The relationship between mammographic density and duration of hormone therapy: effects of estrogen and estrogen progestin

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1 Human Reproduction Vol.20, No.6 pp , 2005 Advance Access publication April 21, 2005 doi: /humrep/deh820 The relationship between mammographic density and duration of hormone therapy: effects of estrogen and estrogen progestin Fang-Ping Chen 1,3, Yun-Chung Cheung 2, Li-Fen Teng 1 and Yung-Kui Soong 1 1 Department of Obstetrics and Gynecology and 2 Department of Radiology, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan, ROC 3 To whom correspondence should be addressed. fangping@cgmh.org.tw BACKGROUND: The purpose of this study was to examine the effects of duration of hormone therapy (HT) and treatment regimens on mammographic density. METHODS: A retrospective study was carried out of of 467 postmenopausal women who received estrogen or estrogen progestin and had regular mammographic density determination by the Breast Imaging Reporting and Data System between 1994 and RESULTS: The fraction of women using HT who had an increase in mammographic density became more important over time. Further analysis of the effects of regimens after 4 years of HT shows that the increase in mean density was much greater in women receiving combined HT than in those receiving estrogen alone. The incidence of increased mammographic density showed significantly progressive increases over the duration of combined HT from 7.5 to 22.4%. CONCLUSIONS: Although most women using HT maintained breast density at pre-treatment levels, there is a note of caution for women using long-term HT, especially those using combined estrogen progestin. Key words: estrogen/estrogen progestin/hormone therapy/mammographic density/post-menopause Introduction Until the reports from the Women s Health initiative (WHI) highlighted the adverse effect on breast cancer in women using hormone therapy (HT) for 5 years or more (Writing Group for the Women s Health Initiative Investigation, 2002), HT was increasingly prescribed to post-menopausal women for relief of climacteric symptoms as well as for the prevention of osteoporosis. In accord with the findings of the WHI (Writing Group for the Women s Health Initiative Investigation, 2002), a recent collaborative re-analysis of data from 51 epidemiological studies has also shown that the risk of breast cancer increases with long-term HT use (Collaborative Group on Hormonal Factors in Breast Cancer, 1997). However, HT is still prescribed to many postmenopausal women to relieve the climacteric symptoms. The duration of treatment is crucial for achieving the benefits from long-term HT use, such as prevention of osteoporosis, decreasing risk of bone fracture, and reducing the incidence of colon and endometrial cancers. Therefore, the effects of long-term HT on the breast are worth further evaluation It has been suggested that opposed HT has a stronger effect in changing mammographic density than unopposed HT (Greendale et al., 1999; Lundström et al., 1999). In addition, several studies have demonstrated that women with higher breast density on mammography are at increased risk of developing breast cancer (Byrne, 1997; Boyd et al., 1998). Therefore, mammographic screening is always considered important for safe surveillance of post-menopausal women, especially for those using HT. Although the initial effects of HT on mammographic density have been well studied, the relationship between duration of HT and mammographic density has not been thoroughly examined. In this study, we investigated the changes of mammographic density during long-term HT, as well as the differences between estrogen alone and combined estrogen progestin. Materials and methods Study sample From 1994 to 2001 we studied 1415 post-menopausal women attending the Keelung Chang Gung Memorial Hospital gynaecological clinic. They had not received HT before and requested HT for climacteric symptoms. Before beginning HT, all of these patients underwent examinations, including mammography, liver function, lipoprotein metabolism and gynaecological evaluation. They had no contraindications for estrogen or progesterone treatment. Women with the following conditions were excluded from HT: bleeding of undiagnosed cause; findings suggesting malignant disease of the breast; known or suspected estrogen-dependent tumours or fibroids; alcoholism; Rotor or Dubin Johnson syndrome; severe liver or kidney disorders; endometrial hyperplasia; or severe hypertension. In addition, we only enrolled women who had regular follow-up q The Author Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved For Permissions, please journals.permissions@oupjournals.org

