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. Email: fangping{at}cgmh.org.tw
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Abstract |
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Key words: estrogen/estrogenprogestin/hormone therapy/mammographic density/post-menopause
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Introduction |
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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 estrogenprogestin.
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Materials and methods |
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In 467 post-menopausal women, 200 (42.8%) patients had undergone hysterectomy due to benign gynaecological disorders and were using only 0.625 mg/day conjugated estrogen (Premarin; Wyeth-Ayerst Canada Company, Montreal, Quebec, Canada). The other 267 women were treated with combined 0.625 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 12 years after HT.
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 12 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-RADSTM Committee, 1998). A score of 1 indicated almost entirely fat; 2, scattered fibroglandular 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 estrogenprogestin. The comparison of scores of mammographic density before and after HT was carried out using the 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 estrogenprogestin was also carried out by Fisher's exact and Wilcoxon rank sum test.
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Results |
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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, 16.76 and 18.44% of women after 12, 23, 34, 45 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 (1.283.21% over >5 years).
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Discussion |
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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 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 (12 years) evaluations or did not reveal the actual duration. In our study, we found that long-term 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, 1.283.21% 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 estrogenprogestin treatment induced more proliferation than estrogen alone (Cline et al., 1996
). The WHI (Writing Group 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 estrogenprogestin 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
; Senda
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 estrogenprogestin, 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 estrogenprogestin, 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 estrogenprogestin. For patients needing long-term HT, we recommend close follow-up by mammography and even more detailed evaluation of the potential of exogenous hormones inducing epithelial hyperplasia in those with increased breast density.
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References |
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Submitted on November 22, 2004; accepted on January 26, 2005.
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