Pharmaceutical Journal Vol 263 No 7069 p712-715
October 30, 1999 Continuing Education

(1) The menopause and its implications

By David Purdie, MD, FRCOG and Isabel Crawford, BSc, MRPharmS

The menopause is a subject of interest and concern to all women and a time of physical and emotional distress to many. This alone places a requirement upon professionals involved in health care to understand its causes, its symptoms and long-term effects, to explain these to women in plain English, and to offer advice on treatments which, in the individual concerned, will confer a clear net advantage.
The precise definition of menopause comes from the Greek menos (a month) and pausos (an ending), and hence the word simply means the ending of the monthly reproductive or menstrual cycle. The median age at which this occurs is 51 in the UK - a figure that is remarkably constant across Europe and the US.
The climacteric, in contrast, may be defined as that era in a woman's life (usually between 45 and 55) when she moves from fertility to the infertility of older age. The end of cyclic bleeding - the menopause - is thus only one event in a whole array of anatomical, physiological and psychological changes which make up the climacteric, just as the menarche - the beginning of cyclical bleeding - is only one event in the array of changes which constitute puberty. However, the menopause as defined by the lay population is something else again. Many women describe themselves as being "in menopause" or "on the change" when they begin to experience symptoms that they attribute to the menopause. They similarly describe "the change" as only being completed when these symptoms finally disappear - a process which can last weeks, months or even years.
In general, a well woman of any age with a regular menstrual cycle may be said to be premenopausal. A woman with a cycle but with symptoms of oestrogen deficiency is said to be perimenopausal and remains so for up to six months of amenorrhoea. After this, she may be described as postmenopausal. The ending of menstrual bleeding, the true menopause, can only be diagnosed in retrospect. However, what really matters is the major change in the hormonal arrangements which underpins not only the end of menstrual cycles, but also the symptoms and the later physical consequences. That change is ovarian failure.

Ovarian failure The ovary is not like the other endocrine glands, such as the pituitary or the thyroid, which, if free of disease, will operate lifelong. From before birth, the ovarian clock is set to run down to hormonal exhaustion some 50 years later. The reason for this is that during intrauterine life each ovary is filled or primed with about three quarters of a million eggs, or oocytes. These vital cells have a high mortality. Fewer than 400 of them will ever be ovulated (released on to the ovarian surface), collected by the fallopian tube and made available for fertilisation. All the rest progressively become atretic or functionally inactive. The source of oestrogen in the plasma of a premenopausal woman is the granulosa cells which surround and prepare the chosen ovum as it develops in its follicle each month. They produce the classic pattern of oestradiol in the bloodstream shown in Figure 1.

Figure 1: The pattern of oestradiol in the circulation of a healthy, premenopausal woman with a menstrual cycle and the oestradiol levels achieved by various formulations of HRT

The granulosa cells thus produce the central, or mid cycle, peak of oestradiol which, in turn, triggers ovulation on about day 14 of the cycle. The smaller peak in the second half of the cycle is caused by oestradiol flowing from the corpus luteum. The corpus luteum is the remains of the ovulated follicle, which also produces progesterone, helping to prepare the uterus for a possible implantation.
As a women passes through her forties the number of prime oocytes declines steeply. Although many are left in each ovary, very few are functionally able to be prepared for ovulation. Oestrogen production thus begins to fail. When this happens, the production of two hormones from the pituitary gland, FSH (follicle stimulating hormone) and LH (luteinising hormone) increases in a vain attempt to stimulate the failing ovary.¹ Eventually all oocytes are exhausted and, with no developing follicles, there can be no oestrogen production to stimulate the monthly build-up of the womb lining, the endometrium.
With no build-up, there can be no shedding or menstruation and the menopause has occurred. Oestrogen levels are now at their nadir with a concentration in plasma of usually less than 70pmol/L, compared with premenopausal levels of up to 1000pmol/L. It is noteworthy that 70pmol/L is a level below that found in many healthy men of the same age. It is also worth noting that our species, Homo sapiens, is virtually unique with regard to survival through and beyond the menopause.
In general, throughout the animal kingdom, life does not continue after the end of reproduction, although among chimpanzees - our nearest cousin - "grandmothers" have occasionally been observed. Generally, once the genes have been passed on to the next generation, death is close. However, in humans of the developed world, death is, on average, anything but close. The most recent figures indicate a life expectancy in the UK of about 75 years for men and approximately 81 years for women. Given that the menopause occurs at about 50 years of age, this means that women in this country will spend some 30 years (or nearly 40 per cent of their lives) in the postmenopausal era - an era of significant oestrogen deficiency. This would be of little consequence if all that the lost oestrogen did was to drive the reproductive cycle and prepare the body for pregnancy and lactation. If that was the totality of oestrogen action, the menopause would be a welcome and necessary end. However, oestrogen is also a major player in the normal function of many organ systems far removed from reproduction, for example, the bones, the blood vessels, the brain, the gut and the immune system. Thus, when the ovary fails to produce oestrogen, those other systems which have hitherto depended on their monthly, cyclical pulse of oestradiol have to make shift without it. And there, as Shakespeare said, lies the rub.