2 F.-P.Chen et al. and maintained the same regimen and dosage of HT for at least 2 years after their first mammogram. In total, this study was comprised of 467 women. The other women were excluded for reasons such as discontinuation or irregular use of HT or follow-up, changing regimens or dosage of HT, and lack of evaluation by breast ultrasound. In 467 post-menopausal women, 200 (42.8%) patients had undergone hysterectomy due to benign gynaecological disorders and were using only mg/day conjugated estrogen (Premarin; Wyeth-Ayerst Canada Company, Montreal, Quebec, Canada). The other 267 women were treated with combined mg/day conjugated estrogen plus 2.5 mg/day medroxyprogesterone acetate (Provera; Pharmacia & Upjohn Company, Kalamazoo, MI). Breast follow-up by mammographic screening was scheduled for every user with an interval time of 1 2 years after HT. tissue; 3, heterogeneously dense; and 4, extremely dense. Mammographic density was rated separately for each breast, and the breast with the highest density was used for analysis. Statistical analysis Statistical analysis was evaluated by istat Healthcare Consulting Co. Ltd. t-tests were used to assess the differences of baseline characteristics between estrogen alone and combined estrogen progestin. The comparison of scores of mammographic density before and after HT was carried out using the x 2 test. The changes in mean mammographic density between before and after HT were compared using Friedman test and signed rank test. The comparison between estrogen alone and combined estrogen progestin was also carried out by Fisher s exact and Wilcoxon rank sum test. Measures From 1994 to 2001, a total of 1438 mammograms of 467 women with the screening technique including the mediolateral oblique and cranio-caudal views of bilateral breast were available. In addition to the first mammogram before the start of HT and the second screening mammogram after 1 2 years of HT, there were 371 (79.4%) patients for the third, 281 (60.2%) for the fourth, 179 (38.3%) for the fifth, and 179 (38.3%) for the sixth mammogram. Mammographams were reviewed blind by a senior radiologist (Y.-C.C.) who specialized in breast examinations. Breast densities were coded on a 4-point scale according to the American College of Radiology Breast Imaging Reporting and Data System coding (American College of Radiology BI-RADSe Committee, 1998). A score of 1 indicated almost entirely fat; 2, scattered fibroglandular Table I. Baseline characteristics by hormone therapy treatment groups Results From 1994 to 2001, there were 467 women who met the initial criteria for inclusion in our analysis. Data on age at start of HT, age at menopause, duration from menopause to start of HT, body mass index (BMI), duration of HT use and regimens (estrogen alone or combined estrogen progestin) are summarized in Table I. At the time of starting HT, the mean age of women in our samples was 50.4 (SD, 5.8; range 43 69) years. As shown in Table I, although women using estrogens alone (n ¼ 200) tended to be younger than women receiving combined estrogen progestin (n ¼ 267), there was no significant difference (P ¼ 0.066). There were no statistical differences in alone HT a Overall P-value No. (% of total) 200 (42.8) 267 (57.2) 467 (100) Age at start of HT 49.2 ^ 5.6 (43 69) 51.3 ^ 5.7 (43 67) 50.4 ^ 5.8 (43 69) (range), years Age at menopause 46.2 ^ 4.8 (42 56) 47.8 ^ 5.1 (43 59) 47.1 ^ 5.0 (42 59) (range), years Body mass index, kg/m ^ ^ ^ Duration from menopause 3.1 ^ ^ ^ to start of HT, years Duration of HT, years 3.2 ^ ^ ^ a HT ¼ combined estrogen progestin. Table II. Changes in mammographic density by duration of hormone therapy (HT) Duration of HT, years Before HT (n ¼ 467) 1 2 (n ¼ 467) 2 3 (n ¼ 371) 3 4 (n ¼ 281) 4 5 (n ¼ 179).5 (n ¼ 179) 2 0 (0.0%) 1 (0.27%) 1 (0.36%) 0 (0.0%) 0 (0.0%) 1 6 (1.28%) 6 (1.62%) 8 (2.85%) 3 (1.68%) 3 (1.68%) (90.15%) 316 (85.18%) 229 (81.49%) 146 (81.56%) 143 (79.89%) 1 36 (7.71%) 47 (12.67%) 42 (14.95%) 27 (15.08%) 30 (16.76%) 2 4 (0.86%) 1 (0.27%) 1 (0.36%) 3 (1.68%) 3 (1.68%) P-value a,0.001,0.001,0.001,0.001,0.001 Mean density P, b 1.99 ^ ^ ^ ^ ^ ^ 0.72 Change of mean density 0.08 ^ ^ ^ ^ ^ 0.47 P-value c,0.001,0.001,0.001,0.001,0.001 a x 2 test for density distribution from each visit to baseline. b Friedman test. c Signed rank for density change from each visit to baseline. 1742

