Menopause and post-menopause

5 Menopause and post-menopause GORDANA

M. PRELEVIC

MD, MSc, DSc, FRCP

Senior Lecturer in ReproductiveEndocrinology HOWARD

S. J A C O B S

MD, FRCP, FRCOG

Professor of Reproductive Endocrinology

Division of Endocrinology, Department of Medicine, University College London Medical School, London WIN 8AA, UK

From the endocrine point of view, menopause is considered a deficiency state and oestrogen therapy regarded as restoring the pre-menopausal endocrine milieu. Oestrogen therapy alleviates acute climacteric symptoms and also reduces the risk of cardiovascular disease, osteoporosis and Alzheimer's disease. Cardiovascular protection seems to be the major benefit of oestrogen replacement: it reduces morbidity and mortality from coronary heart disease by approximately 50%. The mechanisms are complex and not fully understood. In this review we discuss currently available data on the effects of hormone replacement therapy on serum lipids and lipoproteins, the vessel wall (endothelium dependent and endothelium independent), blood flow, cardiac function, blood pressure, haemostasis, insulin sensitivity and direct anti-atherosclerotic effect as possible mechanisms of cardioprotection. Oestrogen therapy reduces the rate of post-menopausal bone loss, increases bone mineral density (BMD) and decreases fracture rate. Recent evidence suggests that initiation of oestrogen therapy in older women produces larger increases in BMD which might provide a significant protective effect at the time when fracture is common. The incidence of Alzheimer's disease is reduced by 50% in post-menopausal women taking oestrogen replacement. Limited clinical trials of oestrogen treatment in women with this disease have documented beneficial effects on cognitive function. The results of epidemiological studies of the effects of oestrogens on breast cancer risk are conflicting but recent evidence suggests that the risk is increased in current users after 5 years of use and among older women. In contrast, increase in the risk of venous thromboembolism is most significant within the first 12 months of therapy, strongly suggesting the importance of individual susceptibility. Key words: Alzheimer's disease; breast cancer risk; cardiovascular disease; hormone replacement therapy; menopause; oestrogens; osteoporosis. T h e term ' n a t u r a l m e n o p a u s e ' defines the p e r m a n e n t cessation of m e n s t r u a t i o n r e s u l t i n g f r o m the loss of o v a r i a n activity ( W H O , 1996). BailIi~re's Clinical Endocrinology and Metabolism-311 Vol. 11, No. 2, July 1997 Copyright © 1997, by Bailli~re Tindall ISBN 0-7020-2357-4 All rights of reproduction in any form reserved 0950-351X/97/020311 + 30 $12.00/00

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Menopause, the final menstrual period, can only be determined retrospectively, after at least 12 months of amenorrhoea. Median age at the menopause is currently around 50 years in Western industrialized societies (in Britain it is 50.78 years, in the United States 49.8 years and in White South Africans 48.7 years). It occurs earlier in Black women (Ginsburg, 1991). In addition to race, nutrition and smoking influence the age at menopause. It has been suggested that age at menopause may be a biological marker of ageing, later menopausal age being associated with longevity (Snowden, 1990). Although 'premature menopause' should be defined as occurring at an age less than two standard deviations below the median estimated for the referent population (WHO, 1996), in practice an age of 40 years is used as an arbitrary cut-off. The term 'peri-menopause' describes the phase immediately before and the first year after menopause. The term 'menopausal transition' is best reserved for the period before the final menstrual period. Its average duration is 3.8 years (McKinley et al, 1992). The term 'post-menopause' defines the phase after the final menstrual period (WHO, 1996). The term 'pre-menopause' refers to the whole of the reproductive period prior to the menopause. BIOLOGY OF MENOPAUSE The biological bases of the menopause are changes that occur in the structure and function of the ovary. The number of ovarian follicles present in the ovary, and thus the number of ovarian granulosa cells available for hormone secretion, appears to be a critical determinant of age at menopause. The supply of oocytes is finite: about 7 million germ cells can be found in the ovaries of the human fetus at the fifth month of intrauterine life but these cells do not thereafter divide. The rate of follicle decline is approximately linear on a semilogarithmic scale until an age of about 35-40 years (Gougeon, 1984). It accelerates thereafter until after the menopause, when essentially no follicles remain (Richardson et al, 1987). The relationship between follicle number, menstrual pattern and age was clarified in a study published by Richardson et al (1987). They estimated follicle numbers in 17 healthy women 44-45 years of age, divided into three age-matched groups according to the pattern of their menses in the previous 12 months. Follicle counts in the women with regular menses were 10-fold greater than in peri-menopausal women. Follicles were virtually absent from the ovaries of post-menopausal women. These observations indicate that the size of the follicular reserve is the major determinant of the transition from regular menses to the peri-menopause as well as to the menopause itself. Richardson (1993) hypothesized that the elevated follicle-stimulating hormone (FSH), seen in the last decade of menstrual life, stimulates a greater proportion of follicles to enter the growing phase and hence to be destined for atresia. Although little is known about the factors affecting the

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rate of atresia, studies in rodents have shown that the rate of depletion is retarded by lowering gonadotropin levels (hypophysectomy, pharmacological suppression of gonadotropin secretion and food restriction) (Richardson et al, 1987). As women approach the menopause, menstrual cycles become irregular. The progressive shortening of the cycle is caused by shortening of the follicular rather than the luteal phase (Lenton et al, 1984). About 25% of women aged 40-45 years and 40% in the 45-50 age group have anovulatory cycles. An important consequence of the increasing number of anovulatory cycles is unopposed oestrogenic stimulation of the uterus which underlies increased incidence of endometrial hyperplasia that occurs at this time. During the menopausal transition, hormonal levels are variable and unpredictable and endocrine assessment of ovarian function is of poor predictive value with respect to timing of the menopause (Burger, 1994). All possible combinations of hormonal patterns can be observed during this phase. The first hormonal change is an increase of FSH concentrations in the early follicular phase which precedes alterations in menstrual pattern and oestradiol concentrations (Reyes et al, 1977). The FSH changes may signal the need for increased hypothalamic-pituitary activity to activate ageing oocytes that are likely to be of progressively poorer quality. On the other hand, the increased FSH induces more rapid maturation of follicles, resulting in accelerated loss of oocytes. On the basis of in vitro fertilization data, there has been a suggestion that FSH concentrations on day 3 of the cycle reflect the reproductive potential of that cycle and are a better predictor of number of oocytes retrieved, transferred and ongoing pregnancies than the woman's chronological age (Toner et al, 1991). While a significant increase in FSH was found in the 40-45 year age group with a progressive increase throughout the forties, luteinizing hormone (LH) becomes significantly elevated only in the oldest group (Lee et al, 1988; Lenton et al, 1988). Two hypotheses have been suggested to explain the selective increase in FSH. The first is a decline in inhibinmediated negative feedback control of FSH secretion. Alternatively, there may be an age-related reduction in the sensitivity to feedback inhibition at the hypothalamopituitary level (Lenton et al, 1988). In regularly cycling women there is a progressive decline in serum inhibin as a function of increasing age (McNaughton et al, 1992). Inhibin concentrations are lower during both the follicular and the luteal phases of the cycle in women over 45 years of age than in younger controls (Richardson, 1993). The levels are undetectable after menopause (McLachlan et al, 1986). Thus it appears that inhibin is a biomarker of the number and/or quality of follicles that remain in the ovary. By 2-3 years after the last menstrual period, serum FSH levels increase to values 10-15 times higher than follicular-phase levels in young women and LH levels are about 3 times higher (Wide et al, 1973). The levels of both gonadotrophins subsequently decrease with age and are negatively correlated with body mass index, in contrast to oestrone and oestradiol levels, which are positively correlated with it (Kwekkeboom et al, 1990).

