Symptoms of the menopause

There are a number of symptoms associated with perimenopause, although some women will experience none of these. They include hot flushes and night sweats (vasomotor symptoms), urogenital symptoms, depression, anxiety, irritability and mood swings (psy­chological effects), joint pains, migraines or headaches, and sleeping problems.

Short-term symptoms

Vasomotor symptoms

The most commonly reported symptoms in the West are hot flushes and night sweats, and a recent study has demonstrated that women may experience symptoms for a median duration of 7.4 years.

Hot flushes are characterized by a feeling of intense warmth, often accompanied by profuse sweating, anxiety, skin reddening, and pal­pitations, and sometimes followed by chills.

The exact pathophysiology underlying vasomotor symptoms is not known; oestrogens undoubtedly play a role, as flushing occurs at times of relative oestrogen withdrawal, and replacing oestrogen improves symptoms. However, oestrogen levels remain low, and flushing improves with time. Moreover, women who have never been exposed to oestrogen will not flush, unless first treated with oestrogen, which is then withdrawn. This suggests that it is the with­drawal of oestrogen, rather than low circulating levels that are re­sponsible for this symptom, and this would seem to be supported by the symptoms experienced by premenopausal women following surgical removal of the ovaries.

Menopause induced by surgery is associated with about a 90% probability of hot flushes during the first year and symptoms associ­ated with surgical menopause are often more abrupt and severe and can last longer than those associated with a non- surgical menopause.

Hot flushes are the most common indication for the prescription of hormone therapy (HT) since it is effective in over 80% of cases. Concern that the risks of HT outweighed the benefits, following publication of the WHI trials (10), led to a dramatic decrease in the use of HT.

HRT may not be suitable for women with a history of hormone­dependent cancer, for example, breast cancer, and other treatment modalities may be considered; however, none are as effective as HRT.

NICE does not recommend the use of selective serotonin re­uptake inhibitors (SSRIs), serotonin noradrenaline reuptake in­hibitors (SNRIs), or clonidine as first-line treatment for vasomotor symptoms alone (2), and while there is some evidence that isofla­vones or black cohosh may relieve vasomotor symptoms, caution is advised, as interactions with other medicines have been reported. In

addition, there are multiple preparations available, these may vary and their safety is uncertain.

Urogenital symptoms

The female urogenital tract arises embryonically from the urogenital sinus, and high-affinity oestrogen and progesterone receptors have been found in the vagina, urethra, trigone of the bladder, and pelvic floor musculature.

A loss of oestrogen results in urogenital ageing. The vaginal walls become pale and thin as a result of reduced collagen, decreased elastin, and thinning of the epithelium. A loss of elasticity, and a re­duction in vaginal secretions, leads to a susceptibility to trauma and pain during intercourse, which in turn can lead to pain and irritation after sex.

The vaginal pH becomes less acidic, and increases the likelihood of urinary tract infections. There may also be urinary frequency and urgency, and nocturia, and as such, menopause-related genitouri­nary changes are not confined to the vulva and vagina. What has long been termed vulvovaginal atrophy or atrophic vaginitis has now been recognized to be inadequate, and a terminology consensus conference, comprising the International Society for the Study of Women's Sexual Health and the North American Menopause Society, formally endorsed new terminology—genitourinary syn­drome of menopause—in 2014.

Genitourinary symptoms attributable to the menopause can af­fect up to 50% of women; however, these are underdiagnosed and undertreated. They may be chronic and, without treatment, are un­likely to improve over time. By increasing skin collagen content, and increasing acid mucopolysaccharides and hyaluronic acid, oes­trogen therapy encourages the growth and development of vaginal epithelial cells which make up the thick layers of the vaginal wall, and condone a moist, supple, and elastic environment.

Vaginal symptoms and sexual dysfunction

Vaginal symptoms become apparent 4-5 years after the menopause and are present in 25-50% of all postmenopausal women. Symptoms may include vaginal dryness (75%), dyspareunia (38%), vaginal itching, burning, and pain (15%). Dyspareunia can adversely affect a postmenopausal woman's sexual quality of life or intensify pre­existing sexual disorders.

Vaginal oestrogens are an effective treatment for menopause- related vulval and vaginal symptoms and a Cochrane review re­ported equal efficacy across all products tested: creams, pessaries, tablets, and vaginal rings (12). On behalf of the International Menopause Society Writing Group, Sturdee and Panay (13) recom­mend treatment of established vaginal atrophy to restore physiology and alleviate symptoms. These have subsequently been supported by NICE. Local oestrogen therapy will lower vaginal pH, thicken the epithelium, increase blood flow, and improve vaginal lubrica­tion.

A 2009 review of topical oestrogen demonstrated no evidence of endometrial proliferation after 6-24 months of use, therefore pro­gestins and the monitoring of endometrial thickness are not required with topical oestrogens (2, 14). However, any postmenopausal bleeding should be investigated in the usual way.

Use of vaginal oestrogen for women with a history of breast cancer is controversial. Vulval and vaginal symptoms are common in this group of patients particularly those on endocrine therapies such as aromatase inhibitors and antioestrogens. In a case-control study, there was no documented increase in recurrence in those women receiving endocrine therapy and use of local oestrogen compared to non-use (15). However, in another study of breast cancer survivors, there was an initial, albeit unsustained, increase in circulating oes­trogen concentrations (16), measured using an ultra-sensitive oes­trogen assay. These women should be referred to a specialist clinic, to discuss the risks and benefits of treatment.

