Introduction

The menopause is a natural phenomenon which occurs in all women when their finite number of ovarian follicles are depleted. As a result, oestrogen and progesterone hormone levels fall, and luteinising hormone (LH) and follicle stimulating hormone (FSH) increase in response. Menstruation becomes erratic and eventually stops and there are a number of secondary effects described as "menopausal symptoms" - see below.^[1]

The climacteric, menopausal transition stage, or perimenopause, is the period of change leading up to the last period. The menopause itself is a retrospective diagnosis of the time when menstruation permanently ceases. It can only be defined with certainty after twelve months' spontaneous amenorrhoea.

Premature menopause (occurring before the age of 40) can occur in primary ovarian failure, surgically-induced menopause (hysterectomy with or without bilateral oophorectomy), radiation-induced menopause and chemotherapy-induced menopause.

Epidemiology^[1]

• Menopausal transition stage usually begins when women are in their mid-to-late 40s. The final menstrual period (FMP) usually occurs between the ages of 40 and 58. Average age of menopause in the UK is 52.
• Population studies identify smoking and low socio-economic factors as being associated with premature menopause. Other factors that can affect the age at which women have their final period include age at menarche, parity, previous oral contraceptive history, BMI, ethnicity, family history, and a history of breast surgery.^[2]
• Most women do not seek medical advice for menopausal symptoms. Variations in consultation patterns for menopause depend on many factors, including cultural and educational differences as well as psychosocial difficulties.

Presentation

Epidemiological studies have identified only vasomotor dysfunction and vaginal dryness as being consistently associated with the menopausal phase. Other common symptoms, such as mood changes, sleep disturbances, urinary incontinence, cognitive changes, somatic complaints, sexual dysfunction and reduced quality of life, are less specific for the menopausal period and more affected by social or cultural circumstances and expectations.^[1]

Menstrual irregularity

• The majority of women notice irregularities to the menstrual cycle, which may last up to four years.
• The cycle may lengthen to many months or shorten to 2-3 weeks.
• A slight increase in the amount of menstrual blood loss is common.
• For some women, three consecutive months of amenorrhoea, or mean cycle lengths longer than 42 days, are predictors of impending menopause.^[1]
• Approximately 10% of women have an abrupt cessation of periods.^[3]

Hot flushes and sweats

• These are hallmark symptoms. Hot flushes commonly affect the face, head, neck and chest, and last for a few minutes.
• A recent meta-analysis suggests that in an average woman, vasomotor symptoms increase from two years prior to the FMP, peak at one year following it and return to normal after eight years. However, there is considerable variation between individual women.^[4]

Urinary and vaginal symptoms

• These may include dyspareunia, vaginal discomfort and dryness, recurrent lower urinary tract infection and urinary incontinence.
• Vaginal discomfort is clearly linked to low oestrogen levels, but the association with urinary incontinence is less evidence-based. Further research is required to assess the effectiveness of hormone replacement in such cases.^[5]

Sleep disturbance

• This is a common subjective symptom reported by women but not confirmed by polysomnography.^[6]
• Symptoms may be secondary to vasomotor symptoms, are affected by psychosocial factors, and may contribute to depression, irritability and poor concentration.

Mood changes

• These may include anxiety, nervousness, irritability, memory loss, depression and difficulty concentrating.^[3]
• One study suggested that a tendency to develop psychological symptoms may be linked to factors such as level of education, high BMI and low physical activity.^[7]

Loss of libido

• This can be caused by a number of hormonal factors, and oestrogen, progesterone and testosterone have all been implicated.
• Vaginal dryness, performance of an ageing partner, loss of self-image and other psychosocial factors also play a part.

Other changes

These may include brittle nails, thinning of the skin, hair loss and generalised aches and pains. These are thought to be due to falling oestrogen levels.^[3][8]

Differential diagnosis

The diagnosis will usually be obvious from the clinical picture but may be difficult in younger women in the early stages of the menopause.
Other causes of secondary amenorrhoea, such as pregnancy and hypogonadotrophic hypogonadism, may need to be considered.

Investigations

Investigations are of limited value.

• FSH levels:
  • These vary markedly during the perimenopause and single measures are unreliable. FSH levels may be helpful in confirming the menopause in later stages.
  • Women with suspected premature menopause (symptoms under the age of 40) or following a hysterectomy with ovarian conservation, should have serial FSH levels taken because of the implications of premature ovarian failure.
  • Levels should be tested when the woman is not taking oestrogen-based contraception or hormone replacement therapy (HRT).
  • FSH levels of greater than 30 IU/L are generally considered to be in the postmenopausal range, and should be repeated in 4-8 weeks to confirm this.
  • Levels above 12 IU/L are considered to be raised in women still having menstrual bleeds.^[3]
• TFTs can help differentiate thyroid disease symptoms from menopausal symptoms.

NB: LH, estradiol and progesterone levels are generally unhelpful in clinical practice.

Associated diseases

The relationship between the menopause and the development of associated conditions is sometimes difficult to differentiate from age-related morbidity, but is best demonstrated in cases of premature primary and secondary ovarian failure.

