In the second of our articles, the short-term symptoms experienced during the menopause, and the different treatments available for dealing with them are reviewed
The menopause, when correctly and strictly defined simply as the cessation of the menstrual cycle itself, is asymptomatic. On the other hand, climacteric ovarian failure (the final exhaustion of the egg cells which removes the oestrogen drive from the menstrual cycle and hence causes the menopause) is usually anything but asymptomatic. Indeed, it may be the cause of considerable physical and emotional distress to women. However, it should be noted that some women pass through the climacteric - the decade of change from fertility to infertility - without significant symptoms and without need of professional help.
Some women elect to accept the effects of the menopause as a natural, if uncomfortable, end to their reproductive years - just as they accepted the discomfitures of puberty. However, most women today will not tolerate significant disruption of their personal, domestic or professional lives by menopausal symptoms, and will seek help.
In a previous article (PJ, October 30, p712) we summarised the physical and psychological symptoms of the menopause. Here, we look at the measures that may be deployed to ameliorate, or even abolish, these symptoms.
Hormone replacement therapy (HRT) is the term in general use in the UK to describe the therapeutic use of oestrogen in postmenopausal women. Oestrogen has been in use for over 50 years and continues to evolve both as a therapeutic and as a preventive treatment for the symptoms and longer term consequences of the menopause, respectively.
Vasomotor symptoms Hot flushes and night sweats are cardinal symptoms of the menopause and are due to a disturbance of the central thermoregulator, or thermostat, which is located in the hypothalamus and is kept stable by normal circulating oestrogen. In their now classic paper of 1977, Whitehead and Campbell carried out a six month, randomised, placebo-controlled, crossover trial in which symptomatic menopausal women received three months of oestrogen followed by three months of placebo, or vice versa.1 They found that the vasomotor symptoms of hot flushes and night sweats were significantly reduced, indeed often abolished, by oestrogen, an observation which has been frequently confirmed.
Patients report an improvement in the frequency and severity of symptoms, often within one week. The full effect is visible at 12 weeks, when all patients prescribed HRT should have their first critical review. If the patient's flushing and sweating is not significantly improved by this time, serious consideration should be given to its having another cause, such as stress, hyperthyroidism or, rarely, phaeochromocytoma. The patient's practitioner or specialist should be advised accordingly by the patient or pharmacist.
In parallel with the reduction in night sweats, the patient may report an increase in sleep duration and quality.
Other physical effects The principal symptom of the menopause is tiredness. Many women note an improvement in their energy levels with HRT, but some do not. A careful inquiry has to be conducted in this last group to detect which of the many causes of loss of energy may be operating.
Many patients complain of headaches as an accompaniment of the natural menopause. There is no guarantee that these will reduce in severity or frequency with the use of HRT - a wait and see policy has to be adopted during the three month trial period. Indeed, some women report a decline in headaches at the menopause and an increase in their frequency when on oestrogen. With migraine, the picture is equally confused. However, if a patient develops true aura-associated migraine for the first time on HRT, she should be advised to see her practitioner.
Joint pain is another area of great uncertainty. It is undoubtedly the case that many women complain that the menopause brings an aching, creaking and discomfort, sometimes in many joints, as if a natural lubricating oil had been withdrawn. Equally, a careful history will often reveal that women receiving oestrogen report an improvement in joint mobility and a reduction in discomfort. Thus, it is sensible not to initiate empirical treatment of arthralgia in menopausal women with a non-steroidal anti-inflammatory agent but to test the effect of three months of HRT and only then, if there is no relief, proceed to utilise other agents. The physical and psychological symptoms of the menopause in European women have been clarified and illuminated by the studies of Oldenhave.2
Psychological symptoms The psychological symptoms of the menopause are not nearly so specific as their physical counterparts.
Tiredness, loss of energy, irritability, loss of short-term memory and depression in a 50-year-old can have many origins, of which the menopause is only one (if the most likely one). Faced with such an array of symptoms it can be difficult to know where to start and it is in such circumstances that HRT itself can be a useful diagnostic tool.
A three months trial of treatment with a recognised HRT regime will subtract from the patient's symptom load those symptoms which are oestrogen-dependent. Thus, it may be found that HRT treatment has abolished her mood swings and irritability but that she remains significantly depressed. In such a circumstance, professional psychiatric support should be considered. Conversely, a patient may report resolution of her night sweats, loss of concentration and depression, but that she remains unable to sleep. Here again, specialist treatment can now be brought to bear on the residual problems.