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Cross-sectional studies of hormonal levels around the time of menopause suggest that 20-40% of women have oestrogen concentrations consistent with the presence of functioning follicles in the first 6-12 months after the final menstrual period (Longcope et al, 1986). By 12-24 months after menopause, oestrogen levels fall into the post-menopausal range in most women (Longcope et al, 1986) (Table 1). The recent finding of elevated oestrone conjugate excretion throughout the menstrual cycle in peri-menopausal women (Santoro et al, 1996) suggests the ovary is able to produce adequate quantities of oestrogen. The decline in luteal-phase progesterone secretion in the peri-menopause may aggravate the relatively unopposed oestrogen state, further predisposing peri-menopausal women to endometrial hyperplasia, dysfunctional uterine bleeding and uterine myomata. After the menopause, quantitatively the most important circulating oestrogen is oestrone, formed by extraglandular conversion of adrenal androgen precursors, particularly androstenedione (Sitteri and MacDonald, 1973). Testosterone levels decline by about 20% and androstenedione by about 50%, although, after oophorectomy, the decrease in serum levels of both androgens is about 50% (Hughes et al, 1991). After natural menopause, in some women the ovaries undergo stromal hypertrophy and hyperplasia, with increased capacity to produce androstenedione and testosterone (Utian, 1992). DHEA-S declines linearly with age and is not specifically affected by the menopause (Meldrun et al, 1981) (Table 1). Table 1. Blood production rates of steroids in women (rag/day). Reproductive age Androstenedione Dehydroepiandrosterone (DHEA) DHEA- S Testosterone Oestrogens

2-3 6-8 8-16 0.2-0.25 0.350

Post-menopause 0.5-1.0 1.5-4.0 4-9 0.05-0.1 0.045

MENOPAUSAL SYMPTOMS Complications of the menopause are the immediate symptoms of acute oestrogen deficiency and the long-term problems of osteoporosis, coronary heart disease (CHD) and Alzheimer's disease. Acute menopausal symptoms are experienced by about two-thirds of women. Severity and duration are variable but in at least one-third of women who do experience these symptoms they are severe enough to require medical help. As a rule symptoms are more pronounced if a woman experiences an abrupt cessation of ovarian function, as after oophorectomy. Typical symptoms, which form the acute climacteric syndrome, can be grouped into vasomotor phenomena and psychosomatic symptoms. While the vasomotor symptoms are more uniform (although the perception of such symptoms by individual women may differ), psychosomatic

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symptoms and particularly their intensity are strongly determined by psychological, social and cultural characteristics of the woman. In general, hot flushes and sweats are more common in European and North American women than in other populations (Avis et al, 1993; Tang, 1993). Dietary habits, such as ingestion of phyto-oestrogens, may contribute to these differences. Climacteric symptoms are most prominent within the first few years after the menopause. They persist for longer than 5 years in 25% of women and in a small minority may be lifelong. The cause of psychological symptoms (difficulty in making decisions, poor concentration, memory impairment, loss of confidence, feeling unworthy) that may occur at the time of the menopause is controversial (Matthews et al, 1990). Some clinicians consider that psychological symptoms are the consequence of physical aspects of the menopause, such as vasomotor symptoms, insomnia and atrophic vaginitis, while others attribute psychological symptoms to coincident life events. The difficulties with sleep seem to have a multifactorial basis. They usually present as either intermittent sleep or early awaking rather than true insomnia (Erlik et al, 1981). Disrupted sleep (as a result of hot flushes and night sweats) may contribute to emotional instability. Genitourinary atrophy, caused by lack of oestrogens, leads to symptoms such as pruritus and dyspareunia. Urethritis, with dysuria, urgency incontinence and urinary frequency are further results of thinning of the lining of the urethra and bladder. The frequency of post-menopausal dyspareunia associated with vaginal atrophy is not well established but, on the basis of women attending menopausal clinics, it is estimated to be 10%. Women with symptoms that arise from atrophy of the genital tract have serum oestradiol concentrations that are about half of those in women without such symptoms (Hutton et al, 1978). BENEFITS AND RISKS OF MENOPAUSAL HORMONE R E P L A C E M E N T Cardiovascular disease protection

Epidemiological and angiographic data CHD is the leading cause of death in women. It is relatively uncommon in pre-menopausal women but the increased incidence of the disease is seen with the loss of ovarian function at the menopause, Epidemiological evidence suggests that protection against cardiovascular disease (CVD) is the major benefit of menopausal hormone replacement therapy (HRT) (Stampfer and Colditz, 1991). Oestrogen replacement therapy reduces morbidity and mortality from CHD by approximately 50% (Barrett-Connor and Laakso, 1990; Stampfer et al, 1990; Barrett-Connor and Bush, 1991) in normal post-menopausal women and also in those with established CHD (Henderson et al, 1991). Oestrogen

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therapy is also associated with a reduction in the risk of death from stroke (Paganini-Hill et al, 1988). Angiographic studies have provided particularly strong evidence for the benefits of oestrogens (Gruchow et al, 1988; Sullivan et al, 1988; MacFarland et al, 1989; Hong et al, 1992). Oestrogen therapy reduces coronary stenosis, as documented by a repeat coronary angiogram (MacFafland et al, 1989; Sullivan et al, 1990). The reduction is greater in those with the most severe occlusion at the initial examination. The 10 year survival was better with oestrogen treatment when coronary disease was present and oestrogens were less protective in the absence of coronary artery disease (Sullivan et al, 1990). Oestrogen treatment also improves survival after coronary bypass surgery (Sullivan et al, 1994). These observations indicate that oestrogen replacement therapy may have an important role not only in primary but also in secondary prevention of CVD. Women with risk factors for CVD such as smoking, hypertension or history of myocardial infarction seem to be those who have the most to gain from HRT (Barrett-Connor and Bush, 1991). If CVD is reduced by 50% by oestrogen replacement, what are the mechanisms? Several are involved but the picture is not completely understood (Table 2). Table 2. Possible mechanisms of cardioprotective effects of oestrogens. Favourable impact on serum lipids and lipoproteins Increase high-density lipoprotein (HDL) cholesterol Decrease low-density lipoprotein (LDL) cholesterol Decrease lipoprotein (a) (Lp(a)) Reduce oxidation of LDL cholesterol Direct anti-atherosclerotic effect in arteries Lower uptake of LDL cholesterol in blood vessels Prevent cholesterol deposition in vascular lesions? Direct vascular effects Reduce vascular tone Preserve endothelial function Increase production of nitric oxide from blood vessels Increase prostacyclin release Inhibit endothelial production of endothelin-1 Inhibit endothelin-1-induced vasoconstriction Direct inotropic action on the heart Effects on haemostasis Decrease plasma fibrinogen Reduce plasminogen activator inhibitor Improvement in peripheral glucose metabolism Decrease fasting blood glucose Decrease serum insulin levels

Effects on lipids and lipoproteins The magnitude of the lipid changes in post-menopausal women taking oestrogens suggests that they can account for only 20-30% of cardiovascular benefit of HRT (Bush et al, 1987).