Non-hormonal treatment options include lubricants and moisturizers. Lubricants are non-physiological, but may reduce friction-related irritation of vaginal tissues, while moisturizers are hydrophilic, insoluble, cross-linked polymers which reduce vaginal pH. In a trial of vaginal moisturizer compared to low-dose vaginal oestrogen, both preparations were found to be effective, but the moisturizer provided only temporary benefit.

Urinary symptoms

Overactive bladder is a highly prevalent disorder, with higher rates and symptom severity in postmenopausal women. Oestrogen de­ficiency has been implicated in the aetiology of urinary tract symptoms with up to 70% of women relating the onset of their in­continence to their last menstrual period.

The Fourth International Consultation on Incontinence has given oestrogen a grade C recommendation based on a level of evidence of 2 of overactive bladder and concluded that there is no solid evidence to support the use of HT, oral or vaginal, for the treatment of urge urinary incontinence. Grade A recommendations include weight reduction, supervised pelvic floor muscle training, and bladder training and antimuscarinics (18).

Long-term consequences

Osteoporosis

The onset of the menopause, with associated decline in oestrogen, results in a decrease in bone mineral density and a subsequent sig­nificant increase in the prevalence of osteoporosis, which continues to increase through the postmenopausal period. The number of hip fractures worldwide due to osteoporosis is expected to rise threefold by 2050, from 1.7 million in 1990 to 6.3 million.

The National Osteoporosis Guideline Group advises that fracture probability should be assessed in postmenopausal women, using a fracture risk assessment tool (FRAX), for cases in which such an as­sessment would influence management (19).

The optimal management of osteoporosis is aimed at primary prevention for those at risk, while general management includes as­sessment of the risk of falls and their prevention, maintenance of mobility, and correction of nutritional deficiencies, particularly of calcium, vitamin D, and protein.

Pharmacological interventions include bisphosphonates, denosumab, parathyroid hormone peptides, raloxifene, and stron­tium ranelate. All have been shown to reduce the risk of vertebral fracture and some have been shown to reduce the risk of non- vertebral fractures (19).

There is evidence from randomized controlled trials (RCTs), in­cluding WHI, that HT reduces the risk of spine and hip, as well as other osteoporotic fractures even in women at low risk. It would ap­pear that half of the traditional doses (oestradiol 2 mg, conjugated equine oestrogen 0.625 mg and transdermal 50 mcg patch) may be effective in conserving bone mass although the effect of oestrogen on bone mass is dose dependent.

Regulators do not recommended HT as first-line treatment in the prevention of osteoporosis, because risks outweigh benefits; how­ever, a statement released by the British Menopause Society states that ‘whilst this may be true for a population with no increased osteopor­osis risk,... the risk-benefit ratio changes favourably when targeting a population with increased osteoporosis risk’. Oestrogen remains the treatment of choice in women with premature ovarian failure, and may be the best option in women under the age of 60, however, ‘the ini­tiation of standard dose HT is not recommended solely for fracture prevention in women over 60’ (20). All women using oestrogen for symptoms should be made aware that it has a bone protective effect (2).

Cardiovascular disease

Cardiovascular disease is the leading cause of death in women world­wide, but is often unreported in women before the age of55. Menopausal status has been included in the Framingham risk calculator as an inde­pendent risk factor and a premature menopause is associated with a doubling of risk. It has been proposed that hypo-oestrogenism plays a role, but there has been some conflicting data over the years with re­gard to risk versus benefit of oestrogen replacement.

Before the publication of the WHI results, HT was thought to confer cardiovascular disease risk reduction, particularly in cor­onary events. The principal results of the WHI trial, the largest ran­domized controlled primary prevention trial of the most commonly prescribed HT in the United States, demonstrated an increased number of coronary heart disease events and strokes, and concluded that the risks outweighed the benefits.

However, the average age of participants in the WHI was 63 years, 12 years older than the average age of menopause in the United Kingdom; therefore, it is possible that the women in these studies had established subclinical atherosclerosis.

Subgroup analysis of data from the WHI trials examined HT use stratified by age and time since menopause, and demonstrated more favourable results for all-cause mortality and myocardial infarction in women aged 50-59 years, and those close to meno­pause (21). This ‘window of opportunity’ has been supported by the Danish Osteoporosis trial (DOPS), which demonstrated a re­duction in risk of mortality, heart failure, or myocardial infarction, after 10 years of hormone replacement therapy, started soon after menopause (22).

At present, in women under the age of 60 years, there is no in­crease in cardiovascular disease risk with HT, but there are insuf­ficient data to support the use of HT for cardiovascular disease prevention. Women should be told that there is a small increased risk of stroke when taking oral (but not transdermal) oestrogen, but it should also be noted that the baseline risk of stroke in women under the age of 60 years is very low.

Dementia

Dementia is not a normal part of ageing; it is a term that is used to describe a set of symptoms that occur when the brain is affected by certain diseases or conditions, with Alzheimer’s disease being most common.

Oestrogen facilitates synaptogenesis, induces growth factor pro­duction, protects against oxidative stress, and regulates neurotrans­mission (e.g. serotonin, noradrenaline, and acetylcholine) in brain systems associated with cognition and mood.

Although oestrogens affect brain tissues and brain processes in ways expected to reduce dementia risk and improve the course of cognitive ageing, therapeutic use of oestrogens for dementia is not supported by clinical findings. Many observational studies have implied that oestrogens reduce the rate of Alzheimer’s dis­ease; however, better quality evidence now suggests that there is no benefit of hormone treatment for these patients (23).

Isolating the effects of ageing from the effects of the menopause is difficult, but there is currently no evidence to support the use of HT for improvement or prevention of cognitive decline (2).