Menopause and its Management

The menopause may be defined as the time when menstruation permanently ceases. It can only be defined with certainty after twelve months' of spontaneous amenorrhoea.

As ovarian follicular activity begins to fail, oestrogen levels fall and the reduced negative feedback to the pituitary causes a rise in luteinising hormone (LH) and follicle stimulating hormone (FSH). Oestrogen reduction eventually results in menstrual cycle disruption and other menopausal symptoms.

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

It has been estimated that by the age of 54 years, 80% of women are postmenopausal.¹ The age of onset can be affected by a number of factors including socioeconomic issues,² genotype, the number of full term pregnancies, BMI, and a history of breast surgery.³

Many women do not seek medical advice for menopausal symptoms. Studies of those that do suggest that such women are characterised by greater psychiatric morbidity, a lower level of diffused social support, social dissatisfaction and a greater frequency of severe life events. There are also considerable ethnic differences in presenting symptoms.⁴ One large American study found that nervousness, memory loss, vaginal dryness, loss of sexual interest and night sweats were more prevalent in white women, whilst painful sex and hot flushes were more prevalent in African American women.⁵

• 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. Approximately 10% of women have an abrupt cessation of periods.¹
• Hot flushes and sweats (including night sweats) - these are hallmark symptoms. Hot flushes commonly affect the face, head, neck, and chest, and last for a few minutes. Research into the cause of hot flushes has been hampered by the ability to make objective assessments,⁶ but is currently centred on the genetic factors⁷ controlling the production of endogenous oestrogen and its handling at cellular level.⁸
• Sleep disturbance is a common subjective symptom reported by women but not confirmed by polysomnography.⁹ Symptoms may be affected by psychosocial factors, and may contribute to depression, irritability and poor concentration.¹⁰
• Urinary and vaginal symptoms 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.¹¹
• Mood changes may include anxiety, nervousness, irritability, memory loss, depression, and difficulty concentrating.¹ One study suggested a tendency to develop psychological symptoms may be linked to factors such as level of education, high BMI, and low physical activity.¹²
• Loss of libido - this can be caused by a number of hormonal factors, and oestrogen, progesterone and testosterone have all been implicated.¹³ Vaginal dryness, performance of an ageing partner, loss of self-image and other psychosocial factors also play a part.¹⁴
• Other changes - this 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.^1,15,16

The diagnosis will usually be obvious from the clinical picture but may be difficult in younger women in the early stages of the menopause (also known as the perimenopause). Other causes of secondary amenorrhoea such as pregnancy, and hypogonadotrophic hypogonadism¹⁷ may need to be considered.

Investigations are of limited value.

• Follicle-stimulating hormone (FSH) levels - these vary markedly during the perimenopause, but may he helpful in confirming the menopause in later stages. However, in women with suspected premature menopause (symptoms under the age of 40) or those who have had a hysterectomy with ovarian conservation, serial FSH levels should be taken because of the implications of premature ovarian failure. Levels should be tested when the woman is not taking oestrogen-based contraception or 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.¹
• Luteinising hormone (LH) , oestradiol and progesterone levels are generally unhelpful in clinical practice, although LH levels are occasionally contributory in the perimenopause.
• Thyroid function tests thyroid-stimulating hormone (TSH) and free thyroxine (T4) are sometimes used to differentiate thyroid disease symptoms from menopausal symptoms, and may be particularly helpful if there is inadequate response to hormone replacement therapy (HRT).

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 includes coronary artery disease, stroke and peripheral vascular disease, and is thought to be related to vascular endothelial dysfunction related to oestrogen deficiency.¹⁸
• Osteoporosis - the link with oestrogen deficiency is well documented.¹⁹ The risk of developing post-menopausal osteoporosis is thought to be genetically driven, which may explain the variable response to HRT in some women.²⁰
• Urogenital atrophy - as outlined above. Symptoms of urogenital atrophy may appear for the first time more than 10 years after the last period.¹
• 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.²¹
• Alzheimer's Disease is two to three times commoner in women than men, suggesting a hormonal association, but this is currently under review.²²

Reassurance, education and lifestyle adjustment

This may be sufficient for women experiencing mild, short-term symptoms. The available literature suggests that vasomotor symptoms (i.e. hot flushes) are associated with smoking and greater body weight.²³ Alcohol may also play a part.²⁴ There is some evidence base for various dietary modifications,²⁵ particularly fat restriction.²⁶ Physical activity appears to be beneficial, especially in obesity prevention.²⁷

