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American Journal of Epidemiology Advance Access originally published online on November 28, 2006
American Journal of Epidemiology 2007 165(5):524-529; doi:10.1093/aje/kwk038
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American Journal of Epidemiology Copyright © 2006 by the Johns Hopkins Bloomberg School of Public Health All rights reserved; printed in U.S.A.

ORIGINAL CONTRIBUTIONS

Use of Oral Conjugated Estrogen Alone and Risk of Breast Cancer

Shumin M. Zhang1,2, JoAnn E. Manson1,2,3, Kathryn M. Rexrode1, Nancy R. Cook1,2, Julie E. Buring1,2,4 and I-Min Lee1,2

1 Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA
3 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
4 Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA

Correspondence to Dr. Shumin M. Zhang, Division of Preventive Medicine, Brigham and Women's Hospital, 900 Commonwealth Avenue East, Boston, MA 02215 (e-mail: shumin.zhang{at}channing.harvard.edu).

Received for publication May 10, 2006. Accepted for publication July 26, 2006.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The authors conducted a prospective cohort analysis in the Women's Health Study (1992–2004), a completed randomized trial assessing aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease, to evaluate use of oral conjugated estrogen alone (0.625 mg/day) and breast cancer risk in a time-varying fashion. Over an average of 10 years of follow-up, 305 incident cases of breast cancer (258 invasive and 47 in situ cancers) were documented among 12,718 women aged 45 years or more who were either consistent current users of oral conjugated estrogen alone (0.625 mg/day) or never users of any type of postmenopausal hormones at baseline and during follow-up. The multivariable hazard ratios comparing "consistent current users" with "never users" were 1.11 (95% confidence interval: 0.79, 1.56) for total breast cancer and 1.13 (95% confidence interval: 0.77, 1.64) for invasive cases. No significant associations were observed for use of less than 8 and 8 years or more. Restricting the analyses to women with prior hysterectomy somewhat strengthened the associations, albeit still not significantly. These data, like those from the Women's Health Initiative, show no significant increase in breast cancer risk with use of oral conjugated estrogen alone (0.625 mg/day), but a small increase or decrease in risk cannot be excluded.

breast neoplasms; estrogen replacement therapy

Abbreviations: CI, confidence interval


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
The Women's Health Initiative randomized trial recently reported its findings on the use of oral conjugated equine estrogen alone among women with prior hysterectomy and found that oral conjugated equine estrogen use (0.625 mg/day) was not associated with increased risk for breast cancer, with perhaps even a decrease in risk over an average of 7.1 years of treatment and follow-up with a relative risk of 0.82 (95 percent confidence interval (CI): 0.65, 1.04) for total breast cancer (1). Although this finding appears to be contrary to earlier results from the Women's Health Initiative that showed an increased risk associated with the use of oral conjugated equine estrogen in combination with progestin (2), studies that have specifically evaluated the use oral conjugated estrogen alone (0.625 mg/day) and risk of breast cancer are limited.

To provide additional data, especially on long-term use of oral conjugated estrogen alone (0.625 mg/day), we examined the relation between the use of oral conjugated estrogen alone (0.625 mg/day) and risk of breast cancer in the Women's Health Study.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Study sample
The Women's Health Study is a recently completed randomized clinical trial evaluating low-dose aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease among 39,876 female US health professionals, aged 45 years or older, who were free of cancer and cardiovascular disease at baseline (3–5). Randomized treatment and follow-up in the Women's Health Study were concluded on March 31, 2004. Follow-up rates for morbidity and mortality were 97.2 percent and 99.4 percent, respectively (3–5).

