DRUG THERAPY

Drugs & Aging 2 (3): 174-195, 1992 I I 70-229X/92/0005-01 74/$ I 1.00/0 © Adis International Limited. All rights reserved. ORA187

Sex Steroids and Cancer in Older Women T.R. Varma Department of Obstetrics and Gynaecology, St George's Hospital Medical School, London, England

Contents IN 175 176 177 177

177 179 179

18) 186 186

187

190 191

191 192

Summary

Summary 1. Pathophysiology of Menopause 1.1 Short Term Menopausal Symptoms 1.2 Long Term Menopausal Events 1.2.1 Osteoporosis 1.2.2 Cardiovascular Disease 2. HRT and Cancer Risk 2.1 Endometrial Hyperplasia 2.2 Endometrial Carcinoma 2.3 Breast Cancer 2.3.1 Endogenous Hormones and Receptors 2.3.2 Epidemiological Studies of Breast Cancer 2.3.3 Does Progestogen Use Protect Against Breast Cancer? 2.4 Ovarian Cancer 2.5 Cervical Cancer 3. Conclusions

Menopause and hormone replacement therapy (HRT) continue to be controversial subjects. The main concern is the potential risk of prolonged HRT and the possible development of endometrial and breast carcinoma. There is no obvious evidence at present to suggest that HRT increases endometrial carcinoma provided the patient receives progestogen for a period of 10 or more days (usual period is 12 days) during each month. However the breast does not seem to enjoy this safety margin and there is some concern about possible increase in the incidence of breast cancer if the treatment period is longer than 5 years. The increase in the risk is higher after 15 years of estrogen use. There is no obvious adverse effect on the ovary or on the cervix following HRT.

Sex Steroids and Cancer

Menopause and estrogen replacement therapy continue to be controversial subjects. Although it was fashionable in the 1960s to prescribe estrogens for continued youthfulness, in the 1970s the complications of hormone replacement therapy became apparent; physicians became more reluctant to treat the climacteric and patients became wary of hormone therapy. A woman's life-span has steadily increased so that today more than one-third of her years are postmenopausal. As her life-span increases so do the problems of the climacteric. Before the advent of modern endocrinology, vexations of this phase of a woman's life were often considered to be psychoneurotic. The declining ovarian function with age - rapid for some, slower for others - provokes a variety of disturbances in some women. Some physicians believe that menopause is a physiological event, and therefore any attempt to correct estrogen deficiency would be a meddlesome intrusion into the natural aging process. Others contend that only vasomotor manifestations and atrophic vaginitis are directly due to the estrogen deficiency, and that these manifestations may be treated with oral estrogens given in a cyclic fashion, in the smallest dose and for the shortest period. Still others associate the metabolic changes that occur subsequent to the relative lack of gonadal steroids with the development of osteoporosis, psychogenic manifestations and possibly even atheroscelerosis. However, not all post-menopausal women require estrogen therapy since some women produce sufficient endogenous estrogens to remain ilsymptomatic and prevent such changes. The purpose of this review is to present the current knowledge from the increasing information available about sex steroid hormones and both genital and breast cancer.

175

macteric age or older (~ 45 years). More specifically, over one-fifth (6.4 million women) will fall within the climacteric range (45 to 59 years). In 1991, the number of women in the UK over 45 years old was around 11.4 million, or 39% of the female population. According to government population statistics, this number is set to rise to 13.9 million (or 46% of the female population) by 2015 (fig. 1). At the time of menopause, ovarian function declines and thus gonadotrophin production by the pituitary correspondingly increases in an attempt to stimulate follicular estrogen synthesis. Postmenopausally, serum follicle-stimulating hormone (FSH) and luteinising hormone (LH) levels are markedly elevated in the range of 50 to 200 mUI ml and 40 to 100 mUlml, respectively. Within a year of menopause, serum FSH may increase as much as 20-fold, while the corresponding rise in LH is approximately 5-fold. After a further rise in both FSH and LH levels during the early postmenopausal years, there is a gradual decline with age. 30 years after the onset of menopause serum gonadotrophin levels are only 40 and 50% of the maximum reached; however, these levels are still much higher than those found during the reproductive years. Post-menopausal women produce little, if any, progesterone and this deficiency may lead to improper shedding of the endometrium so that the unopposed exposure to estrogens may cause

45 c

Q

rn "3

40

0

35

Q. Q.

'0 OJ

Ol

30

C OJ l:

25

C\l

1. Pathophysiology of the Menopause

OJ 0..

The average age at which menopause occurs is approximately 50 years with the majority of women experiencing 'the change' between the ages of 48 and 52 years. By the year 2015, approximately 46% of the female population in the UK will be of cli-

.----~-------------------

20

% of total population

- ~--====~--~-~-~~1987 1990 1995 2000 2005 2010 2015 Year

Fig. 1. Percentage of women over 45 years in the UK popu-

lation.

Drugs & Aging 2 (3) 1992

176

................... ,,

20 18 16

I I I I

~ 14 ::::r 12 c;

2> :z:

CIJ

u..

I

10 8 6 4 / 2 e-___ _._--

,

, ,, I

I

--

----

..

100 90 80 70 60 50 40 30 20 10

mately half that of premenopausal women, the percentage of conversion of androstenedione to estrone is increased by aging as well as by obesity, liver disease and several other conditions . 1.1 Short Term Menopausal Symptoms

~

::::r c;

.s 0

~

ti

w

42 44 46 48 50 52 54 56 58 60 Age (years) Fig. 2. Median serum levels of FSH and oestradiol in relation to age in normal perimenopausa1 women.

hyperplasia and possibly even neoplasia (Gambrell & Greenblatt 1979). Because of the failure of the follicles to develop significantly in response to FSH, plasma estradiol levels in postmenopausal women rarely exceed 25 ng/L (fig. 2) whereas peak plasma estradiol levels in premenopausal women are generally in the range of 300 to 500 ng/L. Ovarian estradiol production declines gradually rather than abruptly with some fluctuating levels over some years. Consequently, climacteric symptoms may begin sometime before the menopause occurs. During the childbearing years ovarian estradiol secretion represents the major source of estrogen production. In addition, estrone is produced from aromatisation of androstenedione in the adrenal glands and ovaries. When ovarian estradiol production diminishes at menopause, peripheral conversion of adrenal androstenedione to estrone becomes the principle source of estrogen (Hemsell et al. 1974). Two factors may thus increase estrogen production in postmenopausal women: increased production of androstenedione and increased peripheral conversion of this precursor to estrone. Although the amount of androstenedione produced by normal postmenopausal women is approxi-

The short term consequences of ovarian decline cause symptoms, whereas the long term sequelae may proceed for many years before they become clinically apparent. Approximately 80% of women will experience some estrogen deficiency symptoms during the climacteric. There is little correlation between the plasma estrogen levels and the incidence or severity of symptoms. A wide variety of symptoms and physical changes have been associated with the climacteric status (table I). Vasomotor instability, manifested by hot flushes or night sweats, usually has an insidious onset and increases as serum estrogens decline. Atrophy of the genital epithelium may result in senile vaginitis with associated symptoms, such as irritation burning and dyspareunia. Vulval epithelium and the epithelium lining the lower urinary tract may also undergo atrophic changes and produce urological symptoms. Psychosomatic and psychosexual symptoms may also make life difficult. Increased nervousness, Table I. Short term sequelae of menopause Vasomotor

