Maturitus, 15 (1992) 129-139 Elsevier scientific Publishers Ireland Ltd.
129
MAT 00691
Estrogens, progestins and breast cancer risk in post-menopausal women: state of the ongoing controversy in 1992 RCgine Sitruk-Ware Medical Department, Cibc-Geigy Ltd. and Division of Endocrinology, Department of Internal Medicine, University Hospital, Basle (Switzerland)
(Received March 16, 1992; revision received May 27, 1992; accepted June 3, 1992)
During the past 10 years an extensive literature has been generated concerning the risks and benefits of hormonal replacement therapy in post-menopausal women. Although some of the questions have been answered during this period, controversy about the risk of breast cancer continues. This paper attempts to evaluate the risk of breast cancer in the light of epidemiological, experimental and histological findings. An interpretation of the available data and practical therapeutic recommendations are given. It is concluded that no change in the currently recommended schedule of combined sequential estrogen progestin therapy is necessary at this stage..
Key words: estrogens; progestins; breast cancer; epidemiology
Illtroduction
The rationale for hormonal replacement therapy (HRT) in post-menopausal women has been widely debated and it is now recognized by the scientific community as well founded. The controversy about whether benefits outweigh risks has been recently concluded in favor of the benefits, mainly due to the high protective impact of estrogen replacement therapy on cardiovascular disease (CVD) morbidity and mortality [l]. The benefits of unopposed estrogens, referred to as ERT, are also recognized for osteoporosis prevention. The role of opposed estrogen therapy, i.e. progestin administration with ERT, referred to as hormonal replacement therapy (HRT or combined HRT) in the literature, remains the subject of active debate. Although there is consensus about the need for progestogen therapy in addition to ERT for prevention of endometrial hyperplasia, there is still uncertainty about their impact on breast cancer and CVD risks. The available epidemiological studies
Correspondenceto: R. Sitruk-Ware, Medical Department, Ciba-Geigy Ltd. Basle, Switzerland.
130
assessed differing populations, using or not using different types and doses of progestogens given in various regimens. This complicates practical interpretation of the results. Also, breast physiology has not yet been sufficiently investigated since breast tissue is far less easy to collect than endometrial tissue. No clear data exist on the effect of the various progestogens on mammary tissue. Since the late 1980s it has become clear that any really long-term benefit from ERT would be obtained only if therapy is also continued long term. A recent consensus conference on osteoporosis [2] recommended not less than 5 years of treatment in order to prevent accelerated bone loss. It may be that lifelong treatment is needed to obtain the full benefits, i.e. mainly a decrease in CVD mortality. There is clear evidence that long-term therapy with unopposed estrogens increases the risk of endometrial cancer, but concomitant progestogens may decrease this risk as they prevent endometrial hyperplasia [3]. Although most of the long-term effects of ERT (i.e. unopposed estrogens) are well known, data on the long-term effects of HRT (i.e. combined estrogens and progestogens) are scarce. The controversy remains open regarding: (1) Whether long-term ERT affects the risk of breast cancer (BC); (2) the effects of long-term HRT on breast cancer and cardiovascular disease risks. Recent publications addressing these issues include several long-term prospective epidemiological studies. This article will review both experimental and epidemiological evidence on the role of HRT in breast cancer and address the following questions: 1. What is known about non-contraceptive estrogens (ERT) and the risk of breast cancer? 2. What is known about the role of progestins in the same risk? 3. What is known about the role of estrogens and progestins in breast tissue? 4. How can the available data be interpreted to make practical recommendations in HRT? 5. What additional data should be generated to answer remaining open questions? 1. Epidemiological evidence on the role of estrogens in breast cancer (BC) risk Most of the studies of ERT reported before the mid 1980s were conducted in the United States and concerned the effects of unopposed estrogen, mainly of orally administered conjugated equine estrogens (CEE). Opposed treatment (HRT) became more common after the late 1970s once it was clear that progestins reverse endometrial hyperplasia and hence possibly decrease the endometrial cancer risk linked to unopposed estrogens. However, this practice was rather limited and mainly restricted to European countries. Since then only a few studies have reported results concerning the use of combined HRT. The cohort study of Gambrel1 [4] in the US was the first epidemiological study to specifically evaluate the risk of breast cancer in women using both estrogens and
131