Assessment of postmenopausal hormones
Upon enrollment in the study, all participants in the Women's Health Study completed a baseline questionnaire about their medical history and lifestyle characteristics, including potential risk factors for breast cancer. On the baseline enrollment questionnaire, information was collected about the status (never, past, and current), duration of use (<1, 1, 2, 3–4, 5–7, and ≥8 years), and type of postmenopausal hormones used currently (conjugated estrogen alone, conjugated estrogen and progesterone, nonconjugated estrogens alone, nonconjugated estrogens and progesterone, patch estrogen alone, patch estrogen and progesterone, oral progesterone alone, vaginal estrogen, and other). In addition, we asked for information on the dose of oral conjugated estrogen (≤0.30, 0.625, and ≥0.9 mg/day) and progesterone (<5, 5–9, 10, and >10 mg/day) and pattern of progesterone use (continuous and <2 weeks/month). Similar questions were asked on the 12-month, 36-month, 60-month, and 96-month questionnaires. For simulation of the analysis in the Women's Health Initiative trial (1), the study sample at baseline comprised those who were postmenopausal or of uncertain menopausal status and who were current users of oral conjugated estrogen alone (0.625 mg/day) or never users of any form of postmenopausal hormones. "Uncertain menopausal status" was defined as referring to women who were not sure about their menopausal status and those who had undergone hysterectomy without bilateral oophorectomy prior to menopause and before age 60 years. Consistent current use or nonuse of postmenopausal hormones, as well as cumulative years of use, was analyzed prospectively for the present study in a time-varying fashion. Women who changed their use of postmenopausal hormones were censored at the date the change was reported. For example, current users at 12 months were those who reported use at both baseline and at 12 months, and their duration of use was that reported at baseline plus 12 months. Never users at 12 months were those who reported never use at baseline and no use at 12 months. A total of 12,718 women aged 45 years or older (free of cancer including breast cancer at baseline) were included for the present analysis (4,112 current users of oral conjugated estrogen alone (0.625 mg/day) and 8,606 never users of postmenopausal hormones at baseline). Consistent current users of oral conjugated estrogen alone (0.625 mg/day) were further categorized according to the duration of use at each time point. Because the highest category of duration of use at baseline was 8 or more years in the Women's Health Study, we categorized the duration of cumulative use as less than 8 versus 8 years or more, which not only provided a more precise categorization of cumulative duration of use but also used categories of similar duration to the average length of treatment and follow-up of the Women's Health Initiative trial (1). To simulate conditions in the Women's Health Initiative (1), we also conducted an additional analysis only among women with prior hysterectomy at baseline (3,657 current users of oral conjugated estrogen alone (0.625 mg/day) and 2,769 never users of postmenopausal hormones).

Ascertainment of breast cancer
The methods used for follow-up and endpoint ascertainment including breast cancer in the Women's Health Study have been previously detailed (3, 4, 6). Breast cancers were ascertained via self-report on follow-up questionnaires and confirmed by blinded medical record review. Among women in the present study, 305 developed incident breast cancer (258 invasive and 47 in situ cancers) over an average of 10 years of follow-up. The Human Research Committee at the Brigham and Women's Hospital approved this study.

Statistical analysis
Person-years for each participant were calculated from the date of the randomization to the date of diagnosis of confirmed cancer, death, change of postmenopausal hormone use during follow-up, or March 31, 2004, whichever occurred first. Time-varying Cox proportional hazards regression models were used to calculate hazard ratios associated with the cumulative use of oral conjugated estrogen alone (0.625 mg/day) and their corresponding 95 percent confidence intervals using the PROC PHREG procedure with counting process input (SAS Institute, Inc., Cary, North Carolina). We first estimated hazard ratios according to the category of exposure with adjustment for age (years) and randomized treatment assignments (aspirin vs. placebo; vitamin E vs. placebo). We further performed a multivariable analysis that additionally adjusted for baseline body mass index (kg/m2, continuous variable), family history of breast cancer in a first-degree relative (yes, no), history of benign breast disease (yes, no), age at menarche (<12, 12, 13, ≥14 years), age at first birth (<25, 25–29, ≥30 years), parity (0, 1–3, ≥4 births), age at menopause (<50, ≥50 years, uncertain), surgical menopause due to bilateral oophorectomy (yes, no), physical activity (total kcal/week, continuous variable), smoking status (never, past, current), alcohol intake (g/day, continuous variable), and multivitamin supplement use (never, past, current). We also performed a secondary analysis according to tumor characteristics (histologic grading and differentiation and hormone receptor status) by using polychotomous logistic regression. All statistical tests were two sided.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
At baseline, compared with never users, current users of oral conjugated estrogen alone (0.625 mg/day) tended to be younger, leaner, younger at menopause, and current users of multivitamin supplements. They were also more likely to have a prior hysterectomy, surgical menopause due to bilateral oophorectomy, and a personal history of benign breast disease, but they were less likely to be current smokers. Family history of breast cancer in a mother or sister, age at menarche, parity, physical activity, and alcohol consumption were not appreciably different between them (table 1). The percentages of women who currently used oral conjugated estrogen alone (0.625 mg/day) at baseline were 8.8 percent for less than 1 year, 5.8 percent for 1 year, 10.0 percent for 2 years, 15.9 percent for 3–4 years, 18.5 percent for 5–7 years, and 41.1 percent for 8 or more years. The median value of duration of current use of oral conjugated estrogen alone (0.625 mg/day) was 6 years at baseline. The median value of cumulative duration of current use of oral conjugated estrogen alone (0.625 mg/day) during follow-up was approximately 10 years.