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The most well-recognized oestrogenic effect on lipoprotein metabolism is a reduction of serum total and LDL cholesterol. This effect is achieved primarily by up-regulating LDL apolipoprotein B100-E (apoB100-E) receptors in the liver and other sites. LDL particles also are partially depleted of their cholesterol content (Campos et al, 1993; Crook, 1996). The reduction in particle size is counterbalanced by the anti-oxidant effect of oestrogen (Sack et al, 1994). Some oral oestrogen preparations also affect the synthesis and clearance of LDL precursors such as very-lowdensity lipoprotein (VLDL) (Walsh et al, 1991). Cholesterol appears to fall more markedly in women with hypercholesterolaemia than in those with normal cholesterol concentrations (Tonstad et al, 1995). Both dose and route of administration are important in relation to the LDL lowering effect of oestrogens. Oral oestrogens reduce LDL cholesterol by 10-15% (Rijpkema et al, 1990) but transdermal oestradiol has a smaller effect (Crook et al, 1992; Whitcroft et al, 1994). In women, HDL cholesterol levels have a stronger relationship with coronary heart disease than do those of LDL (Jacobs et al, 1990). Oestrogens increase HDL cholesterol levels by about 10% but only when given orally (Crook et al, 1992). The mechanism behind this increase is increased hepatic synthesis of apoA1 and inhibition of hepatic lipase activity, although the significance of the latter mechanism has recently been challenged (Brinton, 1996). The large HDL particles (HDL2 subfraction) induced by oestrogen are thought to be the most important in relation to a protective effect against the development of atherosclerosis. Transdermal oestradiol monotherapy neither increases nor decreases HDL cholesterol (Crook and Stevenson, 1996). Progestogens with androgenic activity reduce HDL levels, thus attenuating oestrogen-induced increases in HDL. Both the type and the route of oestrogen administration determine its effects on triglycerides. Oral conjugated equine oestrogens (CEOs) increase fasting triglyceride levels in a dose-dependent manner by promoting VLDL apoB100 synthesis as a part of a hepatic first-pass response (Crook, 1996). Doses of 0.625 mg/day of CEO increase fasting triglyceride levels by 20-25% (Rijpkema et al, 1990), doses of 1.25 mg/day increase levels by about 40% (Walsh et al, 1991). Orally administered oestradiol has little or no effect on triglyceride levels, but transdermal oestradiol causes a reduction in triglyceride by 15-20% (Crook et al, 1992). CEOs should not be used in women with moderate hypertriglyceridaemia (2-4 mmol/1). Therapy with transdermal oestradiol may normalize moderately raised triglyceride level. Orally administered oestradiol, however, improves post-prandial remnant clearance, which might be another mechanism for the beneficial effects of oestrogen on CHD (Crook, 1996). Tibolone reduces serum triglyceride (Kloosterboer et al, 1990) and HDL cholesterol (Crona et al, 1983) with no effect or a slight reduction of total and LDL cholesterol. The most striking effect of tibolone on lipids is a reduction of up to 40% of Lp(a) concentrations (Rymer et al, 1993). Whether this effect provides cardiac benefit is not known because we do not know whether reduced Lp(a) induces cardiovascular protection or

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whether it is only a marker for arterial disease. The clinical significance of lowering Lp(a) by tibolone and oestrogens is therefore unknown (Crook et al, 1995). Interest in Lp(a) was raised with the discovery that its apoprotein (a) has close structural homology with plasminogen and therefore might provide protection from CVD via changes in plasminogen metabolism. Although progestogens tend to oppose the effects of oestrogens on triglyceride and HDL levels, they do not alter the effect on LDL and Lp(a). Therefore while combined therapies may attenuate the increase in HDL they do not oppose oestrogen-induced falls in LDL levels (Crook, 1996). The lipid profile in women using combined therapies containing micronized natural progesterone and medroxyprogesterone acetate (MPA) (Writing Group for the PEPI Trial, 1995) or dydrogesterone (Crook et al, 1995) is indistinguishable from the profile seen with oestrogen monotherapy. Oestradiol at physiological levels has an anti-oxidant capacity that is independent of its effects on serum lipid concentrations. Both acute and 3 week administration of 17~-oestradiol significantly inhibited oxidation of LDL in post-menopausal women (Rifici and Khachadurian, 1992; Sack et al, 1994). Equine oestrogens (especially equilin) exhibit higher anti-oxidant potency than oestrone and 17~3-oestradiol (Subbiah et al, 1993). Direct effects of oestrogen on the vessel wall The early observation of Stampfer et al (1986) that the cardioprotective effect of oestrogens drops to half in past users compared with current users, together with the recent evidence that there is no association of HRT with intima media thickness of the carotid artery (Nabulsi et al, 1996), suggests that the well-known association of HRT with reduction in atherosclerotic cardiovascular disease might be attributed to more acute, largely physiological effects. The effects considered are due to improved arterial function rather than to an effect on atherosclerosis itself. Oestrogens cause arterial relaxation by either an endothelium-dependent (i.e. stimulation of nitric oxide (NO), inhibition of endothelin-1 production) or an endothelium-independent mechanism(s) (i.e. calcium-antagonist-like effects) (Miller et al, 1988; Collins et al, 1993; Ylikorkala et al, 1995). There is evidence in monkeys and humans that endothelial function is impaired by oestrogen deficiency and corrected (vasodilatation or less vasoconstriction in response to pressor stimuli) by administration of oestrogen (Sullivan, 1996). Studies of both brachial (Gilligan et al, 1994a) and coronary (Gilligan et al, 1994b) arterial blood flow reveal that administered oestrogen quickly enhances endothelium-dependent vasodilatation. Some investigators (Jiang et al, 1991) have reported that oestrogen can block calcium channels. When sustained, these favourable effects of oestrogens on vascular tone may reduce clinical events without producing significant changes in the atherosclerotic process (Sullivan, 1996). Stimulation of vascular estrogen receptors by oestrogen increases production of NO and prostacyclin. Oestrogen's effect on NO may be the most important mechanism by which it modulates vasomotor tone and may be