Hot flushes Sweats Palpitation Headache

Psychological

Irritability Lethargy Emotional lability Forgetfullness Loss of libido Poor concentration

Urogenital

Vaginal dryness Dyspareunia Distal urethral syndrome

Skin and appendages

Dryness Dry hair Brittle nails

177

Sex Steroids and Cancer

depression, anxiety, insomnia, headache, loss oflibido and palpitation are some of the distressing symptoms. While these early symptoms may be extremely distressing, they do not cause significant disease or death. However, the same cannot be said about the long term sequelae of osteoporosis and cardiovascular disease. 1.2 Long Term Menopausal Events

1.2.1 Osteoporosis The importance of estrogen deficiency in the aetiology of osteoporosis in women has been established. Osteoporosis may be defined as a decreased amount of bony tissue per unit volume of bone which leads to a structural weakness in bone, and may predispose to fracture, particularly of the wrist, femoral neck and vertebrae. Approximately 50% of women will experience an osteoporotic fracture during their lifetime. While fractures of the wrist or hip cause obvious pain, crush fractures of the vertebrae may be asymptomatic. Patients with a low peak bone mass at the time of the menopause and the fast 'bone-losers' after menopause are more likely to become osteoporotic, although loss of trabecular bone can occur at 5% per year in the years immediately following the menopause and, therefore, even patients with a normal bone density initially may eventually be at risk. About 35 000 hip fractures occur in England and Wales each year, and the cost of osteoporotic fractures is in excess of £500 million annually. This therefore represents a huge medical problem which will become worse as the aging population increases. Fracture of the femoral neck is associated with a 15 to 20% mortality because of the associated problems of immobility, such as chest infections and embolism; 50% of the survivors will never return to an independent existence because of decreased mobility and inability to cope alone (Wallace 1983). Of all hip fractures, 80% are associated with osteoporosis (Gordon 1978). Hip fractures are 10 times more frequent in women than in men. Several studies have shown

Table II. Risk factors for the development of osteoporosis • • • • • • • • •

Female sex Loss of ovarian function Race - European or Asian Nulliparity Low bodyweight Poor diet in childhood Alcohol abuse Smoking Family history of osteoporosis

Secondary causes of bone loss • Steroids • Thyrotoxicosis • Hyperparathyroidism

that estrogen therapy prevents osteoporosis, decreases vertebral and other fractures, and prevents further loss of height. Most studies indicate that estrogen therapy inhibits the resorption of calcium from bone, and at least 3 have shown that the addition of a progestogen to estrogen therapy may actually increase bone mass by promoting bone formation (Christiansen et al. 1980, 1981; Nachtigal! et al. 1979a). The diagnosis of early osteoporosis is now possible with the development of accurate methods of measuring bone density, such as dual-photon absorptiometry or computerised axial tomography (CAT) scanning of the spine, but as yet these are not generally available. Predicting which patients are likely to develop osteoporosis from risk factors is still generally inaccurate (table II). Until adequate screening tests are available to all women at the time of the menopause, many preventable cases of osteoporosis and subsequent fractures will occur.

1.2.2 Cardiovascular Disease The most important long term consequence of estrogen deficiency is an increased risk of cardiovascular disease, including myocardial infarction, angina and stroke. As long ago as the 1950s, studies showed the association between premature menopause and ischaemic heart disease. Population studies show that below the age of 50 the risk of ischaemic heart disease is much greater in men,

178

Drugs & Aging 2 (3) 1992

Table III. Age-adjusted acute myocardial infarction (MI) mortality rates (per 1 000) and number of deaths (n) by other cardiovascular risk factors, and use of estrogen replacement therapy (adapted from Henderson et al. 1986)

Risk factor

Estrogen replacement therapy no

(n)

yes

(n)

3.8 10.7

(38) (18)

2.0 5.2

(19)* (9)

Previous hypertension no yes

3.6 6.4

(24) (32)

2.0 3.0

(14)* (14)*

Smoking no yes a

4.9 4.7

(39) (17)

2.0 4.1

(13)' (15)

Previous MI/Angina no yes

a Includes previous smokers. Abbreviation and symbol: MI = myocardial infarction; ,

= p < 0.05.

but by the age of 70 the incidence is approximately equal in the sexes. The reduction in estradiol levels at the time of menopause changes the lipid and the lipoprotein levels; there appears to be an increase in total cholesterol and low density lipoprotein (LOL)-cholesterol, with a decline in high density lipoprotein (HOL). These changes are associated with an increased cardiovascular risk in men and the same may be true for women. Whittman et al. (1989) studied 294 premenopausal and 319 postmenopausal women aged 45 and 55 years, and their findings suggested a greatly increased rate of atherosclerosis after ovarian involution. Lobo (1990) reported that estrogen appeared to protect against the development of cardiovascular disease by a number of mechanisms. Estrogen decreases LOL-cholesterol and increases HOL-cholesterol levels possibly through induction of LOL receptors and inhibition of hepatic lipase, which degrades HOL cholesterol. However, estrogen also appears to have a direct beneficial effect on vesselwall physiology which may be mediated through increased production of prostacyclin. While lipid changes may account for some of the increased risk, other factors, such as changes in glucose tolerance and direct effects of estrogen on arterial and venous blood flow, are likely to be important.

Myocardial infarction rarely occurs in women prior to menopause. Consequently, it has been suggested that estrogens might provide a protective effect against atherosclerosis and cardiovascular disease (Henderson et al. 1986; Whitehead & Lobo 1988). Younger women who have had a bilateral oophorectomy have a higher incidence of myocardial infarction unless estrogen replacement therapy (ERT) is begun soon after castration (Johansson et al. 1975; Rosenburg et al. 1976). Burch et al. (1976) observed a 63% decrease in expected deaths from heart disease in 1000 estrogen-treated women followed for 15 years. Similarly, significantly lower incidence of cardiovascular disease has been reported in estrogen-treated women as compared with those never using estrogens (Hammond et al. 1979a; Henderson et al. 1986) [table III]. Oespite the benefits and substantial protection against the risk of cardiovascular disease with ER T alone, Beaglehole (1988) expressed concern regarding the effect on the cardiovascular system of estrogen and progestogen combinations in hormone replacement therapy (HRT). The consensus of opinion suggests that ERT is beneficial to postmenopausal women and there is a 50% reduction in risk of getting coronary artery disease. Prescribed sensibly, ERT is safe and has few associated risks of side effects. The major concerns with

179

Sex Steroids and Cancer

ERT relate to the possible link between estrogens and various cancers.

2. HRT and Cancer Risk The natural incidence of hormone-dependent cancer with age is illustrated in figure 3. The role of hormones, particularly estrogens, in the pathogenesis of genital and mammary malignancy has been considered almost from the time estrogen was isolated by Allen Doisy in 1923. eust et al. (1989) summarised the risk of hormone-dependent cancer and HRT (table IV). Some of the early reports were based on a higher incidence of endometrial cancer in postmenopausal women with estrogen-secreting ovarian tumours. Other studies associated endometrial cancer with polycystic ovary syndrome in young women. Interest was renewed in the mid1970s when several retrospective studies implicated estrogen therapy in an increased risk of endometrial adenocarcinoma in postmenopausal women. That estrogens may also be aetiologically involved in carcinoma of the breast has been debated for many years. However, recent reports have failed to incriminate ER T as a cause of breast cancer in. postmenopausal women. When HRT first became established in the 1960s and 1970s, estrogens were prescribed cyclically for 3 weeks out of 4 (unopposed therapy). In the mid1970s it became apparent that such treatment increased the incidence of irregular vaginal bleeding, endometrial hyperplasia and carcinoma (Ziel & Finkle 1975). The cancer risk increased from 1 (untreated) to 4 (estrogen-treated) per I 000 women per year (Peterson et al. 1986). While the survival of those who developed cancer during ERTwas extremely good (99% at 5 years), the increase in risk was cumulative with each year of use. Thus, 60 out of 1000 estrogen-exposed women would develop this malignancy after 5 years of treatment an~ 220 after 10 years. Although unopposed estrogen therapy increases the risk of endometrial cancer, the magnitude has been exaggerated by the methodology used in retrospective studies (Mack et al. 1976; Shapiro et al. 1985; Smith et al. 1975; Ziel & Finkle 1975).