3 The relationship between HT and breast density Table III. Changes in mammographic density by patterns of hormone therapy (HT) Duration of HT 1 2 years 2 3 years 3 4 years 4 5 years.5 years (n ¼ 116) (n ¼ 63) (n ¼ 116) (n ¼ 63) (n ¼ 170) (n ¼ 111) (n ¼ 211) (n ¼ 160) a (n ¼ 267) (n ¼ 200) Decreased (%) 3 (1.5%) 3 (1.1%) 4 (2.5%) 3 (1.4%) 3 (2.7%) 6 (3.5%) 2 (3.2%) 1 (0.9%) 2 (3.2%) 1 (0.9%) No change (%) 177 (88.5%) 244 (91.4%) 137 (85.6%) 179 (84.8%) 93 (83.8%) 136 (80.0%) 55 (87.3%) 91 (78.5%) 54 (85.7%) 89 (76.7%) Increased (%) 20 (10.0%) 20 (7.5%) 19 (11.9%) 29 (13.7%) 15 (13.5%) 28 (16.5%) 6 (9.5%) 24 (20.7%) 7 (11.1%) 26 (22.4%) P-value b Mean density 0.10 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 0.50 P-value c a estrogen progestin. b Fisher s exact test is used to compare changed density from each visit to baseline between estrogen alone and combined estrogen progestin. c Wilcoxon rank sum test is used to compare changed density from each visit to baseline between estrogen alone and combined estrogen progestin. the duration of using HT and BMI between the women receiving estrogen alone and those receiving combined estrogen progestin. Table II shows the overall relationship between the duration of using HT and the changes of mammographic densities. Compared with the baseline mammographic density (1.99 ^ 0.65) before starting HT, the mean density and the changes of mean density significantly increased after using HT (P, 0.001). Although the percentages of increased mammographic densities progressively increased with the duration of using HT (8.57, 12.94, 15.31, and 18.44% of women after 1 2, 2 3, 3 4, 4 5 and.5 years of HT, respectively), the majority of women remained unchanged compared with their initial score. Few women evidenced decreased mammographic density after HT ( % over.5 years). Table III shows the association between different regimens of HT and mammographic density. Women using combined estrogen progestin for. 4 years had significant increases in the change in mean density scores compared with those using estrogen alone. Although in both groups, most of the women maintained the same score of mammograhic density during HT, the incidence of increased breast density was progressively increased over the duration of combined estrogen progestin (7.5, 13.7, 16.5, 20.7 and 22.4% of women after 1 2, 2 3, 3 4, 4 5 and.5 years, respectively, P, 0.001). In women using estrogen alone, the incidence of increased mammographic density did not show a significant difference over time. For further confirmation of the effects of the duration of HT use, 179 women using HT for.5 years were evaluated alone. Table IV demonstrated that the changes of mean density score significantly increased after using 2 year HT (P ¼ and P, 0.001). In addition, the incidence of increased mammographic density progressively increased over time (1.1, 8.4, 14.0, 16.8 and 18.4% of women after 1 2, 2 3, 3 4, 4 5 and.5 years, respectively, P, 0.05). Discussion In addition to confirming the findings of other previous studies, our study also reveals several strengths that have not been formally evaluated before. We believe that this is the only study to distinguish between overall duration of HT and mammographic density changes, as well as to examine the long-term effects of opposed versus unopposed estrogen. However, since no women developed breast cancer in our study, there was no strict evidence to identify whether those women with increasing breast density are at higher risk for breast cancer. In our study, not only did use of HT significantly increase the mean mammographic density, especially in the first 2 years, but also long-term use was associated with the increased probability of increased density. Our study confirmed findings from previous studies demonstrating an association between using HT and increased breast density (Laya et al., 1995; Greendale et al., 1999; Lundström et al., 1999; Sala et al., 2000; Rutter et al., 2001). We further 1743

4 F.-P.Chen et al. Table IV. Changes in mammographic density in 179 women using hormone therapy (HT) for.5 years Duration of HT, years Before HT years 1 3 (1.68%) 6 (1.68%) 5 (2.79%) 3 (1.68%) 3 (1.68%) (97.21%) 161 (89.94%) 149 (83.24%) 146 (81.56%) 143 (79.89%) 1 2 (1.12%) 15 (8.38%) 25 (13.97%) 27 (15.08%) 30 (16.76%) 2 0 (0.0%) 0 (0.0%) 0(0.0%) 3 (1.68%) 3 (1.68%) P-value a Mean density P, b 1.90 ^ ^ ^ ^ ^ ^ 0.72 Change of mean density 0.01 ^ ^ ^ ^ ^ 0.47 P-value c ,0.001,0.001,0.001 a x 2 test for density distribution from each visit to baseline. b Friedman test. c Signed rank for density change from each visit to baseline. reveal the effects of duration of HT on mammographic density, in which long-term use was associated with increased incidence of having an increased parenchymal breast density from 8.57 to 18.44% during. 