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Toxicologic Pathology
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Journal Article

The Proliferation in Uterine Compartments of Intact Rats of Two Different Strains Exposed to High Doses of Tamoxifen or Toremifene

Stefan Karlsson

Orion Corporation, ORION PHARMA, FIN-20101 Turku, Finland, stefan.karlsson{at}orion.mailnet.fi

Michael J. Iatropoulos

American Health Foundation, Valhalla, New York 10595, USA

Gary M. Williams

American Health Foundation, Valhalla, New York 10595, USA

Lauri Kangas

Orion Corporation, ORION PHARMA, FIN-20101 Turku, Finland

L. Nieminen

Orion Corporation, ORION PHARMA, FIN-20101 Turku, Finland

Uterine cell proliferation was studied in intact Sprague-Dawley (SD) and Fischer 344 (F344) rats exposed to the antiestrogens tamoxifen (TAM; 5, 10,20, or 40 mg/kg) and toremifene (TOR; 21.2 or 42.4 mg/kg). The antiestrogens were administered to animals via gavage daily for 2 or 12 wk. Uterine proliferation was assessed using markers for the proliferating cell nuclear antigen (PCNA) and by the bromodeoxyuridine (BrdU) method. Diethylstilbestrol (DES) was used as an estrogenic reference compound. The antiestrogens either reduced or prevented changes of myometrial and stromal proliferation indices (PI). TAM and TOR caused a time-dependent reduction of endometrial glands without an associated decrease in cell proliferation. In the luminal columnar epithelium, the antiestrogens depressed PCNA PI but enhanced BrdU PI, indicating a low continuous DNA synthesis in otherwise quiescent cells. The antiestrogens induced focal hyperplastic multilayered epithelia with PCNA-positive basal cells along segments of the luminal uterine epithelium. We suggest that this hyperplastic epithelium represents remnants from the glandular epithelium. DES was less efficient in inducing these changes but induced squamous metaplasias in the F344 rats. Uterine effects of the 2 antiestrogens were comparable with the exception of 1 TAM-exposed (40 mg/kg) SD rat that showed squamous metaplasia. F344 rats were more sensitive to the estrogenic action of DES than were the SD rats.

Key Words: Antiestrogens • diethylstilbestrol • endometrium • breast cancer • triphenylethylenes • proliferating cell nuclear antigen • bromodeoxyuridine

Toxicologic Pathology, Vol. 26, No. 6, 759-768 (1998)
DOI: 10.1177/019262339802600608
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