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particularly important in atherosclerotic arteries (Williams et al, 1996). NO is a potent vasodilator and inhibitor of platelet aggregation. It also inhibits smooth-muscle cell proliferation and/or migration (Garg and Hassid, 1989) and may retard atherogenesis by inhibiting monocyte adhesion. Support for an endothelium-mediated effect of oestrogen on vascular reactivity comes mainly from the studies of Williams et al (1990, 1992), which showed that in post-menopausal women with atherosclerosis both acute oestradiol administration and long-term oestrogen replacement therapy improve or enhance endothelium-dependent relaxation in response to acethylcholine (Williams et al, 1990, 1992; Gilligan et al, 1994b). Herrington et al (1994) showed that oestrogen replacement therapy was associated with a dose-dependent relaxation in response to acetylcholine in women undergoing coronary arteriography, whereas dose-dependent vasoconstriction was seen in the women not receiving oestrogen therapy. Intracoronary infusion of oestradiol potentiated endothelium-dependent vasodilation in both large and small coronary arteries (Gilligan et al, 1994b). In a supporting study, installation of oestradiol into coronary artery attenuated acetylcholine-induced coronary artery constriction in nine postmenopausal women but not in seven men of similar age (Collins et al, 1995). Long-term administration of oestrogen stimulates transcription of NO synthase and enhances its activity in non-vascular tissue (Weiner et al, 1994). Whether such up-regulation occurs in vascular tissue is not clear. Serum nitrate and nitrite levels are higher in post-menopausal women receiving long-term oestrogen replacement, suggesting enhanced production of NO (Rosselli et al, 1995). It is unlikely, however, that acute improvement in endothelium-dependent vasodilation, observed in as little as 15 minutes, can be explained by classic steroid hormone receptor interaction (Williams et al, 1992; Gilligan et al, 1994a). Receptor-independent mechanisms, such as the ability of oestrogen to act as an anti-oxidant, have therefore been postulated to account for the rapid restoration of endothelium-dependent vasodilatation. Another important factor released from the vascular endothelium is prostacyclin, a potent vasodilator and platelet inhibitor. Prostacyclin levels in oestrogen-treated women are increased by oestrogen (Fogelberg et al, 1990; Mikkola et al, 1995; Yang et al, 1996). Oestrogens inhibit production of endothelin, the most potent vasoconstrictor produced by endothelial cells (Ylikorkala et al, 1995). It has also been shown that 17~-oestradiol has a relaxing effect on endothelin-1contracted coronary arteries (Jiang et al, 1991, 1992). The most likely explanation for these effects is that oestrogen possesses some calciumantagonist-like effects in certain blood vessels (Collins et al, 1993; Han et al, 1995). Indeed, oestradiol improves coronary ischaemia in postmenopausal women with severe atherosclerosis, reducing the incidence of angina pectoris (Rosario et al, 1993). Physiological levels of 17[3-oestradiol selectively potentiate endothelium-dependent vasodilation in healthy post-menopausal women. Such levels also potentiate both endothelium-dependent and endotheliumindependent vasodilation in post-menopausal women with risk factors for

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atherosclerosis and evidence of impaired vascular function (Gilligan et al, 1994b). At least four isoforms of oestrogen receptors have now been identified in vascular smooth-muscle cells, one of them being a potential inhibitor of oestrogen action (Inoue et al, 1996). In pre-menopausal women expression of oestrogen receptors is inversely correlated with coronary atherosclerosis (Lorsodo et al, 1994). Progesterone receptors are present in the arterial wall. There is evidence that cellular actions of progestogen in arteries are mediated through its own receptor as well as through down-regulation of oestradiol receptors. Currently, the concern about progestogens compromising the cardioprotective actions of oestrogens is based on the recognition that they may have an adverse effect on arterial physiology (Sarrel, 1995). For example, therapy with MPA diminishes the beneficial effects of oestrogens on dilator responses to acetylcholine (Williams et al, 1994). Different progestogens may have different effects on the coronary arteries. An anti-proliferative effect of oestrogen in vascular smooth-muscle cells may contribute to its cardioprotective effects. However, when oestrogens are administered at physiological doses to atherosclerotic arteries, endothelium-mediated responses appear to predominate (Williams et al, 1996). Oestrogen protects the integrity of blood vessels by multiple mechanisms. For example, it promotes and stimulates endothelial cell proliferation and migration (Morales et al, 1995). Through its angiogenic activity, oestrogen helps to repair injured blood vessels. It also inhibits proliferation in vitro of smooth-muscle cells from animals and humans, regardless of gender, and in animal models inhibits intimal thickening after angioplasty (Yang et al, 1996) and balloon injury (Chen et al, 1996).

Direct anti-atherosclerotic effects Animal studies support a direct anti-atherosclerotic effect of oestrogen. Ovariectomized monkeys fed an atherosclerotic diet and also receiving oestrogen replacement had 50% less coronary atherosclerosis than those who did not receive oestrogens (Adams et al, 1990). Again, rabbits fed a high-cholesterol diet and treated with oestrogens had one-third of the aortic accumulation of cholesterol compared with untreated rabbits (Haarbo et al, 1991). This effect was not reduced by cotreatment with progestogens. A recent pilot study reported significant plaque regression with oestrogen replacement in post-menopausal women (Akkad et al, 1996).

Effects on blood flow and cardiac function Oestrogens increase blood flow in several vascular compartments, including uterus, skeletal muscle, brain and heart (Bourne et al, 1990; Gangar et al, 1991; Pines et al, 1991; Prelevic and Beljic, 1994). Oestrogen replacement increases stroke volume, cardiac output and flow velocity over the aortic valve in healthy post-menopausal women (Pines et

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al, 1991; Prelevic and Beljic, 1994), indicating a positive inotropic effect of oestradiol. Both acute (Volterrani et al, 1995) and chronic (Ginsburg and Hardiman, 1990) administration of 171]-oestradiol increases peripheral blood flow in post-menopausal women. The addition of cyclical progestogen did not modify the positive effects of oestrogens on blood flow (Penotti et al, 1993; Prelevic and Beljic, 1994). The mechanism of this effect has not been determined. There is, moreover, no evidence that changes in blood flow alone have an impact on clinical outcome or coronary artery disease. Effect on blood pressure

Studies of the effect of oestrogen on blood pressure in post-menopausal women have produced equivocal results, showing a slight increase (Wren and Routledge, 1983), a decrease (Luotola, 1983) or no change (Utian, 1978). In the recent PEPI trial (Writing Group for the PEPI Trial, 1995) there was little or no effect of any of the regimens (CEO with or without progesterone/MPA) on systolic blood pressure over 3 years. Although therapy with oral oestrogens increases renin substrate in a dose-dependent manner, it only raises blood pressure in predisposed individuals. Other mechanisms, such as changes in blood flow and decreased peripheral vascular resistance, may be more important in the regulation of blood pressure. Recently, a reduction in angiotensinogenconverting enzyme (ACE) activity has been documented in postmenopausal women on HRT (Proudler et al, 1995). This reduction in ACE activity might affect vascular function through changes in angiotensin II and kinin concentration (Proudler et al, 1995). Transdermal oestradiol reduces both systolic and diastolic blood pressure, the effect being opposed by the addition of MPA (Prelevic and Beljic, 1994). While the cardioprotective effect of HRT among normotensive postmenopausal women is widely accepted, its use in post-menopausal women with hypertension remains controversial. It does seem, however, that stressinduced blood pressure responses in post-menopausal women are ameliorated by oestrogen replacement (Lindheim et al, 1992). Effects on haemostatic factors

The results of studies of the effects of oestrogen replacement therapy on components of the coagulation system are inconsistent (Nabulsi et al, 1993). Oestrogen replacement lowers circulating levels of fibrinogen (Writing Group for the PEPI Trial, 1995) and platelet activator inhibitor, but it also reduces the amount of anti-thrombin III and protein C, which are both factors that oppose clot formation (Hazzard, 1989). Synthetic oestrogens are more potent than natural preparations and oral oestrogen formulations may influence coagulation more than transdermal preparations. An increase in plasminogen antigen and activity was observed with CEO, but not with 17l]-oestradiol.