A sensible approach to such psychological problems in a peri- or post-menopausal woman is that the practitioner should probably not treat initially with hypnotics, anxiolytics, antidepressants or, indeed, with any psychoactive drug until the effect of normalising the plasma oestrogen has been tested in a three month clinical trial of HRT. It goes without saying, in this context, that the other common endocrine problem which can produce similar symptoms, hypothyroidism, should be excluded by thyroid function testing.
In general, women taking HRT often report a general improvement in their energy level, their ability to cope with the unexpected, and in their overall outlook and self confidence. These effects have their origins in the restoration of normal oestrogen actions within the central nervous system, not least through the promotion of unbroken refreshing sleep. Libido is another difficult and complex area. Many women report an improvement with HRT and the restoration of genital tract function but, again, some do not and may benefit from the specialised help of a psycho-sexual clinic.
Urogenital symptoms Vaginal dryness and dyspareunia were found in the study of Whitehead and Campbell to be classic symptoms of oestrogen deficiency and remediable by the use of oestrogen. The hormone acts by rapidly building up the depleted layers of vaginal stratified squamous epithelium and restoring the glandular function which provides normal lubrication. The oestrogen may be given as a standard HRT regime but, if this is contraindicated, then it may be given locally as an oestriol, dienestrol or conjugated oestrogens-based cream, as a vaginal oestradiol tablet, a pessary, or a silicone ring containing a small dose of oestradiol. If no hormonal treatment can be deployed and lubrication is required then a product such as K-Y jelly may be used.
With regard to the urinary tract, it is undoubtedly the case that some women report that HRT induces a reduction in nocturnal frequency, urgency and urge incontinence. However, good scientific support for such effects is lacking and women reporting such symptoms should be considered for gynaecological consultation to detect prolapse and for urodynamic assessment. Again, when in doubt, a three month trial of oestrogen may prove so beneficial that referral becomes unnecessary, or so unsuccessful as to render it essential.
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A vast amount of data has been accumulated in recent years on the optimal use of oestrogen and will be summarised here. All HRT regimes are prescription-only medicines and, hence, the patient will present with a prescription selected by a general practitioner or physician after the routine history and physical examination (breasts, pelvis, blood pressure) have failed to disclose any contraindication.
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Panel 1: Daily doses of oestrogen for bone loss prevention
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The first few days or weeks of HRT are among the most critical, as many women stop treatment during this time, often because of poor preparation and counselling.3
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Panel 2: "Start-up" effects of oestrogens
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Women without a uterus - 20 per cent of UK females at age 50 - do not require a progestogen unless the hysterectomy was for endometriosis, in which case a continuous combined HRT or tibolone (to suppress any residual endometrial tissue) should be used.
In general, younger women need more oestrogen; for example, up to two 100mg patches per day may be necessary to control symptoms in young women after premature menopause (age <45). Such women should be given HRT until the age of natural menopause at 51, after which its continuation should be critically reviewed. However, most women will begin HRT at or around the time of the menopause and indeed symptoms may necessitate the beginning of treatment before bleeding has actually stopped.
HRT preparations are not designed to act as regulators of a menstrual cycle and thus, in perimenopausal patients who require improved cycle control, oral contraceptives may be prescribed. This is provided that the patient is a non-smoker and does not carry significant risk of cardiovascular disease.
Cyclical HRT regimes The general arrangement for cyclic HRT regimes is that continuous oestrogen, either oral and transdermal, will be partnered by a discontinuous progestogen, given for 10 to 14 days per month. This secures the maturation of the oestrogen-primed endometrium and then its full shedding as a withdrawal bleed. Such bleeds are not true periods but should resemble them in being of less than a week's duration, not unduly heavy, relatively pain free and on time. A woman who has a regular, predictable, light-to-moderate withdrawal bleed is most unlikely to come to harm. Conversely, a pharmacist who is made aware of a complaint of heavy or unscheduled bleeding should advise a consultation with the general practitioner.
No bleed regimes More accurately called no withdrawal bleed regimes, these treatments were introduced to spare women the inconvenience of a cyclic event that many had hoped was gone for good. Indeed, the return of bleeding and fear of breast cancer remain the top two disincentives for women to begin, or to continue with, a course of HRT.
The combination of daily oestrogen with daily progestogen - the so-called continuous-combined regime - is the usual method of inducing amenorrhoea. The continuous progestogen inhibits production of the oestrogen receptor in the endometrium. Without its receptor, oestrogen is impotent and cannot cause proliferation. These regimes are restricted to women who are a year postmenopause, or who are over the age of 54 years and consequently have a low level of circulating oestradiol. If given too close to the menopause, when oestradiol levels are higher, the result may be unscheduled bleeding. These regimens are well tolerated but patients must be counselled that some spotting and occasional bleeding is not unusual in the first six months of treatment. Should such bleeding not have stopped or not be in decline after six months of treatment, the patient should advise the practitioner who may then adjust the regimen used. Where there is persistent heavy loss, a gynaecological opinion is needed.