Alternative and complementary therapies

Studies support the use of black cohosh in reducing hot flushes, sweating, anxiety and insomnia.²⁸ There is little evidence to support the use of phytoestrogens such as soy products and red clover,²⁹ and their long-term safety has yet to be evaluated.³⁰ A systematic review of the literature suggested that homeopathy and acupuncture may be worth further investigation, but there was little evidence to support the use of magnets or reflexology.³¹

Non-hormonal therapies

These have principally been tried for the management of hot flushes. A systematic review of SSRIs, clonidine and gabapentin suggests that there is evidence for efficacy, but most trials have methodological deficiencies, and adverse effects and cost may restrict use for many women. They may be indicated for highly symptomatic women where oestrogen is contraindicated.^32,33

HRT

Benefits

The advice issued by the Committee on Safety of Medicines (CSM) in 2002, which remains current, is that HRT should only be used for the short-term relief of menopausal symptoms³⁴ (see Risks, below). The current evidence base supports the use of the following:

• Progestogens These are not widely used alone, but have been found useful for the treatment of hot flushes.³⁵ Randomised trials do not however support their use for the relief of psychological or urogenital symptoms.³⁶
• Oestrogens plus progestogens (for women with an intact uterus). A wide evidence base confirms their benefits in the relief of vasomotor symptoms,³⁷ urogenital symptoms,³⁸ sleep disturbance,³⁹ and quality of life.⁴⁰ There is less evidence to support their use in the relief of depressive or other psychological symptoms.³⁹
• Oestrogens alone (for post-hysterectomised women). There is a similar wide evidence base to support the use of unopposed oestrogens for the relief of vasomotor symptoms,⁴¹ urogenital symptoms,⁴² and quality of life.⁴³ Evidence for their use in the relief of psychological symptoms is more equivocal.⁴⁴
• Tibolone is a selective oestrogen receptor modulator (SERM) which has oestrogenic, progestogenic and androgenic properties. Randomised controlled trials suggest it may be a useful helpful in improving sexual function⁴⁵ and vasomotor symptoms.⁴⁶ There is currently no evidence to determine whether or not it may be helpful in improving quality of life or in the relief of psychological symptoms.⁴⁷

Risks

The press release issued by the CSM in 2002³⁴ was based on data from several sources, including the Women's Health Initiative (WHI) study,⁴⁸ the Women's Health Initiative Memory Study (WHIMS),⁴⁹ and the UK Million Women Study.^50,51 The consensus view arising from these studies was that HRT should no longer be used for the long-term prevention of menopause-associated diseases. However, the situation remains under review.The average age of women in the WHI study was 63.3 years,⁵¹ and the opinion of some authorities is that further research is required to clarify the relevance of the findings to all women.⁵²

The current guidance is as follows:

• Progestogens - randomised trials did not report any long-term risks.³⁶
• Oestrogens plus progestogens and oestrogen alone The WHI study found an increase from 30 to 37 cases per 10,000 women in coronary heart disease. It also found that the incidence of stroke increased from 21 to 29 cases per 10,000 women, and that the incidence of breast cancer increased from 21 to 29 cases per 10,000 women.⁴⁸
• The UK Million Women study confirmed the increased risk of endometrial cancer with unopposed oestrogen and that this was substantially reduced by the addition of a progestogen.⁵¹ There appears to be a small but increased risk of ovarian cancer in patients taking sequential HRT for more than ten years.⁵³
• Contrary to previous studies, the WHIM study found that cognitive function deteriorated rather than improved in women given combined HRT over the age of 65. The findings were similar for women on oestrogen-only therapy.⁵⁴
• The CSM acknowledged in their advice that there was a reduction in colon cancer and hip fracture, that the absolute risks were small, that the overall rates of death and all cancers were not increased by combined HRT, and that the situation should be kept under constant review.³⁴
• They also confirmed that continuous combined HRT should only be indicated for non-hysterectomised women who were at least 12 months post-menopausal, and that peri-menopausal women should generally be treated with sequential or cyclical combined HRT. Only hysterectomised women should receive oestrogen-only HRT.⁴⁸
• Tibolone The UK Million women study found a 1.5 increased risk of breast cancer, and a further study using a general practice data base found that the risk of developing endometrial cancer was double that of women using sequential combined HRT.⁵⁵ The risk of thromboembolic events needs further evaluation.

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