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Effects on insulin sensitivity and carbohydrate metabolism Studies of the effect of the menopause on carbohydrate metabolism and insulin sensitivity have produced variable results, data being insufficient to dissociate the relative contribution of ageing, from specific consequences of oestrogen deficiency (DeFronzo, 1979; Lindheim et al, 1994a). In theory, improved carbohydrate tolerance and increased insulin sensitivity might be partly responsible for the protective action of oestrogens on the cardiovascular system. Epidemiological evidence suggests a decreased incidence of non-insulin-dependent diabetes mellitus in post-menopausal women on oestrogen replacement (Manson et al, 1992). Indeed, post-menopausal oestrogen use is associated with lower fasting plasma glucose and insulin concentrations (Barrett-Connor and Laakso, 1990). Type of oestrogen, dose and route of administration are important factors (Cagnacci et al, 1992; Godsland et al, 1993; Lindheim et al, 1994b). Thus an oral oestrogen dose equivalent to 0.625 mg of CEO may increase insulin sensitivity, while a larger dose may induce insulin resistance (Lindheim et al, 1993). Both oral oestradiol and transdermal oestradiol improve insulin sensitivity but most of the progestogens tested oppose this effect.

Prevention and treatment of post-menopausal osteoporosis Effects of oestrogen on bone density and fracture rate Oestrogen therapy reduces the rate of post-menopausal bone loss. The effect persists for as long as therapy is continued but, as with all antiresorptive agents, bone density reaches a plateau after the initial 1 or 2 years of therapy. Bone mass remains stable thereafter throughout the treatment period (Lindsay et al, 1987). When oestrogen replacement is stopped, bone loss resumes. The increase in bone mineral density (BMD) with oestrogen treatment is about 1-3% in cortical bone but as much as 8-10% in trabecular bone (Lindsay, 1993a). This difference is the result of the higher rate of remodelling seen in trabecular bone. The oestrogen-induced increase in bone density in older women results from the same mechanism that causes an increase in BMD in young postmenopausal women (Prestwood et al, 1994). The effect is proportional to the skeletal remodelling space. The response to oestrogens is thus greatest in women who are treated long after the menopause and who have the lowest bone mass (Lindsay and Tohme, 1990). The trophic effect of oestrogen on bone is dose dependent (Lindsay et al, 1984; Selby and Peacock 1986). Doses of 0.625 mg CEO, 2 m g 17 ~-oestradiol or 2 mg oestradiol valerate given orally are optimal in the prevention of early post-menopausal bone loss in the lumbar spine (Table 3). It should not, however, be assumed that the same doses are equally efficacious for the hip. Supraphysiological doses of oestrogens may have added effects on bone formation (Garnett et al, 1990). Transdermal oestradiol prevents bone loss in the spine at all menopausal

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MENOPAUSE AND POST-MENOPAUSE Table 3. Minimum effective oestrogen dose for prevention of bone loss. Type of oestrogen

Daily dose (mg)

CEO Micronized 17l]-oestradiol Oestradiol valerate 17[3-Oestradiol gel Transdermal 17~-oestradiol patch Ethinyl oestradiol

0.625 2.0 2.0 1.5 0.05 0.02-0.03

ages, even at low dosages (0.025 pg/day) (Stevenson et al, 1990; Ettinger et al, 1992; Evans and Davie, 1996). Prevention of bone loss at the femoral neck is, however, not so effective after transdermal oestradiol and the average change in BMD over 3 years was significantly less than in the lumbar spine (Prelevic et al, 1996). Oestradiol implants have two distinct advantages for skeletal protection: high oestradiol blood levels and the assurance of patient compliance. There is apparently a faster increase in BMD in the first 6 months of therapy with implants. However, BMD reaches a plateau later and the overall increase is not greater than with other oestrogen regimens. Not all women respond to the same dose of oestrogen. Some individuals continue to lose bone and develop fractures despite oestrogen therapy (Hassager et al, 1994). The proportion of those who lose bone varies from 5 to 20% (Figure 1) (Prelevic et al, 1996). 0.2

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Dose requirements may be modified by other factors, in particular smoking and calcium intake. Smoking reduces the bioavailability of administered oestrogen by causing 2-hydroxylation of its metabolite, oestrone, with the formation of the catechol oestrogen 2-hydroxyoestrone. The serum oestradiol concentration is reduced by about 50%, an effect which is magnified by the anti-oestrogenic properties of the catechol. Oestrogen users who smoke therefore benefit less from hormone replacement therapy than non-smokers. Oestrogen and calcium act synergistically to increase bone mass, and it has been suggested that a high calcium intake allows oestrogen to be more effective. By supplementing at least 1500 mg/day of calcium, bones may be adequately protected with half the usual dosage of oestrogen (Ettinger et al, 1987). This has particular importance in treating older osteoporotic women and those at increased risk of breast cancer. The timing and duration of oestrogen therapy have recently become subjects of an interesting debate (Kanis, 1995). Although the greatest benefit from oestrogen seems to occur when it is instituted shortly after the menopause, oestrogen therapy increases BMD at all stages of postmenopausal life (Felson et al, 1993). Several studies have shown that oestrogen replacement of 5-10 years' duration, initiated at the time of the menopause, has little or no effect on bone loss or the fracture risk experienced at the age of 70 years, the time when fractures are most common. This has led to the suggestion that therapy might be initiated at age 65 years or when axial BMD falls to 2.5 standard deviations below peak bone mass. Initiation of oestrogen therapy in older women produces large increases in BMD which might therefore provide a protective effect at the time when fracture is common (Kanis, 1995). If proven, such an approach could halve the period of oestrogen use and so reduce the risks of long-term therapy. Ettinger and Grady (1994) estimated and compared predicted benefits of starting therapy at menopause and continuing for the rest of a woman's life with those of starting therapy at menopause and stopping at the age of 65 and with those of starting therapy at age 65 years and continuing for the rest of her life (Figures 2 and 3). Compared with 'never' users, women who take oestrogen continuously beginning at menopause are predicted to have a mean BMD about 22% higher between ages 75 and 85 years and a reduced risk of fracture of about 73%. By contrast, women who begin therapy at menopause but stop at age 65 years are predicted to have a BMD only 8% higher and approximately 23% reduced risk of fracture compared with 'never' users. Those who start using oestrogen at age 65 years are predicted to have a higher BMD of 14-19% than 'never' users and a reduced fracture risk of 57-69%. Starting hormone therapy later in life is therefore predicted to provide almost as much protection against osteoporotic fractures as starting at menopause. Prevention of bone loss or increase in BMD is not always associated with a proportionate decrease in risk of fracture (Consensus Development Conference, 1991). Oestrogen, however, is the only agent shown on longterm follow-up to provide significant protection against wrist, vertebral (Ettinger et al, 1985; Maxin et a!, i995) and hip (Naessen et al, 1990; Kanis

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et al, 1992) fractures, the relative risk being 0.55 compared with those who have never used oestrogen replacement. Oestrogen also significantly reduces the fracture rate in post-menopausal women with vertebral fractures (Lufkin et al, 1992). 1

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Effects of progestogens on bone density The effects of progestogens on bone metabolism are not clear cut. Norethisterone given alone (5mg/day) prevents bone loss in postmenopausal osteoporosis by decreasing bone turnover and increasing bone mineral content (Horowitz et al, 1993). Norethindrolone prevents bone loss as effectively as oestradiol alone or in combination with norgestrel. An increase in trabecular bone has also been documented with MPA treatment. The most recent study, which compared the effects on spinal BMD of a continuous combined regimen (0.625 mg CEO + 5 mg MPA) with that of unopposed oestrogen in late post-menopausal women, showed a greater increment in BMD with the combined regimen (Grey et al, 1996). Treatment with progestogens alone has been proposed for post-menopausal women who are unsuitable for oestrogen therapy. Tibolone, an analogue of norethynodrel, reduces bone resorption and prevents cortical bone loss in experimental animals (Schot et al, 1992). Tibolone prevents bone loss in post-menopausal women (Rymer et al, 1993; Lyritis et al, 1995) and increases BMD in women with established osteoporosis (Pavlov et al, in press).