progestins for their menopause treatment. The results suggested a protective effect of estrogens and progestins on the BC risk. However, this study had methodological shortcomings and was never reproduced. A systematic review of the literature has been performed recently by several authors [5-71 (Table I). DuPont and Page [5] reviewed 37 articles published in the last 18 years. Their meta-analysis of 28 studies provided adequate estimates of BC risk among women using ERT. In this analysis the authors found that the overall relative risk of BC associated with therapy (either ERT or HRT) was 1.07. Only high doses of CEE were associated with a significant risk not higher than 2.0 in all studies. DuPont and Page [5] concluded that the literature does not permit a definitive conclusion on whether BC risk increases with prolonged duration of ERT. Another meta-analysis [6] was published at the same time as that by DuPont and Page [5]. In this study Steinberg et al. [6] reviewed 240 citations from the literature, 34 of which were selected as they studied the relationship between noncontraceptive, menopausal estrogen use and BC. Sixteen case control studies were included in the analysis as the authors described the duration of estrogen use. The authors combined dose-response slopes of the relative risk of BC for each year of estrogen use and calculated the proportional increase in the risk of BC for each year of ERT use. They found that this risk did not increase until after 5 years of ERT and an increase of 30% was observed after 15 years of use (RR 1.3; 95% confidence interval (CI), 1.2-1.6). Among women with a positive family history of BC the estrogen users have a higher risk of BC than non-users. (RR 3.4; CI 2-6 vs. 1.3;CI 1.2- 1.7). Hunt and Vessey [7] also reviewed 14 case control and 7 cohort studies. They paid particular attention to the effect of duration and types of therapy on BC risk. In contrast to the analysis of DuPont and Page [5] (and that of Steinberg [6]), they found
TABLE I META-ANALYSES OF THE EFFECT OF ESTROGEN REPLACEMENT RISK OF BREAST CANCER (BC)
No. studies analyzed RR of BC (95% CI) Overall
THERAPY ON THE
Steinberg 1991
DuPont, Page 1991
16
28
1.08 (0.96-1.2)
Long-tern Family history BBD
1-3 (1.2-1.6) 3.4 (2-6) 1.16 (0.89-1.5)
RR, relative risk; 95% CI, 95% confidence interval; BBD, benign breast disease.
132
that a significant trend existed for a slight increase in risk associated with increased duration of estrogen therapy in 10 studies while only 5 studies showed no relationship between duration of ERT and BC risk. 2. Epidemiological data on combined HRT and BC risk Although the addition of progestin to ERT has been advocated since the late 1970s to prevent endometrial hyperplasia and hence to possibly reduce the risk of endometrial cancer [3], this combination therapy has not been widely prescribed throughout the world. For instance, in the United States there is still no recommendation in the labeling of most estrogen products that adjuvant therapy with progestogens should be used. Very recently the FDA’s Advisory Committee on Fertility and Maternal Health Drugs recommended modifying the labeling of all estrogen products by recommending progestin addition [S]. At present in the US about 14% of post-menopausal women receive replacement therapy, 10.9% as estrogens alone and 2.8% as combinations of estrogens and progestins [8]. The effects of combined estrogen and progestin therapy therefore cannot be evaluated in most epidemiological studies coming from the USA. In contrast, in Europe, although the percentage of women treated during post menopause is markedly lower than that in the US, from 3-4% according to country, a recommendation to add progestin is far more usual. Several estrogen/progestogen combination products have been developed. A few European studies have recently been published evaluating the effects of progestins in HRT [9,10]. They have not shown any statistically significant modifying effect on BC risk due to progestin addition The results of these studies are summarized in Table II. Although it may appear at first glance that progestins increase the BC risk, none of the studies showed statistically significant treatment effects on BC risk. There is currently no conclusive evidence that progestins, when given in association to ERT, either increase or decrease BC risk. Progestins used in various countries differ considerably from the natural hormone and from one country to another. This may explain why the results of the different studies are not uniform. Also, because of the variety of fixed combinations used for HRT, interpretation of the situation is as complex as in the oral contraceptives studies. The hormonal balance between estrogenic and progestogenic components of combinations is important, but not well assessed to date. In the study by Bergkvist [lo] the most common preparations used and referred to as estradiol-containing compounds, were combinations of oral estradiol, estriol and norgestrel or norethisterone acetate. The progestins were given for no more than 7 days per estrogen treatment month. The conversion of estradiol into estrone in the liver after ingestion of oral estradiol leads to high production of estrone which may reach plasma levels as high as 466 pg/ml [ 111. Therefore the cumulative estrogenic exposure is higher than with any other preparation used in HRT. Also, the short duration of each progestin treatment phase does not reflect the currently recommended opposed regimen; addition of at least 12 days of progestins per month of estrogen therapy is advised.
