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Comparative effects of oral conjugated equine estrogens and micronized 17β-estradiol on breast proliferation: a retrospective analysis

Wood, Charles E. DVM, PhD1; Clarkson, Thomas B. DVM1; Chen, Haiying PhD2; Veenstra, Timothy D. PhD3; Xu, Xia PhD2; Scott, Latanya DVM, PhD1; Cline, J. Mark DVM, PhD1

doi: 10.1097/gme.0b013e318168f0ad
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Objective: To evaluate the effects of oral conjugated equine estrogens (CEE) and micronized 17β-estradiol (E2) on breast proliferation in a postmenopausal primate model.

Design: Data from nine studies were analyzed retrospectively. The primary outcome measure was breast epithelial proliferation determined by immunolabeling for the Ki67 antigen. Other measures included progesterone receptor expression and endometrial thickness (as surrogate markers of systemic estrogen exposure) and urinary estrogen metabolite profile. All CEE doses were given at the human equivalent of 0.625 mg/day (n = 281), whereas E2 was given at the human equivalent of 1.0 mg/day or less (n = 131).

Results: Oral CEE resulted in a modest overall increase in breast epithelial proliferation of 75% that reached significance at P < 0.05 compared with placebo in one of four parallel-arm studies. In contrast, oral E2 resulted in a more substantial increase in breast epithelial proliferation of 259% (all studies) to 330% (parallel-arm studies only) that reached significance at P < 0.05 in all five E2 studies evaluated. Breast epithelial expression of progesterone receptor, a widely used marker of estrogen receptor activity, and endometrial thickness showed similar increases after treatment with CEE and E2 (P < 0.05 in all available studies). Relative amounts of urinary methoxyestrogens and the 2-hydroxyestrogen-to-16α-hydroxyestrone ratio were higher after CEE compared with E2 treatment (P < 0.05 for all).

Conclusions: This retrospective analysis of oral estrogen effects in postmenopausal macaques suggests that standard doses of CEE may result in less estrogen-induced epithelial proliferation in the breast compared with E2.

Findings from this retrospective analysis indicate that a standard oral dose of CEE may result in less of an increase in breast epithelial proliferation compared to oral E2. Comparable effects on endometrial thickness and other estrogen-induced markers suggest that this difference is not due simply to lower systemic estrogen exposure.

From the Departments of 1Pathology/Section on Comparative Medicine and 2Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC; and 3Laboratory of Proteomics and Analytical Technologies, SAIC-Frederick Inc., Frederick, MD.

Received November 26, 2007; revised and accepted January 15, 2008.

Funding/support: This work was supported in part by grant RR021322 (C.E.W.) from the National Center for Research Resources, a component of the National Institutes of Health (NIH). Funding for the studies in this analysis was provided by the NIH, the US Army Medical Research Acquisition Activity, the Swedish Medical Research Council, Karolinska Institute Research Funds, the Swedish Cancer Society, NV Organon, and the Martin and Sharleen Cohen Foundation for Biomedical Research. The contents are solely the responsibility of the authors and do not necessarily represent the view of the NCRR or NIH.

Financial disclosure: Dr. Wood, Dr. Clarkson and Dr. Cline have served previously as scientific consultants to Wyeth Pharmaceuticals.

Address correspondence to: Charles E. Wood, DVM, PhD, Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040. E-mail: chwood@wfubmc.edu

©2008The North American Menopause Society