Mechanisms of oestrogen effect on bone Oestrogen reduces the rate of post-menopausal bone loss by reducing bone remodelling to pre-menopausal levels. It has been suggested that oestrogen replacement negatively regulates osteoclast formation and function (Lindsay, 1993b) but the exact mechanism modulating these effects is not known. Whether oestrogens mediate their effects directly or indirectly is also controversial. Oestrogen receptors have been identified both on osteoblasts (Komm et al, 1988) and on osteoclasts (Oursler et al, 1991). Oestrogen may prevent bone loss by limiting osteoclast life span through promotion of apoptosis, the effect being mediated by transforming growth factor ~ (Hughes et al, 1996).

Oestrogen replacement and Alzheimer's disease The higher prevalence of Alzheimer's dementia (AD) in post-menopausal women than in men suggests a role for oestrogen deficiency in the disease (Jorm et al, 1987; Bachman et al, 1992). Beneficial effects of oestrogen replacement on memory have been reported by some authors (Robinson et al, 1994) although not confirmed by others (Barrett-Connor and KritzSilverstein, 1993). The results of epidemiological studies have been controversial. Several studies provide evidence for a reduced incidence of Alzheimer's disease of more than 50% in post-menopausal women on oestrogen replacement (Henderson et al, 1994; Paganini-Hill and Henderson, 1994; Paganini-Hill, 1996). The most recent study (Tang et al, 1996) reported that oestrogen use in post-menopausal women delayed the onset and decreased the risk of AD (Figure 4). Thus the age at onset of Alzheimer's disease was significantly

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later in women who had taken oestrogen than in those who had not. The duration of oestrogen use and dose of oestrogen seem to be important factors in risk reduction because women with a history of long-term use and higher oestrogen doses had the lowest risk (Paganini-Hill and Henderson, 1994; Tang et al, 1996). The most consistent findings of the effects of oestrogens on AD come from clinical trials evaluating oestrogen replacement in the treatment of women with this illness. Although these trials are limited and have been performed on a small number of patients they show that oestrogen treatment can be effective in women with AD, particularly in those with mild and moderate dementia. Honjo et al (1989) documented that oestrogen therapy was associated with improvement in memory (immediate memory in particular), orientation and calculation. In addition to improving cognitive functioning, Ohkura et al (1994) also showed that dementia symptoms improved with oestrogen therapy. 1.0

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Mechanisms of action The mechanisms by which oestrogen may affect AD have not been clarified. Oestrogen receptors can be identified in the hippocampus, a brain structure known to be important for memory. Oestrogen may increase the synthesis of neurotransmitters, exert a direct effect on neural cells, increase cerebral blood flow, suppress apo E synthesis and decrease cerebral amyloid deposition (Honjo et al, 1995; Matsumoto, 1991; Ohkura et al, 1994; Paganini-Hill, 1996).

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Acetylcholine is considered the most important neurotransmitter involved in the modulation of memory, learning and cognitive function. Patients with AD show a marked decrease in the activity of choline acetyltransferase, an enzyme involved in the synthesis of acetylcholine in the cerebral cortex and hippocampus (Coyle et al, 1983). Oestrogen administration to ovariectomized rats increased activity of neural choline acetyltransferase in a dose-dependent manner, and changes in enzyme activity were blocked by an oestrogen antagonist (Luine, 1985; Kaufman et al, 1988). In post-menopausal women oestrogen is able to restore plasma acetylcholine transferase levels (Phillip and Shervin, 1992). Other neurotransmitters such as noradrenaline and serotonin may also be involved in AD and are affected by oestrogen (Cohen and Wise, 1992). Oestrogen is important for maintaining the integrity of neuronal morphology in hippocampal tissue. It acts as a neurotropic factor which stimulates dendrite growth and synapse formation (Matsumoto, 1991; Wong and Moss, 1992). Ovariectomy of adult female rats decreases dendritic density in the CA1 regions of the hippocampus, an effect that can be prevented by oestrogen treatment (Gould et al, 1990). Oestrogen also increases cell size in the ventromedial hypothalamus (McEwen, 1991) and may play a role in the reparative neuronal response to injury (Jones, 1988). Colon cancer and hormone replacement therapy There are now sufficient data to indicate that HRT is associated with a for ever use significant reduction (about 30% and 46% for recent use) in colon cancer incidence (Furner et al, 1989; Chute et al, 1991; Jacobs et al, 1994; Calle et al, 1995; Newcomb and Storer, 1995). Longer use was associated with lower risk (Calle et al, 1995; Newcomb and Storer, 1995). The reduced risk was observed among users of both oestrogen only and combined preparations (Newcomb and Storer, 1995). Although protection diminishes when treatment is stopped there are suggestions that a degree of risk reduction is maintained for about 10 years after cessation of use. Recent evidence that treatment with the anti-oestrogen tamoxifen is associated with increased risk of colorectal cancer provides plausibility for the beneficial effect of oestrogen in the prevention of large-bowel cancer (Rutqvist et al, 1995). The mechanism of action of HRT in lowering risk of colon cancer is not clear. Steroid receptors have been described in colon tumours (McMichael and Potter, 1983) and Issa et al (1994) found that all the colon tumours they examined had abnormal methylation patterns of the oestrogen receptor gene. The relation of this finding, however, to the role of oestrogen in the pathogenesis of colon cancer remains to be elucidated. In vitro studies showed that oestrogens inhibit growth of human colon cancer cells (Lontier et al, 1992). Finally, both progestogens and oestrogens reduce production of secondary bile acids (McMichael and Potter, 1980), thought to be important promoters of colon carcinogenesis (Reddy et al, 1977).

