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Effects of short-term estradiol and norethindrone acetate treatment on the breasts of normal postmenopausal women

Cheng, Guojun MD, PhD1,2; Butler, Ryan BSc3; Warner, Margaret PhD3; Gustafsson, Jan-Åke MD, PhD1,3; Wilczek, Brigitte MD, PhD4; Landgren, Britt-Marie MD, PhD2

Menopause: The Journal of The North American Menopause Society: May 2013 - Volume 20 - Issue 5 - p 496–503
doi: 10.1097/gme.0b013e318276c4ea
Original Articles

Objective The aim of this study was to evaluate among postmenopausal women the effects of a 3-month treatment with estradiol (E2) alone or in combination with norethindrone acetate (NA) on expression of hormone receptors and proliferation in the breast as well as on lipids and climacteric symptoms.

Methods Sixty healthy postmenopausal women were computer-randomized into two groups, with one group receiving 1 mg of E2 and the other group receiving 1 mg of E2 and 0.5 mg of NA daily for 12 weeks. Before and after treatment, middle-needle biopsies were obtained for histology and investigation of the expression levels of estrogen receptors (ERs; ER-α and ER-β), progesterone receptors (PRs; PR-A and PR-B), androgen receptor (AR), the proliferation marker Ki67, and collagen. Climacteric symptoms were recorded, and serum was collected to measure lipoprotein levels.

Results Fifty-six women finished the 12-week study. Proliferating cells (Ki67-positive) were very rare in all but a few of the untreated women. There were proliferating cells in both E2- and E2/NA–treated groups; however, these were not widespread and limited to nests of cells that amounted to 2% of the total epithelial cells. Some of these nests were positive for human epithelial growth factor receptor 2. Treatments caused no marked changes in the expression of ER-α, ER-β, or AR. However, both treatments resulted in an increase in PR-A and PR-B expressions. The presence of collagen was clearly associated with a mammographic diagnosis of dense breasts, but neither hormone treatment affected breast density. Both E2 and E2/NA treatments were effective in relieving hot flashes and sweating without adverse effects on blood pressure, weight, and liver, kidney, and thyroid functions. A decrease in cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was induced by E2/NA but not by E2.

Conclusions This short-term prospective study shows that E2 and estrogen-progestogen treatment can up-regulate PRs but do not significantly affect ERs, AR, proliferation, or breast density.

From the 1Department of Biosciences and Nutrition, Karolinska Institutet, Novum, Sweden; 2Division of Obstetrics and Gynecology, Department of Clinical Science, Karolinska University Hospital at Huddinge, Stockholm, Sweden; 3Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX; and 4Unilabs Mammography Department, Capio St. Görans Hospital, Stockholm, Sweden.

Received June 27, 2012; revised and accepted September 28, 2012.

G.C. and R.B. contributed equally to this manuscript.

Funding/support: This study was supported by grants from the Stockholm County Council (ALF), the Swedish Cancer Society, the Susan Komen Breast Cancer Foundation, and the Robert A. Welch Foundation (E-0004).

Financial disclosure/conflicts of interest: None reported.

Address correspondence to: Guojun Cheng, MD, PhD, Department of Biosciences and Nutrition, Karolinska Institutet, S14186 Huddinge, Sweden. E-mail:,

© 2013 by The North American Menopause Society.