5 years follow-up. In our study, the majority of the mammographic density remained at pre-treatment levels. This is compatible with the study of Sterns and Zee (2000), in which a breast density increase was reported in 8% of post-menopausal women after the start of HT. Other studies comparing mammograms before and after the start of HT have reported an increase in density from 8 to 40% of women, the majority of the increase being between 8 and 12% (Berkowitz et al., 1990; Stomper et al., 1990; McNicholas et al., 1994; Erel et al., 1996; Laya et al., 1995; Persson et al., 1996; Cohen, 1997; Marugg et al., 1997; Rand et al., 1997). However, most of these studies were only short-term (1 2 years) evaluations or did not reveal the actual duration. In our study, we found that longterm use of HT induced increased mammographic density in some women. Therefore, post-menopausal women having increased breast density after HT must consider the potential of exogenous hormones inducing epithelial or stromal hyperplasia. If the effect is epithelial hyperplasia, the risk of breast cancer must be considered. In our study, mammographic density remained at pre-treatment levels in 79.89% of women who used HT for $5 years. In addition, % of the women had a decrease in mammographic density over. 5 years. A decrease of breast density after HT has also been reported (Laya et al., 1995; Sterns and Zee, 2000) in up to 18% of women. This seems to support the conclusion that exogenous hormones preserve the existing parenchyma in the majority of post-menopausal women. In some women, the breast tissue even presents as refractory to the exogenous hormones. However, further evaluation is needed to establish whether the risk of breast cancer in these post-menopausal women can be presumed to be low. In menstruating women, breast epithelial proliferation is increased during the luteal phase, when levels of endogenous progesterone are high (Söderqvist et al., 1997). In an animal model for hormone replacement, continuous combination estrogen progestin treatment induced more proliferation than estrogen alone (Cline et al., 1996). The WHI (Writing Group 1744 for the Women s Health Initiative Investigation, 2002) and several epidemiological studies (Collaborative Group on Hormonal Factors in Breast Cancer, 1997) have reported that estrogen plus progestin appears to be associated with greater risk of breast cancer than estrogen alone. Our study also shows that in long-term HT use, an increase in mammographic density was much more common and more pronounced among women receiving combined estrogen progestin than among those using estrogen alone. Our data are not only in agreement with a number of previous studies (Stomper et al., 1990; Marugg et al., 1997; Persson et al., 1997; Lundström et al., 1999; Sendağ et al., 2001), but also show the need for further evaluation of the effects of progestin on breast density vis-a-vis the duration of exposure. In the present study, we found that in women using combined estrogen progestin, the probability of increased mammographic density was progressively increased as the duration of administration was extended (from 7.5 to 22.4%). In contrast, women using estrogen alone did not show an increased incidence of breast density over time; the majority remained at the pre-treatment level. This seems to be compatible with the report of the WHI in 2004 (The Women s Health Initiative Steering Committee, 2004), in which seven fewer cases in women on estrogen alone than in those on placebo were noted, but the finding was not statistically significant. As a result, since it remains to be defined that the implications of increased mammographic density may impact the sensitivity of mammography or alter the risk for subsequent breast cancer, clinicians must pay more attention to those women receiving combined estrogen progestin, especially with long-term usage. In conclusion, the effects of HT on the breast, as reflected by mammography, do not result in an increase in breast density in the majority of post-menopausal women, but may suspend breast involution. Longer use of HT results in a greater percentage of women developing more glandular tissue as seen on mammography. The implications of the additional glandular tissue are unknown, but might impact on the sensitivity of mammography or alter the risk for subsequent breast cancer. Thus, although most women using HT maintained breast density at pre-treatment levels, there are cautions for women using long-term HT, especially combined

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