The worry about ERT led to a marked decrease in the prescribing of estrogens until it became established that the addition of a progestogen in each cycle (opposed therapy) would negate this risk. A prospective Swedish study by Persson et al. (1989) reported a relative risk of 1.4 in women who took unopposed ERT compared with a risk of 0.9 in a woman taking opposed therapy. They suggested that an adequate dose of progestogen for 12 to 14 days each cycle is protective. Medroxyprogesterone acetate 5mg for 12 days in each month, norethisterone acetate 5mg or dydrogesterone IOmg are the pro-

400

350



Breast Endometrium D. Cervix ... Ovary

o

300

Menopause

250

200

150

100

50

20

30

40

50

60

70

80

90

Age (years)

Fig. 3. Natural incidence of breast, endometrial, cervical and ovarian cancer in women by age.

180

Drugs & Aging 2 (3) 1992

gestogens commonly used. Progestogen added 10 to 13 days per month to HRT reduces the risk of endometrial adenocarcinoma to less than that of untreated women (Gambrell 1986a, 1987a; Gambrell et al. 1980; Hammond et al. 1979b; Sturdee et al. 1978; Sullivan et al. 1988; Whitehead & Fraser 1987). Although ~yclic progestogens have beenadvocated for over 40 years to shed the endometrium in estrogen-treated women, this practice is just beginning to be adopted by physicians. There is increasing evidence that progesterone deficiency may be 1 of many risk factors for breast carcinoma and that combination estrogen-progestogen replacement therapy may also decrease the risk of breast cancer. For women who do not need estrogen replacement, use of the progestogen challenge test to screen asymptomatic postmenopausal women can reduce adenocarcinoma of the endometrium (Gambrell 1986a). Gambrell introduced this test to identify those who are at risk of possible endometrial hyperplasia or carcinoma, and suggested cyclical progesterone therapy until such time as the endometrium no longer responded to progesterone therapy. He advocated oral medroxyprogesterone acetate 5mg for 12 days in each month. 2.1 Endometrial Hyperplasia When subjected to prolonged stimulation by either endogenous or exogenous estrogens in the absence of progesterone or progestogens, the endometrium of some pre- and postmenopausal

Table IV. Hormone replacement therapy (HRT) and cancer risk (adapted from Cust et al. 1989) Carcinoma

Risk from HRT

Endometrial Breast

No increase in risk with opposed therapy No increased risk with short term (~ 5 years) use; possible small increase with long term (~ 10 to 20 years) use No increase in risk No increase in risk

Ovary Cervix

women can become hyperplastic (Siiteri et al. 1973; Whitehead et al. 1979). It is unclear why some, but not all, women exhibit this response. Possible mechanisms include: disordered estrogen metabolism; reduced plasma level of sex hormone binding globulin (ShBG) whereby more of the circulating steroid becomes free to transfer into responsive cells (Davidson et al. 1981); and increased sensitivity of the endometrium to estrogenic stimulation (King et al. 1979). Hyperplasia may be considered as an abnormal increase in the amount of proliferative endometrium which exhibits varying degrees of architectural and cytological atypia. The histological distinction between cystic and adenomatous hyperplasia is of more than academic interest because of differences in their premalignant potential. With cystic hyperplasia the subsequent conversion to adenocarcinoma is low at approximately 1% (McBride 1959); with adenomatous hyperplasia however, the rate is higher and increases with time. Thus, 12% of adenomatous hyperplasia will become malignant after 18 months, and 30% within 10 years (Gusberg 1976). Shanklin (1978) suggested that the development of adenomatous hyperplasia should be considered to be the 'point of no return' in the progression from normal proliferative endometrium, through hyperplasia, to malignant endometrium, since in this study every patient with adenomatous hyperplasia eventually developed endometrial carcinoma. Some investigators believe that the process is ongoing and may take many years. The outcome of untreated endometrial hyperplasia was well demonstrated by Wentz (1974), who followed 115 patients with either adenomatous hyperplasia or adenocarcinoma in situ without any therapy. A significant number of women developed frank invasive carcinoma of the endometrium within 2 to 8 years, including 26.7% of those with adenomatous hyperplasia, 81.8% with atypical hyperplasia and 100% with adenocarcinoma in situ. Gambrell (1987a) reported that any degree of endometrial hyperplasia might be a significant lesion in postmenopausal women. The majority of the European data on HRT and

Sex Steroids and Cancer

endometrial hyperplasia have been generated from prospective studies. Whitehead et al. (1979) and Studd et al. (1980) performed biopsies on postmenopausal women at defined intervals during unopposed estrogen therapy; both groups reported that the development of hyperplasia was 18% with conjugated equine estrogens 0.625mg daily or equivalent, and 32% with conjugated estrogens 1.25mg daily or equivalent, after a mean of approximately 16 months. Importantly, up to one-third of the hyperplasia was of the more sinister adenomatous variety. Both groups also reported that the underlying endometrial status was not reflected by the pattern of vaginal bleeding. Regular withdrawal bleeding and no vaginal bleeding were both associated with endometrial hyperplasia and, therefbre, these patterns of bleeding did not signify as is often assumed that endometrial pathology was absent. Schiff et al. (1982) also reported on the unreliability of the bleeding pattern as an indicator of the underlying endometrial status. There is thus ample evidence that unopposed postmenopausal estrogen use causes a high incidence of abnormal bleeding, an unacceptable incidence of endometrial hyperplasia and increases the risk of endometrial cancer; the risk of cancer may be increased for as long as 10 years after therapy has been discontinued. Unopposed estrogens have a role in the development of endometrial hyperplasia, primarily because of incomplete shedding of the endometrium. Concomitant progesterone or progestogen therapy ensures more complete sloughing of the endometrium which prevents the continued proliferation that may result in hyperplasia and ultimately neoplasia. Progestogens also decrease estrogen receptors in endometrial cells, and induce l7-{3-estradiol dehydrogenase and isocitrate activity, the mechanism by which these cells normally metabolise estrogens. During the 5 years of the prospective study by Gambrell (1987a), 325 patients with postmenopausal bleeding were found to have varying degrees of endometrial hyperplasia. They were treated with progestogens for 7 to 10 days each month for 3 to 6 months and curettage was repeated after therapy.