Symptoms of the menopause

When oestrogen declines, the thermostat becomes unstable and repeatedly signals that the centre of the body is too warm. In response to this false alarm of excess heat, action is taken to discharge heat by opening up the peripheral skin circulation (hence the flush) and by an outpouring from the sweat glands. Flushes usually affect the face, chest and abdomen and can be provoked by a wide variety of triggers including surprise, embarrassment, or a change in temperature.
Distressing as these vasomotor symptoms are by day, they are more serious at night. Nocturnal sweating attacks can be drenching, with many women reporting a need to change night-clothes and even bedclothes to obtain physical relief. More serious is the effect upon sleep. Repeated awakenings, many so short as to be unremembered in the morning, constitute a serious interference with sleep.⁴ To obtain full value from sleep we need to alternate between deep sleep and the rapid-eye movement (REM) sleep that occurs when we dream. The two sleep types combine to produce renewal and refreshment of the central nervous system, which a good sleep provides. Repeated disturbance of this pattern leads to poor quality sleep and it is probably no coincidence that the known symptoms of experimental sleep deprivation - loss of short-term memory, loss of concentration span, irritability and depression - are identical to the symptoms frequently cited by perimenopausal women.

Although sleep deprivation is a likely contributor to the psychological symptoms of the menopause, it is not the whole story. We now know that the principal oestrogen - oestradiol - is a major brain hormone. It is involved in the maintenance of blood flow to the brain and in the production of neurotransmitters. It has powerful effects on the production of dendrites, the processes with which brain cells contact neighbouring neurones or support cells, and it functions as a monoamine oxidase inhibitor.5 It is thus a natural antidepressant. All in all, oestrogen is intimately involved in central nervous system function and it is perhaps not surprising that many women report psychological symptoms at this time (see Panel 2). The occurrence of the menopause in her early fifties means that it often comes at the same time in a woman's life as the death or disablement of parents, the birth of grandchildren, the beginning (or sometimes the end) of her children's, or indeed her own, partnerships. Any of these life events can magnify the stress occasioned by the physical or emotional difficulties of the climacteric.

Panel 2: principal psychological symptoms of menopause Tiredness Anxiety Loss of short-term memory Irritability Depression Mood swings

Urogenital symptoms

As noted above, the endometrium becomes quiescent when shorn of its cyclical oestrogen drive. Welcome as the cessation of periods often is, certain other effects are less agreeable.
The vaginal epithelium is a skin, composed of stratified squamous epithelium. Receptors in the basal layers allow oestrogen to maintain the normal, many-layered thickness of this skin and promote its glandular elements to secrete the natural lubricant which attends arousal. In the absence of oestrogen, the skin shrinks down to become thin, or atrophic, and normal lubrication is seriously reduced. This results in the condition formerly known as atrophic vaginitis, but is now simply, and correctly, termed vaginal atrophy (since inflammation is not present). The thin, dry vagina results in painful intercourse (dyspareunia), and the proximity of blood vessels just below the thin epithelium means that bleeding can be provoked. The reluctance or refusal of many women to participate in painful coitus is entirely justified but may lead to marital disharmony unless her partner understands the difficulty. However, many men, it has to be said, are anything but understanding and the subsequent disputes can only aggravate the psychological problems of a woman who may be already irritable and depressed. Such difficulties can seriously stress a partnership and, if that partnership is already shaky, they can break it.
The lower urinary tract and the lower genital tract share a common embryological origin and, hence, it is not surprising that bladder and urethral problems may also present at this time. Many women report an increase in urinary frequency, with nocturia - another source of sleep loss - and there may also be a degree of urgency, with associated urge incontinence in some cases.⁶ Oestrogen normally acts to stabilise the muscle of the trigone and also increases the closure pressure of the proximal urethra as it leaves the bladder.
A gentle, courteous but thorough inquiry into sexual and urinary difficulties must thus be a central part of history-taking in menopausal women.

Long-term effects of the menopause Bone Bone is a living, dynamic tissue and, like other tissues, it requires to be nourished, drained and constantly renewed. The ceaseless removal of old bone and its replacement by new, lies at the heart of bone physiology in both sexes. Oestrogen plays a vital role in this process, which occurs in about half a million microscopic sites, known as bone remodelling units, from skull to heel (see Figure 2A). In the presence of normal amounts of circulating oestradiol, the amount of bone removed at each remodelling site is precisely matched by the amount of bone formed. If the amount of circulating oestradiol falls to menopausal levels - and that amount is 10-fold less than before the menopause - then the amount of bone removed fails to be matched by the new bone laid down to refill the cavity. "The result is bone loss.7 When the cycle comes round again, the bone deficit increases. The sites at which oestrogen-related bone loss is most severe are the spine, the femoral neck and the distal radius, where the bone design is trabecular (made up of tiny struts and bars) and has a high surface area for remodelling (see Figure 2B). It is at these sites that the progressive erosion of bone tissue gradually leaches the bone's great engineering strength - its ability to absorb stress and shock. The result is a progressive increase in the risk of fracture. The remainder of the skeleton is composed of cortical bone, which is hard and dense and is rarely subject to osteoporosis.
	Figure 2: Bone remodelling (A) In healthy bone, (B) In oestrogen deficiency

