Journal of Clinical Pharmacy and Therapeutics (1991) 16,231-245 ADONIS 026947279100034D

REVIEW ARTICLE THE LONG-TERM RISKS AND BENEFITS OF HORMONE REPLACEMENT THERAPY T. C. Hillard, S. Whitcroft, M. C. Ellerington and M. I. Whitehead Menopause Clinic, Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Denlistry, London, U.K.

SUMMARY

There is increasing awareness that the long-term consequences of ovarian failure can be prevented or reduced with appropriate hormone replacement therapy (HRT). After the menopause, there is a rapid loss of trabecular bone resulting in a one in two lifetime risk of osteoporotic fracture. H R T prevents this bone loss and decreases the incidence of fracture. A minimum of 5 years treatment is recommended for significant benefit. Epidemiological evidence is accumulating that post-menopausal oestrogen therapy reduces the risk of cardiovascular disease and stroke by between 30 and 70",, even in the presence of established risk factors. Given the prevalence of cardiovascular disease, this is likely to be one of the principle benefits of H R T in the next decade. Concerns about the long-term safety of H R T have focused on endomctrial and breast cancer. T h e increase in risk of endometrial cancer associated with oestrogen only therapy is abolished with the sequential addition of a progestogen for 10-12 days each cycle. T h e possible effect of H R T on breast cancer risk has to be considered against the background of a one in 12 lifetime risk of developing this disease. T h e epidemiological studies investigating this relationship are reviewed in this paper. There is a broad consensus that 5-6 years duration o f H R T does not increase breast cancer risk. Longer durations of therapy (10-15 years) have been reported to increase this risk although not all the data are in agreement. Other factors, such as family history and benign breast diseasc, may also influence the risk of breast cancer. T h e potential benefits of H R T on mortality and morbidity are enormous. Against this is a possible small increase in breast cancer risk with long-term usage. Greater awareness of the long term consequences of the menopause and the potential benefits of H R T should be encouraged so that women can make informed decisions about their need for H R T .

Correspondence: D r M. I. Whitehead, Menopause Clinic, Academic Department of Obstetrics and Gynaecology, King's College School of Medicine and Dentistry, Denmark Hill, London SE5 SRX, U.K.

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INTRODUCTION Hormone replacement therapy (HRT) relieves hot flushes and other disabling menopausal symptoms, prevents post-menopausal bone loss and osteoporotic fractures, and reduces arterial disease risk. Thus, while H R T was prescribed for many years mainly for its symptomatic benefits it is now increasingly being advocated as a preventative therapy. With the changing demographics of Western populations, most women can now expect to spend over one-third of their lives in the post-menopausal state. Consequently, the prevention of the long-term sequelae of ovarian failure have taken on much greater significance. As with any prophylactic therapy the risks and benefits must be carefully weighed. LONG-TERM BENEFITS

Osteoporosis Osteoporosis can be defined as a reduction in bone density and strength such that there is an increased risk of fracture even after minimal trauma. Whilst osteoporosis has many causes, post-menopausal osteoporosis is by far the most common type. I t is estimated that by the age of 70 years, one in two women will have sustained at least one osteoporotic fracture (1). T h e classic osteoporotic fractures are those of the distal forearm (Colles), femoral neck and vertebral body (Fig. 1). T h e incidence of hip fracture has doubled over the last 30 years even allowing for demographic changes (2). In 1985, over 35,000 women in England and Wales sustained a femoral neck fracture (3), and the lifetime risk of this fracture in Caucasian women is approximately 1 5 O , . U p to 20", of women die as a direct result of their hip fracture and a further 509, never regain an independent existence (4). T h e precise prevalence of vertebral fractures is harder to establish, as backache in this age group is not always investigated radiologically but is treated symptomatically and the fracture eventually heals. Consequently, the exact costs to the Health Service of osteoporosis are impossible to determine but are likely to be in excess of E700 million per annum (3). Clearly post-menopausal osteoporosis now poses a major public health problem both in terms of patient morbidity and mortality, and financial costs. Once lost, x

40001

35-39

Women

Men

85-

/

85-

Age group (years)

Fig. 1. Incidence rates for the three common osteoporotic fractures (Colles, hip and vertebral) in men and women, as a function of age at time of fracture. [Reproduced from (54) with permission.]

