15
The menopause
Introduction
Human female fertility terminates relatively abruptly in middle-age. This seems to be rather a puzzle as, in evolutionary terms, those genes that ‘favour’ giving birth to as many offspring as possible, would be expected to proliferate. In other words, the genes of mothers who continued giving birth to children for as many years as they could would be expected to be successful. Human children, however, remain dependent on their mothers for many years after birth and, if mothers continued to reproduce until the end of their lives, they would be less able to support the later children to independent maturity. The incidence of congenital abnormality also increases with maternal age. This would be a waste of personal resources without genetic benefit, and would also limit the support such a mother could offer to her grandchildren, in whom she has a quarter-part genetic investment.
The flaw in this otherwise reasonable teleological argument, however, is that previously, the vast majority of women died long before reaching the current average age of menopause, thus diluting the role of longevity in the evolutionary process. The true reasons behind this process of ovarian failure, the menopause, are therefore not yet fully elucidated.
Menopause literally means ‘last menstrual period’ but the word is often used to cover the physiological changes that occur around this time. The fluctuating levels of oestrogen resulting from declining ovarian function lead to changes in a number of systems, and may give rise to significant symptoms. Although physiological, the menopause has important adverse long-term effects on health (Table 15.1) which can, in part, be offset by the use of hormone replacement therapy (HRT). The pros and cons of this treatment will be discussed in more detail and need to be carefully considered on an individual basis before treatment is started.
Physiology
The perimenopause (or climacteric) may begin months or years before the last menstrual period, and symptoms may continue for years afterwards. The median age at menopause in the UK is 50.8 years and it occurs when the supply of oocytes becomes exhausted. A newborn girl has over half a million oocytes in her ovaries: one-third of these disappear before puberty and most of the remainder are lost during reproductive life. In each menstrual cycle, some 20 or 30 primordial follicles begin to develop and most become atretic. As only about 400 cycles occur during an average woman’s lifetime, most oocytes are lost spontaneously through ageing, rather than through ovulation.
In premenopausal women, oestradiol is produced by the granulosa cells of the developing follicle, but, as the menopause approaches, this production becomes very variable. The proportion of anovulatory menstrual cycles increases and progesterone production declines. Pituitary production of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) rises because of diminishing negative feedback from oestrogen and other ovarian hormones, such as inhibin, but other pituitary hormones are not affected. Serum levels of FSH over 30 IU/L can be used clinically to clarify the diagnosis of the menopause (see below), although levels begin to rise significantly around the age of 38 even in normally cycling women. Anti-Müllerian hormone is a better marker of follicular reserve than FSH and is now used in medical practice.
Circulating androstenedione, mainly of adrenal origin, is converted by fat cells into oestrone, a less potent form of oestrogen than oestradiol. After the menopause, this is the predominant circulating oestrogen, rather than ovarian oestrogens.
Signs and symptoms (Table 15.1)
Vaginal bleeding
Irregular periods before the menopause are usually the result of anovulatory menstrual cycles, and, if irregular bleeding persists, endometrial assessment may be required to exclude the possibility of endometrial carcinoma. The menopause itself can be recognized only in retrospect after an arbitrary length of amenorrhoea, usually taken as 6 months or a year. Further vaginal bleeding after this is ‘postmenopausal’ and investigations may again be required. Approximately 10% of those with postmenopausal bleeding have a gynaecological malignancy.
Hot flushes
A ‘hot flush’ is an uncomfortable subjective feeling of warmth in the upper part of the body, usually lasting around 3 min. Approximately 50–85% of menopausal women experience such vasomotor symptoms, although only 10–20% seek medical advice. Flushes are sometimes accompanied by nausea, palpitations and sweating and may be particularly troublesome at night. They are thought to be of hypothalamic origin and may in some way be related to LH release. It is thought that a fall in oestrogen levels affects central neurotransmitters such as alpha-adrenergic or serotonergic systems, which in turn affect central thermoregulatory centres and LH-releasing neurons.
About 20% of women begin experiencing flushes while still menstruating regularly. Flushes slowly improve as the body adjusts to the new low oestrogen concentrations, but in approximately 25% of women, they continue for more than 5 years and can be extremely distressing, impairing quality of life. Exogenous oestrogen administration, in the form of HRT, is effective in relieving these symptoms in about 90% of cases.
Genitourinary atrophy
The genital system, urethra and bladder trigone are oestrogen-dependent and undergo gradual atrophy after the menopause. Thinning of the vaginal skin may cause dyspareunia and bleeding, and loss of vaginal glycogen causes a rise in pH, which can predispose to local infection. Urgency of micturition may result from atrophic change in the trigone. Unlike flushes, these atrophic symptoms may appear years after the menopause and do not improve spontaneously, although they respond well to a short course of local or systemic oestrogen.
Other symptoms
Some studies have suggested that many symptoms, including irritability and lethargy, can be improved by hormone therapy more effectively than by placebo. Most investigators, however, feel that the symptom of depression is not due directly to oestrogen withdrawal; although it has been reported that oestrogen treatment can improve the symptoms of depression. It is possible that this effect may be related to the indirect relief of specific symptoms, such as insomnia caused by night sweats.
Long-term effects
The menopause alters a woman’s susceptibility to breast cancer, cardiovascular disease and osteoporosis.