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Breast cancer risk and hormone replacement therapy One of the most controversial aspects of HRT is its putative association with an increased risk of breast cancer (BC). Biological evidence suggests that endogenous oestrogens affect breast cancer risk and animal studies show that exogenous oestrogens can induce breast cancer (Pike et al, 1993). In the USA the incidence of breast cancer has increased more than 30% since the early 1980s, coincident with the increasing use of HRT (Blot et al, 1987). The results of epidemiological studies of the effect of oestrogens on BC risk are, however, conflicting and most of the evidence is based on metaanalyses and not on controlled intervention studies. Some results suggest no increased BC risk with oestrogen use. Others suggest an increased risk in specific groups, such as women with a family history of BC in a firstdegree relative (Hulka et al, 1982; Wingo et al, 1987; Steinberg et al, 1991), women with benign breast disease (Brinton et al, 1986), women who were exposed to oestrogen for longer durations (Colditz et al, 1995) and higher doses (Dupont and Page, 1991; Tonilo et al, 1995) or women who had ever used oestrogen replacement. It has recently been shown that serum levels of oestrogen are positively associated with short-term risk of BC in postmenopausal women (Tonilo et al, 1995). Two of four meta-analyses (Armstrong, 1988; Dupont and Page, 1991) concluded that there was no overall increased risk; the other two (Steinberg et al, 1991; Sillero-Arenas et al, 1992) concluded that there is a small increase in risk, associated with long-term use. Colditz et al (1995) found a significant increase in BC risk after 5 years of use of oestrogens, the risk being mainly in current users. There was a substantial increase in the risk among women more than 60 years old. They also found that current use of hormones was more strongly associated with in situ disease, a finding consistent with the slightly higher frequency of screening mammography among post-menopausal women taking oestrogens (Colditz et al, 1995). These data are to be contrasted with those from Stanford et al (1995) who reported no increases in BC risk with oestrogen. The impact of combined oestrogen-progestogen therapy on the incidence of BC in post-menopausal women is uncertain. Epidemiological studies have generated the controversy, some of them suggesting a rather negative effect of progestogens (Bergkvist et al, 1989a; Palmer et al, 1991; Colditz et al, 1995) and others a protective effect (Stanford et al, 1995). Overall there seems to be no significant difference between oestrogens given alone or in combination with progestogens. In conclusion, use of oestrogens alone for less than 5 years appears to have no effect on risk of BC and use for 5-9 years may have a small effect, but oestrogen use for more than 10 years may be associated with a 30-80% increase in relative risk (WHO, 1996). Women taking oestrogen replacement have more contacts with their physicians, which results in their being examined and having mammography more often (Barrett-Connor, 1991). This could obviously result in

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earlier diagnosis leading to a spuriously high risk of BC but also to a better prognosis and consequently to a lower risk of fatal BC. This hypothesis might explain some of the controversies and paradoxes of epidemiological studies. Hunt et al (1990) showed for example that the incidence of BC was significantly increased but the relative risk of fatal BC was significantly reduced in oestrogen-treated women. Some data imply that oestrogens may influence the course of BC and that a possible adverse effect of oestrogens on BC risk is counterbalanced by a more favourable clinical outcome in oestrogen-associated tumours (Bergkvist et al, 1989b). The relative survival rate was significantly higher in patients who had received oestrogen treatment, corresponding to an approximately 20-50% reduction in excess mortality (Gambrell, 1984; Bergkvist et al, 1989b; Hunt et al, 1990). In other words, it seems that women who have been on oestrogen fare better than other women if they do acquire BC (Bergkvist et al, 1989b).

Mechanism of action In cell lines, oestrogen has been shown to interact in a complex way with a variety of growth factors which can promote malignant cell growth and accelerate development of metastases (Theriault, 1996). Oestrogen can also effect activation of oncogenes. Three mechanisms have been postulated to explain the induction of a proliferative response in breast epithelial cells by oestrogens: (a) direct stimulation by the interaction of oestrogen with its receptor; (b) an indirect mechanism through induction of synthesis of growth factors acting on the mammary epithelium via an autocrine-paracrine loop; (c) a negative feedback, by which oestrogen removes inhibitory factors from the serum (Russo and Russo, 1996). The effect of progestogens on breast tissue is unclear. Progesterone has been reported to stimulate, to reduce or to have no effect on proliferation of breast cells. Progesterone may act synergistically with oestradiol to enhance cellular proliferation rates in breast tissue of pre-menopausal women (Going et al, 1988). In contrast, when oestrogen stimulation of cell growth was detected, progestogen inhibited cell multiplication, favoured differentiation and abrogated oestrogen stimulation of the cell culture (Allegra and Kiefer, 1985).

Oestrogen replacement for women with previous breast cancer The safety of menopausal hormone use following the diagnosis of BC is an unresolved issue. In discussing the role of HRT in patients treated for BC, it is important to consider the effect of oestrogen and possibly progesterone on occult micrometastases (DiSaia, 1993). It is not currently recommended that oestrogen replacement therapy be used routinely in patients who have been treated successfully for BC. A recent comparative study (Eden et al, 1995), however, reported a reduced recurrence of BC in HRT users. Moreover, in animal models (in the

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rat DMBA system), there was greater reduction in the number of mammary cancers in animals given tibolone than in those given tamoxifen (Kloosterboer et al, 1994). Whether tibolone can be safely given to women with previous BC has yet to be shown.

Venous thromboembolism and hormone replacement therapy Haemostatic alterations induced by post-menopausal oestrogen therapy are smaller but similar in direction to those induced by oral contraceptives (Vandenbroucke and Helmerhorst, 1996). There are, however, two important differences: first, post-menopausal oestrogen is taken in significantly lower doses than contraceptive oestrogen and, second, the oestrogens used in replacement therapy are different from those used in oral contraceptives. It therefore came as a surprise when three studies (Daly et al, 1996; Grodstein et al, 1996; Jick et al, 1996) recently reported a two-fold to fourfold increase in the relative risk of venous thromboembolism (VTE) with oestrogen-only as well as with combined oestrogen-progestogen HRT compared with no therapy. In spite of the increased relative risk, the absolute risk of VTE is low and fortunately accounts for only a modest increase in morbidity. The results of these studies suggest a possible causal relation between current HRT use and both VTE (Daly et al, 1996; Jick et al, 1996) and pulmonary embolism (PE) (Grodstein et al, 1996). The risk of VTE and PE seems to be higher among short-term users, being highest in the first year of exposure to oestrogens, whereas no association was seen with past use. Although the magnitude of estimated risk was greater among users of higher-dose preparations than among users of lower-dose preparation, the difference was not statistically significant. The fact that the risk is higher near the start of therapy (as with oral contraceptives) is important and suggests susceptibility. Risk factors for VTE, such as a family history, severe obesity or an earlier episode of VTE or an illness causing immobilization, should be taken into account when evaluating individual benefits and risks.