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3 T

n = 36

< 30

48

30-40 Age ( y e a r s )

23

69

>40 4

Years post-rnenopouse

Fig. 2. Mean ( & SEM) bone density (g/cm2)L2-L4 with age. n =Numbers of patients. [Reproduced from (5) with permission.]

bone mass cannot be restored to any significant extent, so prevention is of paramount importance. There are two principal determinants of a woman's risk of osteoporosis; her peak bone mass and the subsequent rate of bone loss. T h e former is achieved by the end of the third decade, it is largely genetically determined and thus is not readily amenable to manipulation. Prior to the menopause, there is a gradual age-related decline in bone density in the femoral neck (Fig. 2), but not in the vertebral body (Fig. 3) (5). After the menopause there is a period of accelerated bone loss (Figs 2 and 3) during which up to 5",, of spinal trabecular bone may be lost annually (6). It is during this accelerated period of bone loss that preventative therapy needs to be introduced to achieve its maximum benefit; however, starting therapy some years after menopause may still be advantageous by preventing further loss of bone. Oestrogens are effective in preventing post-menopausal bone loss (7-1 1), and more importantly in reducing the subsequent fracture rate (12, 13). Oestrogens tend to be administered continuously without a treatment break and the currently recommended minimum doses necessary for bone conservation are shown in Table 1. Ideally, treatment should be commenced around the time of the menopause. It has been calculated that 5 years of such therapy immediately after the menopause will reduce the incidence of fracture of the neck of the femur by 50°, (14). Clearly, oestrogens have a beneficial effect in preventing osteoporosis but there are a number of important issues which remain unanswered.

T. C. Hillard et al.

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i

n.35

I

49

Age (years)

24

70

47

54

Years post menopause

Fig. 3. Mean (+_SEM)bone density (gkm') at the femoral neck with age. n=Numbers of patients. [Reproduced from ( 5 ) with permission.]

Table 1. Minimum bone conserving doses of different oestrogen preparations Bone conserving doses of oestrogens Oestradiol valerate Conjugated equine oestrogens Oestradiol TTS (patch) Oestradiol pellet (implant)

Dose 2 mg/day 0,625 mg/day

0.05 mg/day 50 mg

T h e initial studies demonstrating that oestrogens prevented post-menopausal bone loss were performed at peripheral skeletal sites such as the distal forearm and metacarpal. These measurements correspond poorly with those in the more clinically relevant sites, the spine and most importantly, the hip (15). With the introduction of newer scanning techniques such as dual photon absorptiometry (DPA) and dual energy X-ray absorptiometry (DEXA), oestrogens have been shown to conserve bone in the lumbar spine ( 1 0 , l l ) and, more recently, in the femoral neck (1 1) (Fig. 4). This appears to be the principal mechanism whereby oestrogens decrease the fracture rate at these sites. Initial studies were based on treatment with oral oestrogens but non-oral therapies, such as percutaneous creams and the transdermal 'patch' appear as effective as oral

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0)

c

D 0

Time (months)

Fig. 4. Bone density changes (median of initial value) in femoral neck. ( 0 )Untreated; (’’) transdermal HRT; (A)oral H R T . * * P < O . O l , ***P 7 years)

1.2

1.6

3.4 0.9 1.4 0.7 0.8 1.o

Nil

-

1.9

1.6

1,7(>5years) ?with use Nil ? > 20 years

-

-

Nil Nil Nil

Nil

1.0 1.36 1.1

Benign breast

1.1

Tpre-HRT Nil Post-HRT Nil

Nil ?with use ? > 9 years

F H = Family history.

Hip fracture

Lung cancer

Breast cancer

Cervical cancer

Ovarian cancer

Endo. cancer

IHD

CVA

Fig. 7. Leading causes of mortality in women over 50 years in England and Wales. [Adapted from (56).]

other workers have failed to demonstrate a duration dependent increase in risk, even with up to 20 years of treatment (41,45,47). T h e second issue is the type of oestrogen. Data from two studies (32,49) have been interpreted as suggesting that ethinyl oestradiol increases the risk of breast cancer. Thus, studies which include in their analysis patients exposed to ethinyl oestradiol are difficult to interpret unless the data for ethinyl oestradiol are presented separately. T h e third issue is the possible effect on ‘high risk’ groups, e.g. women known to be at an increase in lifetime risk of breast cancer (irrespective of use of H R T ) because of clinically relevant previous benign breast disease or a family history of breast cancer in a pre-menopausal, first degree relative. Brinton et al. (46) observed an increased incidence among women who had surgically confirmed ‘benign breast disease’ and subsequently took H R T long-term (greater than 10 years). However, this group is likely to

