher than normal postmenopausal levels and could result in similar adverse effects to those seen with systemic (oral or transdermal) HT (e.g., venous thromboembolism, stroke, endometrial cancer, breast cancer). This formulation should not be used in patients already on HT.[67] Therefore, other vaginal oestrogen formulations (e.g., conjugated oestrogen cream, estradiol intravaginal tablets and rings) may be preferred. There is no evidence to suggest that any one vaginal oestrogen preparation is more efficacious than another.[68]

Ospemifene is a selective oestrogen receptor modulator indicated for the treatment of dyspareunia in postmenopausal women. In a phase 3 trial, ospemifene increased the percentage of superficial cells and reduced dyspareunia compared with placebo.[69] Hot flushes were the most frequently reported adverse event (ospemifene 7% versus placebo 4%).[69][70]

Breast and gynaecological cancer survivors

Consensus recommendations for the management of menopausal symptoms after breast cancer include:[71][72]

Generally avoiding treatment with systemic menopausal hormone therapy or vaginal oestrogen*
Implementing lifestyle measures (e.g., healthy diet, regular physical activity, smoking cessation, weight loss, limiting or avoiding alcohol, maintaining adequate levels of vitamin D and calcium)
Non-hormonal, pharmacological therapy (e.g., selective serotonin/noradrenaline reuptake inhibitors), and/or cognitive behavioural therapy.

*There are data to suggest that HT does not increase risk of recurrence in women who do not have an oestrogen-dependent malignancy.[73][74] One review suggested that short-term use of HT may result in improvement of menopausal vasomotor and genitourinary symptoms in patients with gynaecological cancer who do not have an oestrogen-dependent malignancy.[73] The use of oestrogens in women with non-oestrogen-dependent malignancy must be tailored to the patient's situation.

Polycarbophil gel, a vaginal moisturiser, can also be offered for symptoms of vaginal atrophy, including dryness and dyspareunia.[75][76] Dyspareunia is common in breast cancer survivors due to atrophy and dryness from lack of oestrogen. In a small trial, lidocaine reduced tenderness in the vulvar vestibule of postmenopausal breast cancer survivors with dyspareunia (median coital pain score 8 on a 10-point scale) compared with normal saline.[75] Intravaginal dehydroepiandrosterone (DHEA) and oral ospemifene are approved for the management of dyspareunia, but safety following breast cancer has not been established.[71]

Reduced libido

Women with distressing low sexual desire and tiredness should be counselled that androgen supplementation is an option, particularly if an oestrogen with or without a progestin has not been effective.

The Endocrine Society recommends against diagnosing androgen deficiency in healthy menopausal women because there is a lack of a well-defined syndrome and data correlating androgen levels with specific signs or symptoms are not available.[77] See Sexual dysfunction in women.

Urinary stress incontinence

Pelvic floor rehabilitation may be useful for urinary stress incontinence.[78] In one study, 73.4% of postmenopausal women randomised to a combination of intravaginal estriol and pelvic floor rehabilitation for 6 months experienced subjective improvement in stress urinary incontinence compared with only 9.71% of women in the control (estriol-only) group.[79] Both groups reported improvement in signs and symptoms of urogenital atrophy.

Sleep disturbance and mood symptoms

Difficulty sleeping or nocturnal restlessness and awakening are common problems during the menopause. Insomnia is often associated with hot flushes (other factors, such as depression or sleep apnoea, may also be involved). But no studies have shown a direct physiological link.

Some women report improved sleep while taking HT.[17][80] In one systematic review of 11 studies of varying quality, progesterone improved VMS and sleep quality.[81]

Data suggest that short-term use of HT may improve mood and depressive symptoms during the menopausal transition and in the early menopause, but study results are inconsistent.[82][83] There is evidence to suggest that cognitive behavioural therapy (CBT) may have a beneficial role in the management of low mood and anxiety in women with menopausal symptoms after breast cancer treatment.[84] There is a lack of good quality evidence relating to CBT specifically in women with depression related to early menopause but given the low risk of harms and strong evidence base for treating depression in the general population it is a reasonable option in women who are perimenopausal with depression.[85]

While HT or other alternatives may improve sleeping patterns, an assessment should be made for other underlying factors that may require targeted treatment. Mood disorders, notably depression, often improve with HT, although conventional antidepressants may be more effective.[86] Women with symptoms of severe depression should be referred for mental health assessment.

Alternative or herbal therapies

A Cochrane review of 43 RCTs involving phyto-oestrogens found that there was a large placebo effect (from 1% to 59%) in most of the trials.[87] This, and other reviews, have found no conclusive evidence that phyto-oestrogens, including isoflavones, are effective for the management of menopausal VMS.[34][87][88]

Acupuncture and reflexology have not been shown to significantly improve VMS compared with placebo.[34]

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