181

Hyperplasia reverted to normal endometrium in 307 patients (94.5%). Of the 18 patients with persistent hyperplasia, 14 had been given a progestogen for only 7 days each month and 4 had been treated for 10 days each month. When progestogen was used for 13 days each month, all hyperplastic tissue reverted to normal endometrium. Based upon available epidemiological (Antunes et al. 1979; Jick et al. 1979; Mack et al. 1976; Shapiro et al. 1980; Smith et al. 1975; Ziel & Finkle 1975), histological (Studd et al. 1980; Whitehead et al. 1979) and biochemical data (Whitehead et al. 1981 a, b), dosages of all estradiol and estrone-based formulations needed for the relief of climacteric symptoms and the conservation of bone mass are likely to provoke endometrial proliferation. Extending the duration of progestogen therapy to 10 days reduces the incidence of hyperplasia to 2% (Studd et al. 1980), and maximum protective effects are obtained after 12 to 13 days of progestogen exposure, the incidence of hyperplasia being zero (Studd et al. 1980; Whitehead et al. 1982). Progestogens can also cause undesirable side effects, and thus may adversely affect physical and psychological well-being and/or increase the risk of other potentially fatal diseases. It is important to emphasise that the incidence and severity of progestogenic side effects will be modified by the type of progestogen, the route of administration, and the frequency of use. Progestogens can be classified in a variety of ways. The classification based upon structure seems most sensible because the chemical configuration appears to influence biological activity and thereby the type of side effects. For example, the 19-nortestosterone derivatives, norethisterone and dlnorgestrel adversely affect plasma lipid levels and lipoprotein metabolism, but the halogenated progesterone derivatives, such as cyproterone acetate, do not. Routes of administration which permit good absorption so that the total administered progestogen dose is lowered without compromising endometrial effect are likely to reduce the incidence of side effects. Because most progestogenic side effects are doserelated, the minimum effective dose should be pre-

Drugs & Aging 2 (3) 1992

182

scribed. Whitehead (1986) stated that, following histological and biochemical studies on the endometrium, the minimum effective dose of norethisterone is 0.7mg, oral progesterone is 300mg, dydrogesterone is 10 to 20mg and medroxyprogesterone is lOmg; dl-norgestrel 75/lg is probably inadequate. The· duration of progestogen therapy should be for 12 days per month to prevent endometrial hyperplasia. At adequate doses, progestogen suppresses DNA synthesis and nuclear estradiol formation (Lane et al. 1983, 1986a,b; Whitehead et al. 1981a, 1982), and thereby prevents endometrial proliferation. By continuously administering the progestogen in combination with the estrogen, various workers have attempted to develop a therapy that induces amenorrhoea. Estradiol 2mg, estriol Img and norethisterone 1mg daily for up to 1 year induced an atrophic endometrium in > 96% of 265 patients (Staland 1981). However, irregular bleeding occurred in 40% of women during the first treatment month, in 10% during the fourth month, and 4% by the fifth month oftherapy. 30% of patients discontinued treatment by the end of 1 year for reasons other than carcinoma or bleeding, side effects such as breast tenderness, weight problems and feeling they did not need the treatment any longer. An identical regimen was studied by Mattsson et al. (1982) with very similar results. Whitehead (1986) stated that maintaining uniform plasma progestogen concentrations with twice-daily administration did not reduce the incidence of irregular bleeding episodes. So far an ideal regimen has not yet been developed for continuous estrogen-progestogen therapy. The current continuous regimens cause too much breakthrough bleeding to recommend widespread use. 2.2 Endometrial Carcinoma The majority of epidemiological studies of estrogens and endometrial cancer have been carried out in the United States, and were mainly of retrospective case-control design (i.e. patients with cancer were compared with control patients with regard to hormonal exposure and other factors). The

Table V. Relative risk of cancer in estrogen users (normal risk = 1) Reference

Endometrial cancer

Breast cancer

Gambrell (1983)

1.8

0.4

Hammond et al. (1979b)

9.3

1.1

Hoover et al. (1976) ~ Gray et al. (1977)

3.1

1.3

Jick et al. (1979, 1980)

20.0

1.1-3.4

Lauritzen & Meier (1984)

0.78

0.92

Mack et al. (1976) ( Ross et al. (1980)

8.0

0.7-2.5

Nachtigall et al. (1979b)

0J18

0/48

a

Estrogen + progestogen therapy; no endometrial or breast cancers in hormone users; 1 endometrial and 4 breast cancers in controls.

results were reported in terms of the relative risk (RR) or the odds ratio. The RR estimates for endometrial cancer in 10 selected studies published in the United States since 1975 (table V) varied considerably in association with estrogen treatment (Persson 1985). The variation in these risk estimates is probably due to methodological differences regarding histopathological criteria of cancer, selection of cases and controls, and assessment of estrogen exposure (Hulka 1980). Nevertheless, several features in the epidemiological data suggest that the relationship between estrogen exposure and endometrial cancer is a causal one (Cramer 1980): I. Significant association between estrogens and uterine cancer have been confirmed in several studies. 2. A relationship between increasing duration of exposure and increasing risk has been found. 3. A temporal correlation between the incidence rate of endometrial cancer and prescription of ERT has been demonstrated. 4. The association is biologically credible since the risk of endometrial cancer has been found to be increased in connection with other hyperestrogenic states, such as obesity, anovulation and liver disease.

Sex Steroids and Cancer

These studies reported well-differentiated early lesions that resulted in no increased mortality. Indeed, Chu et al. (1982) reported that women with endometrial cancer who had used unopposed estrogens had a significantly better survival than nonusers and it is now often stated that estrogenrelated cancers are associated with a low mortality. However, an epidemiological study on estrogens and adenocarcinoma of the endometrium suggested that the long term use of estrogens increases the risk for both localised and widespread endometrial cancer (stages III and IV combined, relative risk: 3.1) [Shapiro et al. 1985]. These data also suggested that women who have taken estrogens for ~ 1 year remain at increased risk for at least 10 years after they discontinue the treatment. It has been equally established that adding cyclic progestogen therapy to ERT will greatly decrease the risk of, and indeed may protect against, endometrial carcinoma (Gambrell et al. 1978, 1980; Hammond et al. 1979a,b; King et al. 1979; Nachtigall et al. 1979b; Studd et al. 1980; S(urdee et al. 1978; Thorn et al. 1979; Whitehead et al. 1981 a). A population-based case-control study of endometrial cancer was undertaken by Voigt et al. (1991) to evaluate the benefits of progestogen use. They stated that the risk of endometrial cancer among women (aged 40 to 64 years) who had used unopposed estrogen for > 3 years was over 5 times that of women who had not used hormones (RR = 5.7, 95% c.1. 2.5 to 12.8), whereas those who had also used progestogen for at least 6 months of that time (1985 to 1987) had an RR of only 1.6 (95% c.1. 0.6 to 3.9). The RR was 2.4 when progestogen was used for < 10 days a month as compared with 1.1 when progestogen was used for ~ 10 days. These results provide additional evidence that the use of progestogen for ~ 10 days per cycle can reduce the excess risk of endometrial cancer associated with long term postmenopausal ERT. It has been suggested that since the retrospective American epidemiological studies associated mainly conjugated equine estrogens (65% of which is estrone sulphate) with an increase in risk of endometrial hyperplasia and carcinoma, then this preparation must possess special carcinogenic