Summary on risks and benefits From the endocrine point of view, menopause is considered a deficiency state and oestrogen therapy as restoring the pre-menopausal endocrine milieu. The primary indications for menopausal HRT are climacteric symptoms and the prevention of osteoporosis, CVD and Alzheimers' disease. Menopausal therapy is, however, neither an elixir of eternal youth nor a panacea for the problems of post-menopausal women. It is not without risks and is not tolerated by all women. It is also not required by all women although it is recommended for most. Post-menopausal therapy needs to be individualized. Decisions about who should be treated, with what preparation and for how long depend on many factors, such as the woman's age and her past medical and family

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history, the indication for treatment and the potential risks and side-effects in each individual case. For example, the risk of HRT in a woman who is at increased risk for BC may outweight its benefits, particularly if she has few risk factors for heart disease and osteoporosis. The initiation and duration of treatment are matters requiring careful judgement and monitoring. Because the potential risks of therapy seem dose related it is justifiable to use only the minimum dose required and for the shortest possible period for effective treatment and prophylaxis. Despite some of the potential advantages of transdermal oestrogens, there are no definitive data showing benefit of this type of therapy on cardiovascular outcomes. Thus far, all the studies that have shown a cardiovascular benefit (i.e. on events rather than than on surrogate markers) used CEO. Alternatives to oestrogen replacement therapy are the selective oestrogen receptor modulators (SERMs) such as droloxifene, raloxifene and levormeloxifene. These agents act as oestrogen agonists on bone, heart and serum lipids but express antagonistic properties at breast and uterus (Draper et al, 1995; Ke et al, 1995). The discovery of SERMs has important practical implications. In theory such therapy will provide protection for the cardiovascular system and bones without risk of BC and endometrial hyperplasia and thus presents an ideal therapy for post-menopausal women. We await clinical studies to prove such effects and long-term safety. REFERENCES Adams MR, Kaplan JR, Manuck CB et al (1990) Inhibition of coronary artery atherosclerosis by 17beta oestradiol in ovariectomized monkeys: lack of an effect of added progesterone. Arteriosclerosis 10: 1051-1057. Akkad A, Hartshome T, Bell PR & A1-Azzawi F (1996) Carotid plaque regression on oestrogen replacement: a pilot study. European Journal of Vascular and Endovascular Surgery 11: 347-348. Allegra JC & Kiefer SM (1985) Mechanisms of action of progestational agents. Seminars in Oncology 2: 3-5. Armstrong BK (1988) Oestrogen therapy after the menopause--boom or bane? Medical Journal of Australia 18: 213-214. Avis N, Kaufert PA, Lock M et al (1993) The evolution of menopausal symptoms. In Bailli~re's Clinical Endocrinology and Metabolism, vol. 7, pp. 17-32. London: Bailli6re Tindall. Bachman DL, Wolf PA, Linn R et al (1992) Prevalence of dementia and probable dementia of the Alzheimer's type in the Framingham study. Neurology 42: 115-119. Barrett-Connor EL (1991) Postmenopausal estrogen and prevention bias. Annals oflnternal Medicine 115: 455-456. *Barrett-Connor E & Laakso M (1990) Ischaemic heart disease risk in postmenopausal women. Effects of oestrogen use on glucose and insulin levels. Arteriosclerosis 10: 531-534. *Barrett-Connor E & Bush TL (1991) Estrogen and coronary disease. Journal of the American Medical Association 265:1861-1867. Barrett-Connor E & Kritz-Silverstein D (1993) Estrogen replacement therapy and cognitive function in older women. Journal of the American Medical Association 269: 2637-2641. Bergkvist L, Adami HO, Persson I et al (1989a) The risk of breast cancer after estrogen and estrogen-progestin replacement. New England Journal of Medicine 321: 293-297. Bergkvist L, Adami HO, Persson I et al (1989b) Prognosis after breast cancer diagnosis in women exposed to estrogen and estrogen-progestogen replacement therapy. American Journal of Epidemiology 130: 221-228.

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Blot WJ, Devessa SS & Fraumeni JF Jr (1987) Declining breast cancer mortality among young American women. Journal of the National Cancer Institute 78: 451--454. Bourne T, Hillard TC, Whitehead MI et al (1990) Oestrogens, arterial status and postmenopausal women. Lancet 335: 1470-1471. Brinton EA (1996) Oral oestrogen replacement therapy in postmenopausal women selectively raises levels and production rates of lipoprotein A-I and lowers hepatic lipase activity without lowering the fractional catabolic rate. Arteriosclerosis, Thrombosis and Vascular Biology 16: 431--440. Brinton EA, Hoover R & Fraumeni JF (1986) Menopausal oestrogens and breast cancer risk: an expanded case-control study. British Journal of Cancer 54: 825-832. *Burger HG (1994) Diagnostic role of follicle-stimulating hormone (FSH) measurements during the menopausal transition--an analysis of FSH, oestradiol and inhibin. European Journal of Endocrinology 130: 38-42. Bush TL, Barrett-Connor E, Cowan DK et al (1987) Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 75:1102-1109. Cagnaeci A, So!dani R, Carriero PL et al (1992) Effects of low doses of transdermal 17 beta oestradiol on carbohydrate metabolism in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 74: 1396-1400. Calle EE, Miracle-McMahill HL, Than MJ & Heath CW (1995) Estrogen replacement therapy and risk of fatal colon cancer in a prospective cohort of postmenopansal women. Journal of the National Cancer Institute 87: 517-523. Campos H, Sacks FM, Walsh BW et al (1993) Differential effects of oestrogen on low density lipoprotein subclasses in healthy postmenopansal women. Metabolism 42: 1153-1158. Chen S J, Li H, Dnrand J et al (1996) Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation 93: 577-584. Chute CG, Willett WC, Colditz GA et al (1991) A prospective study of reproductive history and exogenous estrogen on the risk of colorectal cancer in women. Epidemiology 2: 201-207. Cohen IR & Wise PM (1992) Effect of oestradiol on the diurnal rhythm of serotonin activity in microdissected brain areas of ovariectomized rats. Endocrinology 131: 2619-2625. *Colditz GA, Hankinson SE, Hunter DJ et al (1995) The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. New England Journal of Medicine 332: 15891593. Collins P, Rosano GM, Jiang C et al (1993) Cardiovascular protection by oestrogen--a calcium antagonistic effect? Lancet 341: 1264-1265. *Collins E Rosano GMC, Carrel PM et al (1995) 17Beta oestradiol attenuates acetylcholine-induced coronary arterial constriction in women but not men with coronary heart disease. Circulation 92: 24-30. Consensus Development Conference (1991) Prophylaxis and treatment of osteoporosis. Osteoporosis International 1:182-188. Coyle JT, Price DL & DeLong MR (1983) Alzheimer's disease: a disorder of cortical cholinergic innervation. Science 219:1184-1190. Crona N, Silfverstolpe G & Samsioe G (1983) A double-blind cross-over study on the effects of Org OD 14 compared to oestradiol valerate and placebo on lipid and carbohydrate metabolism in oophorectomized women. Acta Endocrinologica 102: 451-455. Crook D (1996) Postmenopausal hormone replacement therapy, lipoprotein metabolism and coronary heart disease. Journal of Cardiovascular Pharmacology 28 (supplement 5): $40-$45. Crook D & Stevenson JC (1996) Transdermal hormone replacement therapy, serum lipids and lipoproteins. British Journal of Clinical Practice 86 (review supplement): 17-21. Crook D, Godsland IF & Stevenson JC (1995) The cardiovascular risk profile of hormone replacement therapies containing dydrogesterone: a review. European Menopause Journal 2 (supplement 4): $25-$30. Crook D, Cust ME Gangar KF et al (1992) Comparison of transdermal and oral estrogen/progestin hormone replacement therapy: effects on serum lipids and lipoproteins. American Journal of Obstetrics and Gynecology 166: 950-955. Daly E, Vessey ME Hawkins MM et al (1996) Risk of venous thromboembolism in users of hormone replacement therapy. Lancet 348: 977-980. Draper MW, Flowers DE, Neild JA et al (1995) Antiestrogenic properties of raloxifene. Pharmacology 50: 209-217.

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