133 TABLE II RISK OF BREAST CANCER ASSOCIATED WITH DIFFERENT TREATMENT INCLUDING PROGESTINS: CASE CONTROL AND COHORT STUDIES
SCHEDULES
First author
Date
Country
Type
Treatment
RR
95% Confidence interval (CI)
Gambrel1
1983
USA
Cohort
Ewertz
1988
DK
Case Control
Bergkvist
1989
S
Cohort
Kaufman
1991
Palmer
1991
us CDN CDN
Case Control Case Control
E+P P only P only E + P combined E + P sequential E + P others E + P androgen E+P
129
MAT 00691
Estrogens, progestins and breast cancer risk in post-menopausal women: state of the ongoing controversy in 1992 RCgine Sitruk-Ware Medical Department, Cibc-Geigy Ltd. and Division of Endocrinology, Department of Internal Medicine, University Hospital, Basle (Switzerland)
(Received March 16, 1992; revision received May 27, 1992; accepted June 3, 1992)
During the past 10 years an extensive literature has been generated concerning the risks and benefits of hormonal replacement therapy in post-menopausal women. Although some of the questions have been answered during this period, controversy about the risk of breast cancer continues. This paper attempts to evaluate the risk of breast cancer in the light of epidemiological, experimental and histological findings. An interpretation of the available data and practical therapeutic recommendations are given. It is concluded that no change in the currently recommended schedule of combined sequential estrogen progestin therapy is necessary at this stage..
Key words: estrogens; progestins; breast cancer; epidemiology
Illtroduction
The rationale for hormonal replacement therapy (HRT) in post-menopausal women has been widely debated and it is now recognized by the scientific community as well founded. The controversy about whether benefits outweigh risks has been recently concluded in favor of the benefits, mainly due to the high protective impact of estrogen replacement therapy on cardiovascular disease (CVD) morbidity and mortality [l]. The benefits of unopposed estrogens, referred to as ERT, are also recognized for osteoporosis prevention. The role of opposed estrogen therapy, i.e. progestin administration with ERT, referred to as hormonal replacement therapy (HRT or combined HRT) in the literature, remains the subject of active debate. Although there is consensus about the need for progestogen therapy in addition to ERT for prevention of endometrial hyperplasia, there is still uncertainty about their impact on breast cancer and CVD risks. The available epidemiological studies
Correspondenceto: R. Sitruk-Ware, Medical Department, Ciba-Geigy Ltd. Basle, Switzerland.
130
assessed differing populations, using or not using different types and doses of progestogens given in various regimens. This complicates practical interpretation of the results. Also, breast physiology has not yet been sufficiently investigated since breast tissue is far less easy to collect than endometrial tissue. No clear data exist on the effect of the various progestogens on mammary tissue. Since the late 1980s it has become clear that any really long-term benefit from ERT would be obtained only if therapy is also continued long term. A recent consensus conference on osteoporosis [2] recommended not less than 5 years of treatment in order to prevent accelerated bone loss. It may be that lifelong treatment is needed to obtain the full benefits, i.e. mainly a decrease in CVD mortality. There is clear evidence that long-term therapy with unopposed estrogens increases the risk of endometrial cancer, but concomitant progestogens may decrease this risk as they prevent endometrial hyperplasia [3]. Although most of the long-term effects of ERT (i.e. unopposed estrogens) are well known, data on the long-term effects of HRT (i.e. combined estrogens and progestogens) are scarce. The controversy remains open regarding: (1) Whether long-term ERT affects the risk of breast cancer (BC); (2) the effects of long-term HRT on breast cancer and cardiovascular disease risks. Recent publications addressing these issues include several long-term prospective epidemiological studies. This article will review both experimental and epidemiological evidence on the role of HRT in breast cancer and address the following questions: 1. What is known about non-contraceptive estrogens (ERT) and the risk of breast cancer? 2. What is known about the role of progestins in the same risk? 3. What is known about the role of estrogens and progestins in breast tissue? 4. How can the available data be interpreted to make practical recommendations in HRT? 5. What additional data should be generated to answer remaining open questions? 1. Epidemiological evidence on the role of estrogens in breast cancer (BC) risk Most of the studies of ERT reported before the mid 1980s were conducted in the United States and concerned the effects of unopposed estrogen, mainly of orally administered conjugated equine estrogens (CEE). Opposed treatment (HRT) became more common after the late 1970s once it was clear that progestins reverse endometrial hyperplasia and hence possibly decrease the endometrial cancer risk linked to unopposed estrogens. However, this practice was rather limited and mainly restricted to European countries. Since then only a few studies have reported results concerning the use of combined HRT. The cohort study of Gambrel1 [4] in the US was the first epidemiological study to specifically evaluate the risk of breast cancer in women using both estrogens and
131