183

properties (Ziel & Finkle 1976) not present with other estrogen formulations containing estradiol and estriol. However, Whitehead et al. (1979) reported that at equivalent doses, estradiol valerate caused the same degree of endometrial stimulation as conjugated estrogens. Oral conjugated estrogens 0.625 and 1.25mg, estradiol valerate 2mg and piperazine estrone sulphate 1.5mg daily induced similar levels of nuclear estradiol and cytoplasmic progesterone receptor (Whitehead et al. 1981 b). Synthetic estrogens such as diethylstilbestrol (stilboestrol) are also linked to increased risk (Antunes et al. 1979). In postmenopausal women receiving estrone-based preparations, estradiol remains the predominant intranuclear estrogen within the endometrium (King et al. 1980; Whitehead et al. 1981a,b). Hence, estrogen formulations which selectively increase plasma estradiol values, such as estradiol implants, are likely to be associated with marked endometrial proliferation. Thus, the high incidence of hyperplasia (56%) reported with estradiol implants (Studd et al. 1980) is not surprising. Unlike the estrone- and estradiol-based preparations, low dose estriol (2mg daily) appears to have little proliferative effect upon the endometrium, but also does not appear to conserve bone mass and is no better than placebo in relieving acute symptoms. In terms of cancer risk, there are carcinogenic substances and 'promoter' substances. Carcinogenic substances convert a normal cell into a malignant cell, but without the presence of a promoter substance it will take a long time for the converted cell to develop into a tumour cell. The promoter substances thus accelerate carcinogenesis, although they themselves are not carcinogenic. There is no certain evidence that estrogens of a steroid nature have a carcinogenic effect; on the other hand, they can have an accelerating or 'promoter' effect on an already transformed cell (Astedt 1982). The study by Salmi (1979) indicated that the natural hormones estradiol and estriol have only slight promoter effects, whereas estrone, which is the estrogen mainly produced in the postmen-

184

opausal age, has been associated with a moderate promoter effect (Siiteri 1975). In several studies a causal relationship has been found betw~en the duration of treatment and the increase in risk, the risk being significantly increased after 2 to 4 years of estrogen use and thereafter rising with the duration of medication (Hulka 1980; Vessey & Bungay 1982). It is still unclear if the duration-dependent increase in risk of endometrial cancer is linear or exponential (Cramer & Knapp 1979). Shapiro et al. (1985) reported that women who had taken unopposed estrogens for at least 1 year remained at an increased risk for endo" metrial cancer for at least 10 years after discontinuing therapy. They suggested long term gynaecological surveillance. Hunt et al. (1987) reported that the incidence of endometrial cancer in 4544 women receiving HRT was significantly elevated to almost 3 times the expected rate (adjusted odds ratio = 2.84; there was evidence of a rising trend in the odds ratio with interval since first use, although this did not reach statistical significance). In a case-control study, Lawrence et al. (1989) demonstrated that despite a statistically significant increase in risk with longer use of estrogen (p < 0.05), estrogen exposure actually contributed little to the overall risk of advanced-stage endometrial cancer. Lawrence et al. stated that the advanced stage endometrial cancer was not necessarily associated with just estrogen exposure. Other factors including increased weight, lower parity, diabetes and socioeconomic factors, such as education and access to medical services, were found predominantly in the group of patients with advanced-stage endometrial cancer. Paganinni-Hill et al. (1989) reported 50 cancers of the endometrium among 5160 women aged 44 to 100 years, who had contributed 23 786 patient-years of follow-up. Women who had used ER T had a RR of endometrial cancer of 10 compared with women who had never used estrogens (p < 0.0001). RR increased significantly (p < 0.0001) with increasing duration of use; women who had used estrogens for ;.: 15 years had a RR of 20 [95% confidence interval (CI) 7.2 to 54] compared with nonusers, while current and recent users (i.e. those who had

Drugs & Aging 2 (3) 1992

used estrogen within 1 year of the initial survey) had the greatest risk (RR = 25, 95% CI 9.2 to 69). Women who had last used estrogen;': 15 years ago still had a significantly increased risk (RR = 5.8, 95% CI 2.0 to 17). Increasing dosage plus duration ofERT was also associated with an increasing RR of endometrial cancer. Women who reported exclusive use of conjugated equine estrogens < 0.625mg day had a RR of 1.2 (95% CI 0.5 to 2.7) compared with that of women who never used such estrogens. By contrast, women who exclusively received a dosage of > 1.25 mg/day had a RR of 3.8 (95% CI 1.7 to 8.5). Women who received 2 to 5 years of ERT were twice as likely, and those who reported > 6 years of ERT were more than 3 times as likely to have endometrial cancer as were women who had never used ERT. The finding of an increased risk persisting after> 6 years after cessation of ERT is consistent with some studies (Kelsey et al. 1982; Mack et al. 1976; Shapiro et al. 1980; Weiss et al. 1979), but contrary to others (Hu1ka et al. 1980). Persson et al. (1989) conducted a prospective cohort study involving 23 244 women aged> 35 years receiving noncontraceptive estrogens and followed for a mean of 5 to 7 years to give a total of 133373 patient years. 74 cases of carcinoma and 33 cases of premalignant lesions occurred. The RR of endometrial carcinoma was 1.8 (95% CI 1.1 to 3.2) after exposure to any estrogen compound without progestogen for> 6 years, 2.2 (CI 1.2 to 4.4) after> 3 years of exposure to conjugated estrogens without progestogens, and 2.7 (CI 1.4 to 5.1) after > 3 years of exposure to estradiol compounds without progestogen. Estradiol compounds and conjugated estrogens when taken for> 3 years without progestogen were associated with 2- to 3-fold increase in the risk of endometrial neoplasia, whereas other estrogens were not. When carcinoma and premalignant conditions or lesions were considered together the results were similar, but the RR was higher. Risk of carcinoma did not increase when progestogens were cyclically added to estrogens for the entire treatment period (RR 0.9, CI 0.4 to 2.0).

Sex Steroids and Cancer

Thus, use of progestogens either removes the increased risk or delays its onset. Cyclic administration of ERT is claimed to be safer than continuous therapy (McDonald et al. 1977), but some authors have been unable to confirm this finding (Antunes et al. 1979; Whittaker et al. 1980). In some studies, the risk has been found to correlate with estrogen dosage; Gray et al. (1977) stated that users of conjugated estrogens> Img had a 2-fold risk compared with those receiving < Img. As mentioned earlier, the use of progestogens for several days in each treatment cycle has been shown to decrease the occurrence of endometrial hyperplasia (Paterson et al. 1980). Some evidence has also indicated that progestogens protect against the development of endometrial cancer related to estrogen therapy (Hammond et al. 1979b; Persson et al. 1989). Gambrell (I 982a, b) reported that the incidence rate for endometrial cancer in an untreated population in Texas between 1975 and 1979 was 242.2/100000 women, 434.4/100000 women in estrogen users and 70.8/100000 women in patients receiving combined estrogen-progestogen therapy; the difference was highly significant (p < 0.001). The risk of developing endometrial cancer may also be influenced by specific personal features of the patient. Obesity, nulliparity, late menopause, diabetes and hypertension have been linked with an increased risk of developing endometrial cancer (MacMohan 1974; Rubin et al. 1990). There is an increase in the incidence of endometrial cancer in the presence of estrogen exposure and those associated risk factors (Davidson et al. 1981). An increased risk for development of endometrial cancer associated with estrogen use generates concern not only to physicians, but also to patients. These risk factors must be placed in proper perspective. For example, there is a 3- to 9-fold increased risk of endometrial cancer in postmenopausal women who are 11 to 23kg overweight (Gusberg 1976). In the case-control studies, the failure to provide the natural incidence of endometrial carcinoma greatly magnifies the extent of the problem. The probability of untreated postmenopausal women developing adenocarcinoma