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  		TABLE 1. Age-adjusted baseline characteristics of the participants according to the use of oral conjugated estrogen alone in the Women's Health Study, United States, 1992–2004

 
Relative to never use of postmenopausal hormones, consistent current use of oral conjugated estrogen alone (0.625 mg/day) was not statistically significantly associated with risk of breast cancer (table 2). The age- and randomized treatment-adjusted hazard ratios were similar to those from multivariable analyses. The multivariable-adjusted hazard ratios were 1.11 (95 percent CI: 0.79, 1.56) for total breast cancer including both invasive and in situ cases and 1.13 (95 percent CI: 0.77, 1.64) for invasive breast cancer only. No significant associations were observed for women who used oral conjugated estrogen alone (0.625 mg/day) for less than 8 years (hazard ratio = 0.85, 95 percent CI: 0.51, 1.42) or for 8 years or more (hazard ratio = 1.25, 95 percent CI: 0.86, 1.82) (table 2). Associations did not appear to differ according to histologic grading and differentiation or to estrogen- or progesterone-receptor status (data not shown). The associations became somewhat stronger when we included only the 6,426 women with prior hysterectomy at baseline in the analysis, although the associations still remained not significant. The multivariable hazard ratios comparing "consistent current users" with "never users" were 1.30 (95 percent CI: 0.84, 2.03) for total breast cancer including both invasive and in situ cases and 1.39 (95 percent CI: 0.85, 2.28) for invasive breast cancer only. There also were no significant associations for those who used oral conjugated estrogen alone (0.625 mg/day) for less than 8 years (hazard ratio = 1.05, 95 percent CI: 0.58, 1.92) and for 8 years or more (hazard ratio = 1.44, 95 percent CI: 0.89, 2.33) (table 2). Because the number of cases was limited in these subgroup analyses, the confidence intervals were wide.


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  		TABLE 2. Hazard ratios and 95% confidence intervals of breast cancer according to the use of oral conjugated estrogen alone in the Women's Health Study, United States, 1992–2004

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
In this prospective cohort study, the use of oral conjugated estrogen alone (0.625 mg/day) was not statistically significantly associated with risk of breast cancer. Similar to results from the Women's Health Initiative trial (1), our results also observed no significant increase in risk among those who used this dose of oral conjugated estrogen alone for less than 8 years. There also was no significant increase in risk of breast cancer associated with the use for 8 years or more. The associations became somewhat stronger when we included only the 6,426 women with prior hysterectomy, albeit they still were not significant, which may be due to the reduced risk of breast cancer associated with hysterectomy. Hysterectomy without bilateral oophorectomy can cause early age at menopause (7) and may thus lower the risk of breast cancer (8).

