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Effects of estradiol with oral or intravaginal progesterone on risk markers for breast cancer in a postmenopausal monkey model

Wood, Charles E. DVM, PhD1; Sitruk-Ware, Regine L. MD2; Tsong, Yun-Yen PhD2; Register, Thomas C. PhD1; Lees, Cynthia J. DVM, PhD1; Cline, J. Mark DVM, PhD1

doi: 10.1097/01.gme.0000247017.41007.80

Objective: To evaluate the effects of oral estradiol given with either oral or intravaginal micronized progesterone (P4) on risk biomarkers for breast cancer in a postmenopausal monkey model.

Design: This experiment was a two-way crossover study in which 20 ovariectomized adult female cynomolgus macaques were treated (in equivalent doses for women) with oral estradiol (1 mg/d) + oral micronized P4 (200 mg/d) or intravaginal P4 delivered by Silastic rings (6- to 10-mg/d release rate). Hormone treatments lasted 2 months and were separated by a 1-month washout period. The primary outcome measure was breast epithelial proliferation.

Results: Serum P4 concentrations were significantly greater in subjects receiving oral P4 (10.9 ng/mL) compared with intravaginal P4 (3.8 ng/mL) at 2 to 3 hours after oral dosing (P < 0.0001) but not at 24 to 28 hours after oral dosing (2.9 ng/mL for oral P4 vs 3.2 ng/mL for intravaginal P4 at 2 months, P = 0.19). Serum estradiol concentrations were significantly lower after oral P4 than after intravaginal P4 (P < 0.05 for all time points). Oral P4 resulted in significantly decreased body weight (−2.5%) compared with intravaginal P4 (+3.6%) (P = 0.0001). Markers of breast proliferation, sex steroid receptor expression, and endometrial area did not differ significantly between oral P4 and intravaginal P4 treatments (P > 0.1 for all).

Conclusions: Despite different pharmacodynamic profiles, oral and intravaginal P4 had similar effects on biomarkers in the postmenopausal breast.

Micronized progesterone delivered by vaginal ring is readily absorbed into the systemic circulation and produces more stable serum concentrations than oral administration. However, no significant differences were found between standard doses of oral and intravaginal progesterone (P4) on breast epithelial proliferation. These findings do not support the idea that intravaginal P4 has an inherently safer risk profile than oral P4 in the postmenopausal breast.

From the 1Department of Pathology/Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; and 2Center for Biomedical Research, Population Council, New York, NY.

Received July 24, 2006; revised and accepted September 27, 2006.

Funding/support: This work was supported by the Martin and Sharleen Cohen Foundation for Biomedical Research (J.M.C.) and grant number 5 K01 RR21322-02 (C.E.W.) from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH). The contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH.

Financial disclosure: None reported.

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:

©2007The North American Menopause Society