• Cardiovascular disease - including coronary artery disease, stroke and peripheral vascular disease, is thought to be related to vascular endothelial dysfunction related to oestrogen deficiency.^[9]
• Osteoporosis - the link of osteoporosis with oestrogen deficiency is well-documented. The risk of developing postmenopausal osteoporosis is thought to be genetically driven, which may explain the variable response to HRT in some women.
• Urogenital atrophy - as outlined above. Symptoms of urogenital atrophy may appear for the first time more than 10 years after the last period.^[3]
• Redistribution of body fat - body fat tends to be redistributed around the abdomen with age. This is recognised as being an independent risk factor for cardiovascular disease and diabetes.
• Alzheimer's disease - this is two to three times more common in women than men, suggesting an hormonal association, but this is currently under review.^[10] There is no good evidence currently that HRT (oestrogen alone or oestrogen and progestogens) prevents cognitive decline in older postmenopausal women when given over the short- or longer-term.^[11]

Management

Reassurance and support may be all that is needed (viewing menopause as a normal period of physiological adaptation).

• Encourage a healthy lifestyle. There is limited evidence to suggest regular sustained aerobic exercise improves vasomotor and other menopausal symptoms,^[12] but it can improve quality of life and symptoms such as mood and insomnia, and will have cardiovascular and other benefits. Low-intensity exercise such as yoga can also help, but infrequent high-impact exercise can aggravate symptoms.^[13]
• Identify the patient's most troublesome symptoms and discuss management possibilities:
  • Vasomotor symptoms:
    • Hormone replacement therapy (HRT) is undoubtedly the most effective treatment. Progestogens alone are not recommended as a substitute where combined HRT is contra-indicated, because progestogens possibly contribute to increased risk of breast cancer (combined HRT is worse than oestrogen alone), and the doses needed to control vasomotor symptoms can increase the risk of venous thromboembolism (VTE).^[13] Transdermal progesterone creams are not recommended as a replacement for the oral progesterone component of combined HRT.^[13] Duration: for vasomotor symptoms, HRT is usually needed for 2-3 years, but some need longer. This judgement should be made on a case-by-case basis with regular attempts to discontinue. Symptoms may recur for a short time after stopping HRT.
    • Avoidance or reduction of alcohol and caffeine can help.^[14]
    • Gabapentin (900 mg/day) can reduce the number of flash flushes by 45% and severity by 54%,^[15] and a lower dose (600 mg/day) may also be effective, although adverse effects (eg drowsiness) limit its use.
    • Selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) have been shown to reduce flushing symptoms in short-term studies lasting a few weeks(unlicensed), but side-effects may limit use and longer trials have failed to show benefit.^[12] Evidence for the benefit of the SNRI venlafaxine (37.5 mg bd) is the most convincing (a frequent side-effect is nausea), but it may also reduce libido and sexual response.^[13] St John's wort improves mood in a similar manner to SSRIs, but there is no convincing evidence that it has any positive effects on vasomotor symptoms, and it does interact with a number of drugs, including warfarin and the contraceptive pill.
    • Clonidine only has a very marginal benefit (over placebo) possibly reducing the number of flash flushes by one or two per day (trial evidence is contradictory).^[13]
    • Dehydroepiandrosterone (DHEA) - a food supplement - may produce a modest reduction in hot flushes - but it lacks any evidence from controlled trials.^[13]
    • Stellate ganglion blockade with local anaesthetic injection is a new technique for hot flushes and sweating which have been refractory to other treatments, particularly where HRT is contra-indicated (e.g women with breast cancer).
    Betablockers have not been shown to be effective.
  • Urinary and vaginal symptoms:
    • Both standard and topical HRT work well for menopausal atrophic vaginitis. Topical HRT should be used in the smallest effective dose to minimise systemic side-effects, and in short courses which may be repeated, but reviewed regularly.^[16]
    • Lubricants (specifically for use during intercourse) and vaginal moisturisers (longer duration of action) are available without prescription. Replens MD® and Sylk® are moisturisers which can be prescribed in the UK, although evidence for efficacy is scant.^[13]
• Sleep or mood disturbances
  • Consider HRT if these symptoms are primarily caused by hot flushes and night sweats. SSRI or SNRI should be considered as an alternative or adjunct to HRT.
• Loss of libido:
  • Testosterone (patches and implants) is available to help improve sexual desire.^[17]

Premature menopause management

Women with a premature menopause should be offered HRT unless contra-indicated. It is normally continued until they reach age 52 years. There is no evidence that there is any increased risk of breast cancer compared with normally menstruating women of the same age. They may need larger doses of HRT to control vasomotor symptoms.^[18]

Alternative treatments

There is a very good Royal College of Obstetricians and Gynaecologists (RCOG) paper, which discusses these in detail.^[13]

There is some evidence that phyto-oestrogens (most significantly isoflavones (soybeans, chickpeas and red clover and other legumes) and lignans (oilseeds such as flaxseed, present in cereals, vegetables, legumes and fruits) or isoflavone supplementation may help in some small way with menopausal symptoms, although conclusive evidence on efficacy or safety is lacking. A soy-derived preparation, DT56a, appearing to have selective oestrogen receptor modulator (SERM)-like properties, has been shown to reduce hot flashes.^[13][19]

A variety of botanicals are used by women - but evidence is limited and conflicting and their interactions and long-term effects are unknown, so they cannot be recommended. Such botanicals include: black cohosh (Actaea racemosa), evening primrose oil, Chinese herbs (eg dong quai (Angelica sinensis, ginseng), agnus castus (V. agnus-castus).