The alternative way of securing amenorrhoea is to use the gonadomimetic agent tibolone. This agent is an artificial steroid with oestrogenic, progestogenic and some androgenic properties. Tibolone, like conventional HRT regimes, is also bone protective. It increases libido and has commendably few breast-related adverse effects compared with HRT.4
Overall, HRT regimes are well tolerated and give good service. Early start-up effects usually subside but, if they do not, alternative treatments may have to be found. Apart from bleeding with the cyclic regimes, the commonest major concerns among women taking HRT longer term are weight gain, venous thrombosis and, above all, breast cancer.
Weight gain There is no doubt that oestrogen increases appetite. After all, that is one of its central functions in pregnancy, thus encouraging the mother to eat for herself plus the foetus. However, long-term, controlled studies have shown that after 15 years of HRT, there is, overall, no difference in the weight of treated women versus the weight of untreated controls. Early weight gain can occur, however, and women starting oestrogen should be counselled to reduce calorific intake and increase calorific output (ie, take more exercise).
Weight gain is extremely common among women in their early 50s and a particular advantage of oestrogen is that the distribution of fat levels tends to be in the female pattern (ie, of hips and breasts). In untreated women, the male pattern of abdominal or central deposition predominates. The latter is strongly associated with the development of atheroma, against which oestrogen is a primary protector.
Venous thrombosis Venous thrombosis is more common in HRT-treated women than in controls. The low background rate of 1-2 per 10,000 cases per annum of deep venous thrombosis (DVT) and pulmonary embolism rises to about 3 per 10,000 per annum on treatment.5 However, it should be noted that the overall absolute risk is still low, at less than one extra case per 5,000 patient-years of exposure. Risk will be reduced further if due care is applied in excluding from HRT women with a past personal, or indeed family, history of confirmed DVT. In such circumstances, a specialist opinion from a menopause clinic, together with a haematological assessment of coagulation function, is required.
Breast cancer Far beyond all other fears of women receiving HRT looms breast cancer - and with reason. The death rate from breast cancer, 22.4 per 100,000 per annum, recently published in the Government's ironically titled White Paper "Our Healthier Nation", is the fourth highest in Europe. One woman in 12 will have to face breast cancer and virtually all will have a neighbour or relative who develops the disease.
There is little doubt that HRT does exert a small influence on breast cancer risk. If we consider that a naturally late menopause has been known, for over 20 years, to be one of the risk factors for the disease, then it is perhaps not surprising that delaying the menopause artificially with HRT has a similar effect. So it proved in the most comprehensive study on the subject, published in the Lancet in 1997.6 In summary, this study showed that the HRT effect is there, but it is small. If 1,000 women are followed from age 50 to age 70 and take no HRT, there will be 45 cases of breast cancer among them. If all 1,000 were to take HRT for five years - far longer than the average HRT exposure at present - there would be two extra cases in these 1,000 women over 20 years. Put in absolute terms like this, the effect of HRT is seen in a truer perspective and is, incidentally, less of a risk factor for breast cancer than, for example, having a first baby at or after the age of 30.
In summary, oestrogen given for a valid indication and with appropriate checks before starting and annually thereafter, is a safe and reliable means of controlling menopausal symptoms. However, like all good medicines, it treads a fine line between efficacy and toxicity. It is the duty of all who care for women to determine if it is likely that, in the individual case, HRT will safely confer net benefit. If so, it should be offered so that the woman may exercise her right to decide whether or not to take it.
A wide variety of agents have been claimed to assist women through the symptomatic trials of the menopause. Few have been presented at the iron gate of a placebo controlled clinical trial - the true test of efficacy and vital in the area of the menopause, where a major placebo effect may always be expected. Pharmacists will be aware of the tremendous marketing drive behind certain products but should be equally aware that proof of efficacy often lags far behind the claims of advertisements.
Phyto-oestrogens As the name implies, these are oestrogens found naturally in plants (Greek: Phytos - a plant). They have been heavily promoted in recent years as a "natural" alternative to HRT. Natural they are, but to plants, not to H sapiens. The irony of the claim that phyto-oestrogens, such as those found in soya products, are more natural than the native human oestradiol used in HRT preparations will not be lost on pharmacists. There is no doubt that some women report relief of menopausal symptoms when taking phyto-oestrogens but so do many women who are randomised in trials to receive placebo. Two recent placebo controlled trials of phyto-oestrogen efficacy are, therefore, most welcome. An Australian study of 37 postmenopausal women found no difference between the phyto-oestrogen group and the placebo group in respect of hot flushes and the overall symptom load.7
Another study, looking at 51 women, again found no significant advantage in phyto-oestrogen over placebo but the authors commented that there were no adverse clinical effects or endometrial changes.8
A recent review on phyto-oestrogen concluded that there is no reliable evidence for a substantive role for phyto-oestrogens in the treatment of postmenopausal women. However, research should and will continue in the hope of refining these interesting plant hormones for human use.