185

of the endometrium is approximately 100/100000 women per year (Weiss et al. 1979) [fig. 3]. If the RR data are converted to incidence rates, the increased incidence of endometrial cancer from unopposed ERT would be approximately 500 to 800/ 100 000 women/year or even higher. For example, in the original study by Mack et al. (1976), the RR for ERT and endometrial cancer was 8.0 (table V). However, a later report by these investigators (Mack 1978) gave the incidence as 370/100000 women based on their original RR data, and 480/100000 women per year (RR = 7.6) in the study by Ziel and Finkle (1975), and 300/100000 women (RR = 4.9) in the study by McDonald et al. (1977). These incidence rates of between 300 and 480/100000 women per year are very similar to that derived in a prospective study where the incidence of endometrial cancer in unopposed estrogen users was 434.4/100000 women per year, the same as reported by the above workers (Gambrell 1988). Horwitz and Feinstein (1978) in their case-control studies of estrogens and endometrial adenocarcinoma used alternative analytical methods to eliminate the detection bias that arises from increased diagnostic attention received by women with uterine bleeding after estrogen use. Using conventional methods to choose cases and controls, they found the RR was 12.0. However, when cases and controls consisted of patients who had undergone either dilatation and curettage, or hysterectomy because of uterine bleeding, the RR was reduced to 1.7. This study clearly shows how detection bias may have been neglected in other retrospective studies, leading to the conclusion that the magnitude of the association between estrogens and endometrial cancer has been greatly overestimated. This has been at least partially confirmed in a study based on 8998 necropsies in which undetected endometrial cancer was observed 4 to 5 times more frequently than endometrial cancer is diagnosed during life (Horwitz et al. 1981). It is interesting to note that their RR of 1.7 is similar to the RR of 1.8 reported in the prospective study by Gambrell (1988). Furthermore, the number of cancers in the study cohort of the latter group has steadily declined despite continued estrogen-pro-

186

gestogen use (Gambrell 1982a,b). Similarly, Hammond et al. (1979b) reported no endometrial cancers in 72 estrogen-progestogen users, but detected 11 cancers in 207 patients treated with estrogen alone, and in a double-blind study no endometrial cancers were diagnosed in 84 patients using estrogen-progestogen therapy for 10 years but 2 endometrial cancers occurred in 84 placebo recipients (Nachtigall et al. 1979b). A prospective epidemiological study in Sweden involving 23 333 women also suggested that the addition of progestogens could provide protection against the development of endometrial neoplasia following estrogen treatment (Persson 1985). Studies from the UK have not revealed an increased risk of endometrial cancer in estrogen-progestogen-treated postmenopausal women because a combined regimen was always used (King et al. 1979; Studd et al. 1980; Thom et al. 1979; Whitehead 1978). There is no obvious evidence at present to suggest that properly opposed ERT increases the risk of endometrial cancer. However, the dosage and the duration of both estrogen and progestogen therapy need to be monitored carefully to avoid undesirable side effects. 2.3 Breast Cancer Breast cancer is the most frequent malignancy in females accounting for 26% of all cancers in women in the US (American Cancer Society 1986a,b). It is also the leading cause of cancer death, causing 18% of all female cancer deaths in the US until 1986. Worldwide, the mortality rate from carcinoma of the breast varies from a high incidence of 37.7/100 000 women/year in Great Britain to a low incidence of 0.2/100 000 in Honduras, with the US ranking in between with an incidence of 22.1/ 100 000. The incidence of breast cancer increases throughout a woman's lifetime (fig. 3). The American Cancer Society (1986a) estimated that 199 000 new cases of breast cancer were diagnosed in the US in 1985 and that 38400 women would die from breast cancer that year. This is 13 times the number of deaths each year from

Drugs & Aging 2 (3) 1992

endometrial cancer. Unfortunately, this mortality has not changed much during the past 45 years even though death from uterine cancer declined from 31.5/100000 women in 1930 to 8.4/100000 in 1979. The incidence rates of breast cancer have in contrast increased during the past 25 years, although this may be related to increased longevity.

2.3.1 Endogenous Hormones and Receptors Extensive investigations have been performed in an attempt to elucidate the role of endogenous estrogens as a possible cause of breast cancer, yet no clearcut pattern has been delineated. It is paradoxical that some patients with metastatic carcinoma of the breast respond to endocrine ablative surgery (i.e. oophorectomy) or antiestrogen therapy, whereas others may have a remission with estrogen therapy. There is some correlation between the presence of estrogen receptor (ER) activity in breast tumours and the subsequent response to endocrine therapy (Clark et al. 1983). An absence of ERs is indicative of a lack of response to ablative surgery or antiestrogen therapy, whereas the presence of ERs predicts a favourable response in at least 55% of patients. Progesterone receptor activity in breast cancers adds to the predictive accuracy. The presence of both estrogen and progesterone receptors in a mammary malignancy is associated with a 70% chance of favourable response to endocrine manipulation, and indicates a better prognosis and longer disease-free interval after therapy. Unopposed endogenous estrogen stimulation resulting from progesterone deficiency or corpus luteum dysfunction may provide a favourable state for induction of breast cancer in the susceptible individual (Korenman 1980). This theory is supported by data in infertile anovulatory women in whom the risk of subsequent breast cancer was increased 5.4 times compared with the risk in women with infertility due to other causes (Cowan et al. 1981). Chronic anovulation increases the risk of postmenopausal breast cancer by 3.5-fold (Coulan & Annegers 1983). The greatest increase in breast cancer is in women aged between their late 30s and 50s, corresponding to the age of declining ovarian estrogen

Sex Steroids and Cancer

production as menopause is approached. More important is that more women become anovulatory in the premenopausal years, resulting in an abrupt decrease in levels of the cyclic progesterone. If unopposed estrogens had a strong relationship to carcinoma of the breast, the incidence of this malignancy would peak in women aged in their 50s and 60s, and then decline thereafter, as does the incidence of endometrial carcinoma. The incidence of breast cancer differs from cervical, endometrial and ovarian cancer, which peak in the fifth, sixth and seventh decades, respectively, and then either decline or plateau (National Cancer Institute SEER 1980) [fig. 3]. The incidence of breast cancer continues to increase throughout the postmenopausal years when estrogen levels are lower, but not absent. Some studies have found a plateau in this progressive increase in breast cancer incidence between the ages of 45 and 55 years (Vorherr & Messer 1978); however, no such plateau was observed in either the Third National Cancer Survey (Gutler & Young 1975) or the National Cancer Institute SEER data (1980). Whatever the role of female sex steroids as cofactors or predisposing factor for breast cancer, progesterone deficiency seems to be more important than unopposed estrogens (Gambrell 1983; Gambrell et al. 1983; Korenman 1980). 2.3.2 Epidemiological Studies of Breast Cancer Numerous long term studies of large numbers of postmenopausal women have failed to incriminate ER T for any significantly increased risk of breast cancer (Bland et al. 1980; Burch et al. 1976; Casagrande et al. 1976; Hammond et al. 1979; Henderson et al. 1974; Hoover et al. 1976; Jick et al. 1980; Kaufman et al. 1984). There are at least 20 published studies on the epidemiology of breast cancer in estrogen-treated postmenopausal women. The original study by Hoover et al. (1976) suggested that there was a possible increase in the risk of breast cancer after long duration of use and emphasised the importance of dosage. A study by Ross et al. (1980) again stressed the importance of dosage and duration, but reported an increased risk in patients whose ovaries were present compared with