progestins for their menopause treatment. The results suggested a protective effect of estrogens and progestins on the BC risk. However, this study had methodological shortcomings and was never reproduced. A systematic review of the literature has been performed recently by several authors [5-71 (Table I). DuPont and Page [5] reviewed 37 articles published in the last 18 years. Their meta-analysis of 28 studies provided adequate estimates of BC risk among women using ERT. In this analysis the authors found that the overall relative risk of BC associated with therapy (either ERT or HRT) was 1.07. Only high doses of CEE were associated with a significant risk not higher than 2.0 in all studies. DuPont and Page [5] concluded that the literature does not permit a definitive conclusion on whether BC risk increases with prolonged duration of ERT. Another meta-analysis [6] was published at the same time as that by DuPont and Page [5]. In this study Steinberg et al. [6] reviewed 240 citations from the literature, 34 of which were selected as they studied the relationship between noncontraceptive, menopausal estrogen use and BC. Sixteen case control studies were included in the analysis as the authors described the duration of estrogen use. The authors combined dose-response slopes of the relative risk of BC for each year of estrogen use and calculated the proportional increase in the risk of BC for each year of ERT use. They found that this risk did not increase until after 5 years of ERT and an increase of 30% was observed after 15 years of use (RR 1.3; 95% confidence interval (CI), 1.2-1.6). Among women with a positive family history of BC the estrogen users have a higher risk of BC than non-users. (RR 3.4; CI 2-6 vs. 1.3;CI 1.2- 1.7). Hunt and Vessey [7] also reviewed 14 case control and 7 cohort studies. They paid particular attention to the effect of duration and types of therapy on BC risk. In contrast to the analysis of DuPont and Page [5] (and that of Steinberg [6]), they found
TABLE I META-ANALYSES OF THE EFFECT OF ESTROGEN REPLACEMENT RISK OF BREAST CANCER (BC)
No. studies analyzed RR of BC (95% CI) Overall
THERAPY ON THE
Steinberg 1991
DuPont, Page 1991
16
28
1.08 (0.96-1.2)
Long-tern Family history BBD
1-3 (1.2-1.6) 3.4 (2-6) 1.16 (0.89-1.5)
RR, relative risk; 95% CI, 95% confidence interval; BBD, benign breast disease.
132
that a significant trend existed for a slight increase in risk associated with increased duration of estrogen therapy in 10 studies while only 5 studies showed no relationship between duration of ERT and BC risk. 2. Epidemiological data on combined HRT and BC risk Although the addition of progestin to ERT has been advocated since the late 1970s to prevent endometrial hyperplasia and hence to possibly reduce the risk of endometrial cancer [3], this combination therapy has not been widely prescribed throughout the world. For instance, in the United States there is still no recommendation in the labeling of most estrogen products that adjuvant therapy with progestogens should be used. Very recently the FDA’s Advisory Committee on Fertility and Maternal Health Drugs recommended modifying the labeling of all estrogen products by recommending progestin addition [S]. At present in the US about 14% of post-menopausal women receive replacement therapy, 10.9% as estrogens alone and 2.8% as combinations of estrogens and progestins [8]. The effects of combined estrogen and progestin therapy therefore cannot be evaluated in most epidemiological studies coming from the USA. In contrast, in Europe, although the percentage of women treated during post menopause is markedly lower than that in the US, from 3-4% according to country, a recommendation to add progestin is far more usual. Several estrogen/progestogen combination products have been developed. A few European studies have recently been published evaluating the effects of progestins in HRT [9,10]. They have not shown any statistically significant modifying effect on BC risk due to progestin addition The results of these studies are summarized in Table II. Although it may appear at first glance that progestins increase the BC risk, none of the studies showed statistically significant treatment effects on BC risk. There is currently no conclusive evidence that progestins, when given in association to ERT, either increase or decrease BC risk. Progestins used in various countries differ considerably from the natural hormone and from one country to another. This may explain why the results of the different studies are not uniform. Also, because of the variety of fixed combinations used for HRT, interpretation of the situation is as complex as in the oral contraceptives studies. The hormonal balance between estrogenic and progestogenic components of combinations is important, but not well assessed to date. In the study by Bergkvist [lo] the most common preparations used and referred to as estradiol-containing compounds, were combinations of oral estradiol, estriol and norgestrel or norethisterone acetate. The progestins were given for no more than 7 days per estrogen treatment month. The conversion of estradiol into estrone in the liver after ingestion of oral estradiol leads to high production of estrone which may reach plasma levels as high as 466 pg/ml [ 111. Therefore the cumulative estrogenic exposure is higher than with any other preparation used in HRT. Also, the short duration of each progestin treatment phase does not reflect the currently recommended opposed regimen; addition of at least 12 days of progestins per month of estrogen therapy is advised.
133 TABLE II RISK OF BREAST CANCER ASSOCIATED WITH DIFFERENT TREATMENT INCLUDING PROGESTINS: CASE CONTROL AND COHORT STUDIES
SCHEDULES
First author
Date
Country
Type
Treatment
RR
95% Confidence interval (CI)
Gambrel1
1983
USA
Cohort
Ewertz
1988
DK
Case Control
Bergkvist
1989
S
Cohort
Kaufman
1991
Palmer
1991
us CDN CDN
Case Control Case Control
E+P P only P only E + P combined E + P sequential E + P others E + P androgen E+P