Cardiovascular system It has long been observed that the incidence of coronary artery disease is much lower in women under the age of 50 than it is in men. It is equally well known that the female incidence of angina pectoris and coronary thrombosis rise progressively until, in the ninth decade, it approximates to that found in men. The reasons for this are still far from settled but a picture is beginning to emerge of oestrogen activity at several levels of cardiovascular function.
With regard to the blood vessels themselves, it has just been shown that the enzyme aromatase, which manufactures oestrogen from its precursors, is present in the walls of human coronary arteries.⁸ Also present is the oestrogen receptor (ER), the protein to which oestrogen locks on its way to its central function in the cell, that of switching on the oestrogen-sensitive genes of DNA in the nucleus. We know that ERs are present in heart muscle cells and on the endothelial cells of peripheral arteries. This may relate to the general observation that oestrogen relaxes the peripheral circulation, allowing greater perfusion of organs and limbs, a function which it also performs during pregnancy.
The loss of circulating oestrogen at the menopause is also associated with an ominous lipid picture and one which would tend to promote the process of atheroma formation in the arterial tree, especially if the other risk factors of obesity, cigarette smoking or hypertension are also present.
Another action of oestrogen, which is lost at the menopause, is its ability to facilitate the actions of insulin. In conditions of oestrogen deficiency, insulin resistance rises and this is believed to be a major factor in the weight gain and redistribution of body fat that often accompany the menopause. Insulin resistance is also a significant factor in the development of coronary artery and cerebrovascular disease. It is cardiovascular disease which is the principal killer of postmenopausal women (see Figure 3).
Central nervous system The immediate or short-term effects of the menopause on CNS functions have been described above. Equally important is our new understanding of the relationship between oestrogen and that most feared of all the neurodegenerative conditions - Alzheimer's disease (AD). It has been known for many years that AD was more common in older women than in men, even when allowance was made for the longer female survival.⁹
It has been found that a central problem within the brain in this condition is the laying down of a protein - b amyloid - which disrupts nerve cells and their connections. This occurs particularly in the hippocampus, an area ultimately concerned with short-term memory. The production of b amyloid is normally held in check by oestrogen and, hence, the menopause results in unrestrained amyloid production which, if excessive, may eventually trigger the distressing symptoms of short-term memory loss and disorientation that characterise AD. Oestrogen also promotes blood flow to the brain and its action in maintaining inter-neuronal connections is thought to be vital in sustaining cerebral function against the neuronal loss which occurs with the ageing process.

Other functions of oestrogen

This is a rapidly developing field. Oestrogens normally operate through their partnership with the ER, whose sequencing and three-dimensional display, together with techniques to identify it in tissues, has drawn back the curtain on a whole array of unsuspected oestrogenic sites of action. For example, we now know that the hormone is active in the lining epithelium of the colon, but its precise functions here are not clearly understood. However, we do know that it promotes the absorption of vitamin D from the stomach and duodenum, thus reinforcing its protective effects upon bone. At the far end of the gut, it has been found that oestrogen increases rectal closure pressure and helps to protect parous women from the most distressing symptoms of faecal incontinence.
In the eye, it is suspected that lack of oestrogen is involved in the production of cataracts since, in the laboratory, the generation of opacity in lenses can be halted by oestrogen, though not by progesterone. Oestrogen action in the immune system is the subject of intense current research, with potential for greater understanding of such diseases as rheumatoid arthritis and multiple sclerosis.

Conclusion

The menopause is universal if a woman lives into her sixth decade. It may come early or late. It may come surgically after oophorectomy, or medically after chemotherapy or, as in the vast majority, it may come naturally. But is it natural?
This question arises now that our colleagues in anthropology report that throughout all human history, from our evolution as H sapiens in Africa until relatively recently, it was natural for men and women to die young, women often dying with their oestrogen production intact. It may be that, in our remote past, evolution selected oestrogen, the central reproductive hormone, for all its various non-reproductive duties in heart, bone and brain, at a time when life was generally short and climacteric ovarian failure uncommon. Now, with our greatly enhanced life span, we may be experiencing, for the first time in our million year history, a set of diseases such as atherosclerosis, osteoporosis and Alzheimer's, which are, in part, the consequence of the broad action of oestrogen and of our spectacular success in promoting longevity far beyond the menopause.
These considerations lead naturally to the great question of whether (to paraphrase Hamlet) it is nobler in the mind to suffer the symptoms and consequences of oestrogen deficiency, or to take up replacement and, by opposing, end them. We will address that question in a forthcoming article.

Professor Purdie is head of clinical research, at the Centre for Metabolic Bone Disease, University of Hull at Hull Royal Infirmary, and Mrs Crawford is a community pharmacist in Ayrshire