Conjugated Equine Estrogen and Risk of Benign Proliferative Breast Disease: A Randomized Controlled Trial

Department of Epidemiology and Population Health, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 05/2008; 100(8):563-71. DOI: 10.1093/jnci/djn075
Source: PubMed


Estrogens stimulate proliferation of breast epithelium and may therefore increase the risk of benign proliferative breast disease, a condition that is associated with increased risk of breast cancer. We tested the effect of conjugated equine estrogen (CEE) on risk of benign proliferative breast disease in the Women's Health Initiative (WHI) randomized controlled trial.
In the WHI CEE trial, 10,739 postmenopausal women were randomly assigned to 0.625 mg/d of CEE or to placebo. Baseline and annual breast examinations and mammograms were required. We identified women in the trial who reported breast biopsies that were free of cancer, obtained the associated histological sections, and subjected them to standardized central review. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
A total of 232 incident cases of benign proliferative breast disease were ascertained during follow-up (average duration, 6.9 years), with 155 in the CEE group and 77 in the placebo group. Use of CEE was associated with a more than two-fold increase in the risk of benign proliferative breast disease (HR = 2.11, 95% CI = 1.58 to 2.81). For benign proliferative breast disease without atypia, the HR was 2.34 (95% CI = 1.71 to 3.20), whereas for atypical hyperplasia, it was 1.12 (95% CI = 0.53 to 2.40). Risk varied little by levels of baseline characteristics.
Use of 0.625 mg/d of CEE was associated with a statistically significant increased risk of benign proliferative breast disease.

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    • "Estrogen has physiological effects of cell proliferation and differentiation during the cell cycle. Probably in benign proliferative breast disease the steroid hormones antagonizes cell differentiation and apotosis [21,22]. The normal proliferation of cells due to action of endogenous steroid hormones leads to the breast enlargement seen at puberty and the reproductive period. "
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    ABSTRACT: Background Non-cancerous diseases of the breast have assumed increasing importance because of the public awareness of breast cancer. These benign diseases are a recognized important risk factor for later breast cancer which can develop in either breast. The risk estimate of these benign breast diseases has not been well established in sub Saharan Africa. Women with benign proliferative or atypical breast lesions have a two- fold risk of developing breast cancer in western populations. The purpose of this study therefore was to determine the prevalence of proliferative disease ( BPBD) with and without atypia among Ugandan Black women. Methods A cross-sectional descriptive study conducted at Mulago Hospital Breast Clinic between January 2012 and June 2012; 208 women aged 12 years and above with palpable breast lumps were screened. Fine needle aspiration biopsies were taken for cytological examination. Results Of the 208 women with benign breast lumps screened, 195 were recruited in the study. The prevalence of BPBD was 18% (35/195). BPBD with atypia was 5.6% (11/195). The mean age and body mass index (BMI) were 28.4 years and 23.26 kg/m2 respectively. The commonest lesions were fibroadenomas for 57%, (111/195), and fibrocystic change were 21% (40/195). Most BPBD with atypia lesions were in the fibrocystic category. Conclusions Benign proliferative breast diseases are common, found mostly among premenopausal women. A significant proportion of BPBD had atypical proliferation. An accurate breast cancer risk estimate study for BPBD is recommended.
    BMC Surgery 04/2013; 13(1):9. DOI:10.1186/1471-2482-13-9 · 1.40 Impact Factor
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    • "While not related to endogenous hormones, recent observations also support a role for reproductive hormone influence on BBD. In the Women's Health Initiative randomised, placebo-controlled hormone therapy trials, conjugated equine oestrogen resulted in a statistically significant increase in BBD (Rohan et al, 2008). "
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    ABSTRACT: Background: Limited information exists about the endocrine milieu of benign breast disease (BBD), a documented breast cancer risk factor. We compared blood levels of estrogens, testosterone and insulin-like growth factor-1 (IGF-1) between BBD patients by histological type and women without breast pathology. Methods: We studied 578 BBD patients and 178 healthy women in Athens, Greece, who provided blood samples, and completed interviewer-administered questionnaires. Results: Of the BBD patients, 254 had non-proliferative disease, 268 proliferative disease without atypia and 56 atypical hyperplasia. Comparing BBD patients with healthy women, the per cent differences (and 95% confidence intervals) for blood hormones, among pre-menopausal and peri/post-menopausal women, respectively, were: 22.4% (−4.0%, 56.1%) and 32.0% (5.6%, 65.1%) for estradiol; 26.2% (10.1%, 44.8%) and 30.9% (16.8%, 46.6%) for estrone; 19.5% (3.1%, 38.4%) and 16.5% (−5.0%, 42.9%) for testosterone; and −5.2% (−13.8%, 4.4%) and −12.1% (−19.8%, −3.6%) for IGF-1. Steroid hormones tended to be higher in proliferative compared with non-proliferative BBD. Conclusions: Circulating steroid hormones tend to be higher among women with BBD than women with no breast pathology and higher in proliferative than non-proliferative disease; these patterns are more evident among peri/post-menopausal women. In peri/post-menopausal women IGF-1 was lower among women with BBD compared with healthy women.
    British Journal of Cancer 11/2012; 108(1). DOI:10.1038/bjc.2012.493 · 4.84 Impact Factor
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    ABSTRACT: Proliferative lesions of the mammary gland are risk markers and potential precursors for the development of breast cancer in postmenopausal women. In this study we evaluated mammary epithelial proliferation and proliferative lesions in a group of 63 aged postmenopausal macaques randomized by social group to receive one of three experimental diets for 8 months: (1) control; (2) control with 17beta-estradiol (E2) at the human equivalent dose of 1.0 mg per day; and (3) control with the soy phytoestrogen equol (EQ) at the human equivalent dose of 105 mg per day. In normal mammary epithelium, treatment with E2 but not EQ resulted in greater proliferation, epithelial area, and progesterone receptor expression (P<0.05 for all). Mammary lesions included columnar cell change (26/63), columnar cell hyperplasia with and without atypia (13/63), atypical ductal hyperplasia (6/63), and atypical lobular hyperplasia (3/63). Lesions were most common within terminal ductal lobular units. The prevalence of columnar cell hyperplasia (total and atypical cases) was higher in animals treated with E2 compared to control (P<0.05 for both). Compared to normal mammary epithelium, columnar cell lesions (CCLs) showed greater constitutive expression of estrogen receptor-alpha across all groups (P<0.001) and greater expression of progesterone receptor in response to E2 (P<0.01). Independent of treatment, animals with CCLs on histology had greater gene expression of estrogen receptor-alpha and markers of estrogen receptor activity (trefoil factor 1) and proliferation (gene for Ki67 antigen) at a site contralateral to the CCL (P<0.05 for all). These findings demonstrate that the terminal ductal lobular units of the postmenopausal mammary gland contain morphologically distinct cell populations that may hyperrespond to E2 exposure, resulting in specific types of hyperplastic lesions.
    Laboratory Investigation 08/2008; 88(9):938-48. DOI:10.1038/labinvest.2008.64 · 3.68 Impact Factor
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