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those who had an oophorectomy. Brinton et al. (1981, 1986) also emphasised the risks of high dosage ofiong duration and observed that patients with oophorectomy may have a slightly higher risk. Jick et al. (1980) found that hysterectomy with or without oophorectomy seemed to reduce the risk for breast cancer in estrogen users when compared with hormone users undergoing a natural menopause. Steinberg et al. (1991), using a meta-analysis of the effect of ERT on the risk of breast cancer, calculated the proportional increase in risk of breast cancer for each year of estrogen use. They stated that the risk did not appear to increase until after at least 5 years of estrogen use. After 15 years of estrogen use, they found a 30% increase in the risk of breast cancer (RR = 1.3, 95% CI 1.2 to 1.6). The increase in risk was largely due to results of studies that included premenopausal women or women using estradiol (with or without progestogen), studies for which the estimated RR was 2.2 (CI 1.4 to 3.4) after 15 years. They also reported that among women with a family history of breast cancer, those who had ever used estrogen replacement had a significantly higher risk (RR = 3.4, CI 2.0 to 6.0) than those who had not used the therapy (RR = 1.5, CI 1.2 to 1.7). That estrogen replacement therapy may be causally related to breast cancer has been debated for many years, although recent reports have failed to demonstrate a link in postmenopausal women. Kaufman et al. (1984) stated that estrogen use did not increase the risk of breast cancer; the odds ratio for estrogen use> 18 months prior to the diagnosis of breast cancer was 0.8 when compared with women who never used estrogens. The results were similar when known risk factors for breast cancer were taken into account. In users with a family history of breast cancer, the RR was 0.2 (95% CI 0.6 to 0.6). If the age of the first-term pregnancy was before age 20, the RR for breast cancer in the estrogen users was 0.1 (95% CI 0.0 to 0.4). It was concluded that the estrogen use by postmenopausal women did not appear to increase the risk of breast cancer even when taken for many years or in the distant past. Of 10 studies that looked specifically at both

Drugs & Aging 2 (3) 1992

188

endometrial and breast cancer in estrogen users, five found a moderate association between unopposed ERT and carcinoma of the endometrium (table V). However, in the abovementioned 10 studies the association found between estrogens and breast cancer was considerably less convincing (tables V and VI). In a study from Germany, Lauritzen and Meier (1984) did not observe an increase in breast cancer in unopposed estrogen users. In studies by Gambrell (1983) and Bland et al. (1980), a lower RR of breast cancer was observed in four subgroups of estrogen users: prior oophorectomy, any estrogen use at all (RR = 0.8); prior oophorectomy with total milligram dose (TMD) < 1500mg (RR = 0.9); prior oophorectomy with TMD > 1500mg, (RR = 0.7); and intact ovaries with TMD < 1500mg (RR = 0.9). lick et al. (1980) reported that there was no association between current estrogen use and breast cancer in women with previous hysterectomy (RR = 1.1). The risk of breast cancer was similar in those women who had or had not undergone oophorectomy. In women with an intact uterus undergoing a natural menopause there was a positive association between current estrogen use and breast cancer (RR = 3.4). This association varied with age, with an RR of 10.2 in naturally perimenopausal women aged 45 to 54 years and an RR of 1.9 in those aged 55 to 64 years. It should be emphasised that this study found the highest risk of endo-

metrial cancer in estrogen users (RR = 20) [lick et al. 1979]. Note also that these case-control studies can never show a true cause and effect, but only a possible association. Although oophorectomy may lower the risk for breast cancer, it is difficult to understand why hysterectomy with conservation of the ovaries would also lower the risk. Both of the above studies can be criticised because they limited their study populations to women up to age 65 and 75 years, respectively (lick et al. 1980; Ross et al. 1980). Hammond et al. (1979b) reported 4 cases of breast cancer among 301 estrogen users for a period ranging between 5 to 25 years; an equal number was found in the 309 nonusers. Similarly, Hoover et al. (1976) studied patients who attended private practice in Kentucky and reported an insignificantly increased risk (RR = 1.3) of breast cancer in postmenopausal estrogen users. In their follow-up study of the above group plus additional patients, Bland et al. (1980) reported a decreased risk of breast cancer from ERT. These investigators followed 405 postmenopausal women (mean age 59.7 years) from 3 to > 28 years with serial mammography. The 206 estrogen users received therapy for a minimum of 18 months (mean = 6.5 years) and had fewer carcinomas of the breast than the nonusers. Two studies from Germany also observed a lower incidence of breast cancer in long term es-

Table VI. Relative risks of breast cancer associated with varying parameters of menopausal hormone use (adapted from Weiss et al. 1982)

Ever used No Yes

Cases

Controls

RR

95% CI

931 1029

1083 1175

1.00 1.03

(0.9-1.2)

486 249 159 70 49

640 259 141 74 43

0.89 1.09 1.28 1.24 1.47 6.31

(0.8-1.0) (0.9-1.3) (0.9-1.6) (0.9-1.8) (0.9-2.3) (p < 0.01)

Years of use 9 years of use. This is consistent with the finding in 2 other cohort studies (Hoover et al. 1976; Hunt et al. 1987) and 2 case-control studies (Hiatt et al. 1984; Hulka 1987). Exogenous hormone used as either oral contraceptives or HRT was evaluated in reference to subsequent breast cancer risk in a cohort study of 20 341 women in California who were followed for 6 years (Mills et al. 1989). During the follow-up period, 215 primary breast cancers were detected in the cohort. The mean age at diagnosis was 66 years, indicating a primarily postmenopausal case series. This study reported that the use of HR T in 1976 was associated with a 69% increase in breast cancer risk (RR = 1.69) which was statistically significant (CI 1.12 to 2.55). There was no evidence that prolonged use of HR T increased the breast cancer risk, although there was a slight increase in breast cancer risk in women who had used HR T at any time (RR = 1.39), in those with no history of maternal breast cancer (RR = 1.45) and in those with prior benign breast disease (RR = 2.80). Women who were older (> 44 years) at menopause experienced a higher risk of breast cancer than women who were younger.

2.3.3 Does Progestogen Use Protect Against Breast Cancer? Because progesterone does not induce the cyclical shedding of breast cells, it is probable that the protective mechanism of progestogens operates at the intracellular level through changes in receptors and enzymatic activity. The presence of both estrogen and progesterone receptors in breast cancer tissue is related to a longer disease-free interval and decreased mortality. It is more predictive of a favourable response to endocrine manipulation with either ablative surgery or antiestrogen therapy (Clark et al. 1983). There is increasing evidence that adding progestogen to ERT significantly decreases the risk for breast cancer (Gambrell 1983, 1986b, 1988; Gam-