Progesterone Great debate has raged in recent years over the issue of progesterone. This hormone is a natural promoter of gestation - hence its name - and is, of course, largely absent at the end of ovulation, since no corpora lutea can be present in the ovary to manufacture it.
Claims that natural progesterone could increase bone mineral density were found to be based on a study which contained no ethical approval, no control group or statistical analysis, and which was deeply flawed.9 Furthermore, the absorption of transdermal progestogen was shown to be poor and produced blood levels unlikely to achieve any worthwhile effect. However, a beneficial effect of natural progestogen on menopause symptoms has been now attested in a small double-blind, placebo controlled trial. In this trial, 83 per cent of the 25 women receiving 20mg progesterone transdermally per day reported improvement in relief of hot flushes. No effect on their bones was found.10 Further controlled studies are awaited with interest.
In patients who cannot, for various reasons, be offered oestrogen, vasomotor symptoms may be tackled with alternatives, such as clonidine or the progestogens medroxyprogesterone acetate or megestrol acetate. Recently, work from the Mayo clinic has suggested that venlafaxine may be of value in preventing hot flushes, but this requires confirmation.
Oil of evening primrose Preparations containing evening primrose oil (EPO) have been used to combat hormonal imbalance during both the menopause and premenstrual syndrome. EPO is a rich source of g-linolenic acid (GLA, gamolenic acid), which is a prostaglandin precursor. Prostaglandin is thought to be important in maintaining the hormonal balance during the menstrual cycle. GLA deficiency is considered to be partly responsible for breast pain and, by using EPO preparations, improvement in cyclical mastalgia in premenopausal women has been shown. Although the manufacturers of EPO preparations claim that many of the unpleasant vasomotor symptoms of the menopause are significantly improved by taking their products, the long-term beneficial effects have never been conclusively proved to be as good as oestrogen therapy.
Homoeopathic preparations Homoeopathic preparations found to be of some short-term benefit for hot flushes contain pulsatilla and sepia.
Herbal preparations The use of herbal remedies is more common among the middle-aged than the young and, although no good figures are available, it would seem that their use is much more prevalent among women than men.
Some trial data are available from which it would seem that the principal utility of herbal intervention is against the psychological symptoms of the menopause rather than the physical symptoms. Thus, valerian (Valeriana officinalis) has, in the hands of some, but not all, investigators, proved useful in promoting sleep. The South Pacific islanders' traditional use of kava (Piper methysticum) has been shown in trials to elevate mood and feverfew (Tanacetum parthenium), used in the British Isles since the Middle Ages as an antipyretic, has been found to be useful in the prevention of migraine.
However, the best quality and quantity of evidence to support a herbal treatment exists in respect of St John's Wort (Hypericum perforatum). To our knowledge, this is the only herb in this area to have been subjected to a meta-analysis of randomised controlled trials examining its efficacy. This analysis pronounced the agent superior to placebo in the treatment of mild-to-moderate depression, with an acceptably few adverse effects. The field of potential herbal intervention for menopausal women has been recently well reviewed by Ernst.11
Some women will always prefer to use alternative therapy to combat the unpleasant symptoms of the menopause and the pharmacist is often asked for advice about natural products or complementary therapies. Many women have a fear of hormone preparations due to the known side effects, but also because of lack of information and the substantial amount of misinformation that is abroad. There is a cogent view that there is no such thing as a conventional medicine or an alternative/complementary medicine; there are only medicines - those that have been examined for efficacy and safety, and those that have not.
Overall, it should be stressed that the true symptoms of the menopause, caused as they are by oestrogen deficiency, are most effectively treated by oestrogen replacement. No other measure is as useful.
The symptoms of the menopause eventually settle. Sometimes this takes weeks, sometimes it takes years. Pharmacists will often be asked to judge whether the symptoms are capable of amelioration by simple medicaments, by unlicensed products, or whether a full course of HRT will have to be prescribed.
Substantial sums are made by certein commercial enterprises, which play on the anxiety of menopausal women and offer untrialled answers to the problems associated with this time of life. The pharmacist, therefore, has a major role in determining the worth and value of treatments in this complex field and in advocating them according to genuine merit. Both pharmacist and physician, working in concert in this problematic area, have still their ancient duty - to cure sometimes, to relieve often and to comfort always.
This article will form the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme
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