The results from previous studies according to duration of use were mixed. Several studies suggest no increase in risk during early years of use of estrogen alone (ranging from 1 to 14 years) but an increased risk with increasing duration of use (9–18), whereas others indicate no association with duration of use (19–22). In the only two previous studies that have examined the duration of conjugated estrogen use only, no increase in risk of breast cancer was evident until the duration of use was more than 10 years (10) or 15 years or more (9), although the risk estimates were not statistically significant.

Different effects of oral conjugated estrogen alone versus combined oral conjugated estrogen plus progestin on breast cancer in the Women's Health Initiative trial (1, 2) provide evidence that these hormone regimens may affect breast carcinogenesis differently. Consistent with the Women's Health Initiative trial, this study found no overall significant increase in risk of breast cancer associated with the use of oral conjugated estrogen alone (0.625 mg/day) in the present analysis but observed an increased risk associated with the use of combined estrogen and progestin in an earlier investigation (6). Among other studies examining breast cancer risk by the type of postmenopausal hormones, most reported either little effect (9, 11, 20–22) or a modest increase in risk associated with estrogen alone (10, 12, 13, 15–17, 23–25), but they found a greater risk with combined estrogen and progestin (9–13, 15–17, 20–25). However, a few studies found no increase (19) or a similar increased risk of breast cancer (14, 26) with these two regimens. Of these, only four studies have specifically studied the use of oral conjugated estrogen alone rather than combined or unspecified categories of estrogen-alone therapy (9, 10, 21, 24).

The mechanisms by which estrogen alone versus estrogen plus progestin could affect breast carcinogenesis differently remain unclear. Estrogen plus progestin use was associated with greater breast epithelial cell proliferation and breast epithelial cell density than was estrogen use alone or nonuse in a cross-sectional analysis (27). Furthermore, with estrogen plus progestin, breast proliferation was localized to the terminal duct-lobular unit of the breast, which is the site of development of most breast cancers. In the Postmenopausal Estrogen/Progestin Intervention trial, after 12 months, the percentages of women with breast density grade increases were 0 percent in the placebo group, 3.5 percent in the conjugated estrogen alone group, 23.5 percent in the conjugated estrogen plus cyclic medroxyprogesterone group, 16.4 percent in the conjugated estrogen plus cyclic micronized progesterone group, and 19.4 percent in the conjugated estrogen plus daily medroxyprogesterone group (28).

The strengths of our study include its prospective design, repeated assessments of postmenopausal hormone use, detailed data on potential confounders, and high follow-up rates. However, limited numbers of breast cancer cases precluded detailed analysis by subgroups. Our results suggest that the use of oral conjugated estrogen alone (0.625 mg/day) does not increase the risk of breast cancer. However, the present data cannot clearly exclude the possibility of a small increase or decrease in risk associated with oral conjugated estrogen alone. Additional investigations with longer duration of follow-up and larger numbers of cases are needed to confirm these findings.


   ACKNOWLEDGMENTS
 
This study is supported by the National Cancer Institute Career Development Award (CA096619) and research grants CA-47988 and HL-43851 from the National Institutes of Health (Bethesda, Maryland).

The authors would like to thank Marilyn Chown for her statistical analytical support. They acknowledge the contributions of the entire staff of the Women's Health Study under the leadership of David Gordon, as well as Mary Breen, Susan Burt, Marilyn Chown, Georgina Friedenberg, Inge Judge, Jean Mac-Fadyean, Geneva McNair, David Potter, Claire Ridge, and Harriet Samuelson. They also acknowledge the Endpoints Committee of the Women's Health Study (Dr. Wendy Y. Chen) and Natalya Gomelskaya for technical assistance with the manuscript.

N. R. C. received partial research support from Roche Molecular Systems (Pleasanton, California) and served as a consultant for Bayer AG (Leverkusen, Germany) in 2003. J. E. B. received partial research support from Dow Corning Corporation (Midland, Michigan), research support for the Women's Health Study trial for pills and/or packaging from Bayer HealthCare (Morristown, New Jersey) and the Natural Source Vitamin E Association (Washington, DC), and honoraria from Bayer for speaking engagements; she also serves on an external scientific advisory committee for a study by Proctor & Gamble (Cincinnati, Ohio).


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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