Drugs & Aging 2 (3) 1992

brell et al. 1983; Lauritzen & Meier 1984; Nachtigall et al. 1979b). Nachtigall et al. (1979b) followed 84 estrogen-progestogen users for 10 years in a carefully controlled double-blind study and compared them with 84 placebo users. No carcinomas of the breast were diagnosed in the 84 estrogen-progestogen users, but 4 were detected in the 84 placebo users (p < 0.05). Gambrell (l986b, 1988) reported that the incidence of breast cancer was 66.8/100 000 women in estrogen-progestogen users, 142.3/100000 in unopposed estrogen users and 343.5/100000 in nonusers. The difference between the estrogen-progestogen users and the unopposed estrogen users was not significant, but the difference between the estrogen-progestogen users and the nonusers was (p < 0.01). When compared with the expected incidence in this age group according to the National Cancer Institute SEER data (1980), the RR was 0.3 for the estrogen-progestogen users (95% CI 0.1 to 0.8). The study by Lauritzen and Meier (1984) noted a lower incidence of breast cancer in the unopposed estrogen users (123/100 000) compared with the incidence in nonusers (154/100000); however the difference was not significant. The incidence of breast cancer in the estrogen-progestogen users (109/100000) was significantly lower (p < 0.05) when compared with either the incidence in estrogen users or nonusers. Although the numbers of women were smaller, the risk of breast cancer was highest among women who took estrogen and progestogens in combination for extended periods. The RR was 4.4 (95% CI 6.9 to 22.4) in women who used this combination for> 6 years. Among women who had previously used estrogens alone, the RR after ~ 3 years of use of the combination regimen was 2.3 (95% CI 0.7 to 7.8). These results added to the evidence of a slightly increased risk of breast cancer after long term perimenopausal exposure to estrogens, which is not prevented and may even be increased by the addition of progestogens. A review by Key and Pike (1988) on endogenous and exogenous hormonal factors in the causation of breast cancer has led to the hypothesis that combination therapy may in

Sex Steroids and Cancer

fact increase the risk substantially above that associated with estrogen alone. This observation raises concern about the long term treatment with a combination of estrogens and progestogens that has been proposed for widespread use as prophylaxis against osteoporosis in postmenopausal women. It also suggests different endocrine pathways in carcinogenesis in the breast and endometrium. Although progestogens may have antiestrogenic properties in the breast as well as the endometrium, high rates of division of the epithelial cells of the breast in the luteal phase compared with the follicular phase of the menstrual cycle may explain the possibly enhanced risk with combination HRT (Key & Pike 1988). 2.4 Ovarian Cancer Ovarian cancer is more common than endometrial cancer and has a much higher mortality. Certain risk factors are shared by both (e.g. nulliparity) and it was suggested that if there was a similar aetiology, then a similar increase in risk related to estrogen use might be expected. However, it was also argued that estrogens may exert a protective effect on the ovary because the oral contraceptive pill is known to reduce the risk of ovarian carcinoma (Cust et al. 1989). There is agreement between epidemiological studies that there is no significant increase in overall risk of ovarian cancer among estrogen users. Cancer screening programmes in the US have shown no increase in incidence of ovarian cancer in recent years, although an increase might have been expected because of the increased use of estrogen therapy (Cramer et al. 1981). An American national cancer survey (Gutler & Young 1975) undertaken between 1969 and 1971, a time before the widespread use of estrogen therapy, was compared with the National Cancer Institute SEER (1980) programme performed between 1975 and 1977 when there had been a substantial increase in estrogen use. While there was no significant difference in the overall incidence of ovarian carcinoma between the 2 studies, there did seem to be an increase in the incidence of certain types of ovarian

191

cancer, the endometrioid and clear cell carcinomas. These epithelial carcinomas are similar histologically to endometrial carcinoma. Weiss et al. (1982) investigated the incidence of these types of ovarian cancer in more detail. While reporting a small increase in risk, this was not statistically significant and the increases could be due to chance. The apparent increase in these carcinomas when there is no overall increase in risk may be because histological diagnoses were underreported in the 1960s. Cust et al. (1989) stated that there was no evidence to suggest that estrogens either increase or decrease the risk of ovarian cancer in postmenopausal women. No significant link between estrogen use and ovarian cancer incidence was found in other studies (Annegers et al. 1979; Hildreth et al. 1981; Hunt et al. 1987; Weiss et al. 1982). The relationship of ERT to epithelial ovarian cancer was evaluated by Kaufman et al. (1989) in a case-control study conducted mainly in the northeastern US. There were 377 cases diagnosed within a year before hospital admission and 2030 hospital controls; data were collected by interview in the hospital. Compared with women who never took noncontraceptive estrogens, the overall RR estimate for women whose estrogen use lasted at least 1 year and was not opposed by progestogens or testosterone was 1.2 (95% CI 0.8 to 1.9) after taking into account other risk factors for ovarian cancer. For women who used estrogen for a long duration, in high dose preparations or in the distant past, the RR estimates were not significantly different from 1.0. The results suggested that, overall, noncontraceptive estrogen use was not associated with the risk of epithelial ovarian cancer. The data also did not support the hypothesis that estrogens increase the risk of endometrioid cancer. 2.5 Cervical Carcinoma There is no epidemiological evidence that postmenopausal estrogen or progestogen therapy has any effect on the incidence of primary or recurrent cervical carcinoma (Cust et al. 1989). Hunt et al.

192

(1987) did not find evidence to suggest that there was increased cervical cancer risk.

3. Conclusions The proven and almost universally accepted benefits of ERT include relief of vasomotor symptoms, prevention of atrophic vaginitis and prevention of osteoporosis. Estrogens may also help alleviate some of the psychogenic manifestations that are aggravated by menopause. Decreasing the risk of cardiovascular disease may be an additional benefit by estrogen-increased HDL cholesterol. Twelve days of cyclic progestogen reduces the risk of endometrial cancer and hyperplasia. The risk of breast cancer has not been shown to be increased with estrogen therapy. Whereas estrogens prevent demineralisation of bone, the addition of progestogen may promote new bone formation. As with any therapy, postmenopausal women and their physicians must balance the potential risks and benefits of HRT. The protective influence of estrogens on cardiovascular disease and osteoporosis in all likelihood outweighs their harmful influence on endometrial and, possibly, breast cancer (Bush & Barrett-Connor 1985). There are few women in whom HR T is contraindicated and the few short term side effects caused by treatment can usually be overcome by changing the HRT regimen. Against any possible risk must be balanced the well-proven advantages of HRT in terms of both symptom relief and long term protection against osteoporosis and cardiovascular disease.

References American Cancer Society. Cancer statistics: 1986. CA - Cancer Journal for Clinicians 36: 9-25, 1986a American Cancer Society. Cancer statistics: 1987. CA - Cancer Journal for Clinicians 36: 2-13, 1986b Annegers JF, Strom H, Decker DG, et al. Ovarian cancer: incidence and case-control study. Cancer 43: 723-729, 1979 Antunes CMF, Stolly PD, Rosenheim NB, et al. Endometrial cancer and oestrogen use: report of a large case-control study. New England Journal of Medicine 300: 9-13, 1979 Astedt B. On the role of estrogens in endometrial carcinogenesis. Acta obstetricia et Gynaecologica Scandinavica \06 (Suppl.): 33-35, 1982

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Correspondence and reprints: Mrs T.R. Varma, Department of Obstetrics and Gynaecology, St George's Hospital Medical School, Cranmer Terrace, London SW 17 ORE, England.

Sandoz Prize for Gerontologic Research This prize of SwF50 000 is awarded every 2 years by the International Association of Gerontology for research work deemed to have made a significant contribution to the progress of gerontology and/or geriatrics. The prize is to be awarded for the sixth time in 1993 and submissions by or on behalf of appropriate scientists are invited by 15 October 1992. For further information, please contact: Dr John L.C. Dan Victoria Infirmary Southern General Hospital Unit, Victoria Geriatric Unit Mansionhouse Road. Longside. Glasgow G41 3DX

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Sex steroids and cancer in older women.

Menopause and hormone replacement therapy (HRT) continue to be controversial subjects. The main concern is the potential risk of prolonged HRT and the...
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