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Hormone replacement therapy Table 5. Mortality by causeof death (Adapted from 1321with permission) Observed (0)

Ca breast Ca endometrium Ca ovary Ischaemic heart disease CVA Suicide All causes

12 0 8 20 14 11 124

Expected

Ratio

(El

01s

21.9 2.6 7.3 42.04 2 1.64 4.34

0.55

212.5

-

1.12 0.48 0.65 2.53 0.58

have included women with histological abnormalities such as epitheliosis with atypia and certain forms of hyperplasia, which are known to increase breast-cancer risk. Thus, these results may simply reflect expression of the natural history of this condition. Conversely, Brinton also observed that women who developed benign breast disease after they had commenced H R T were not at an increase in risk of breast cancer, even if H R T was prescribed for more than 10 years. It is generally accepted that women with a family history of breast cancer in a pre-menopausal first degree relative are at an increased risk of breast cancer. However, there is no consensus that H R T increases this risk further. Two studies (42,47) did observe an increase in risk of breast cancer in such women but three others (44-46) did not. T h e fourth issue is the effect of progestogen on breast tissue. Although progestogen has anti-mitotic actions in the endometrium, it does not appear to have the same effect on breast tissue. Indeed it may have the opposite effect (50). Bergkvist et al. (49) observed a fourfold increase in risk of breast cancer with combined oestrogen/ progestogen regimens but the numbers in these groups were very small. T h e real effects of progestogen on breast tissue are still not known. A recent consensus conference stated that there was no compelling evidence that progestogens have a protective role on breast tissue and thus, they are not required for hysterectomized women (33). In summary, 5 years of H R T usage has not been associated with a significant increase in risk of breast cancer. Longer-term therapy ( > 10 years) may be associated with an increase in risk, although this remains controversial. Various sub-groups, such as those with certain types of benign breast disease and a relevant family history, may be at greater risk but the data on this conflict. RISK/BENEFIT ANALYSIS Various hypothetical analyses of the balance between risks and benefits have been performed (51-53). These show H R T to be beneficial both in terms of financial costs and overall mortality rates. However, because of the prevalence of cardiovascular disease (Fig. 7) even a small reduction in the incidence of myocardial infarction and stroke due to H R T will dominate any such calculations. T h e epidemiological study funded by the Medical Research Council reported that 5 years of H R T usage reduced overall mortality (all cause) by 42",, as compared to

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national rates (Table 5) (32). Patients in this analysis were on a wide range of H R T preparations and many were on combined oestrogen and progestogen regimens. Since these are the only published data on the long-term consequences of combined H R T they warrant closer inspection. Mortality from breast cancer was lower than expected. However, the incidence was higher than expected, which may reflect a drug effect or an increased detection rate due to closer surveillance in HRT-users. I t remains to be seen whether long-term follow-up will show an increased mortality. There were no fatal cases of endometrial cancer although there were higher than expected numbers of cases. Review of the H R T prescriptions for these women revealed that all had either been taking unopposed oestrogen or had taken progestogen in either an inadequate dosage or for an inadequate duration each month. T h e slight increase in mortality from ovarian cancer was explained by the initial inclusion of two cases, which on independent histological review proved to be secondary deposits from primary cancer in the colon. T h e observed 509; decrease in ischaemic heart disease risk is particularly important, and suggests that the addition of progestogen each cycle will not reduce the cardiovascular benefits of oestrogens. Similar benefits were noted for stroke and other circulatory diseases. T h e observed increased mortality from suicide may be due to selection bias because seven of these 11 patients had a previous psychiatric history.

CONCLUSION Information about the consequences of untreated menopause, particularly osteoporosis and arterial disease risk, should be fully available to women. T h e potential long-term benefits of H R T are considerable. It substantially reduces morbidity and mortality principally due to its effect on osteoporosis and especially cardiovascular disease. Provided it is prescribed correctly, with a sequential progestogen for 12 days each cycle, it does not increase the risk of endometrial carcinoma long-term. There is concern that long-term usage ( > 10 years) may lead to an increase in risk of breast cancer but the data on this remain conflicting. Whether a woman takes H R T or not must be her decision. We believe that many women are not given the opportunity of making an informed choice because they are not provided with the appropriate information. REFERENCES

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