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Multifocal Ductal Cell Hyperplasia in the Submandibular Salivary Glands of Wistar Rats Chronically Treated with a Novel Steroidal Compound

Organon, Department of Toxicology and Drug Disposition, 5340 BH Oss, The Netherlands, eveline.derijk{at}organon.com

Wilma T.M. Ravesloot

Organon, Department of Toxicology and Drug Disposition, 5340 BH Oss, The Netherlands

Theo G.M. Hafmans

University of Nijmegen, Department of Biochemistry, 6500 HB Nijmegen, The Netherlands

Eric Van Esch

Organon, Department of Toxicology and Drug Disposition, 5340 BH Oss, The Netherlands

A high incidence of multifocal ductal hyperplasia was observed in the submandibular salivary gland of rats treated for 26 weeks with a high dose of a novel synthetic steroid with combined estrogenic and progestagenic properties. Hyperplastic foci consisted of microcystic duct-like structures lined by a single or multilayered epithelium, sometimes showing a tendency towards a cribiform growth pattern. The hyperplastic ducts were embedded in a collagen-rich stroma and surrounded by numerous myoepithelial cells. Immunohistochemical methods used for the detection of estrogen- and progesterone receptors revealed that progesterone receptors were abundantly present in the nucleus of epithelial cells within the lesions, exclusively. Estrogen receptors could not be detected in both the normal tissue and hyperplasic foci. The morphological, ultrastructural, and immunohistochemical characteristics strongly suggest that these hyperplastic lesions originated from the intercalated ducts. The rodent-specific granular duct cell was not involved in the pathogenesis as was clearly demonstrated by the lack of immunoreactive epidermal growth factor within the lesions. Lesions were not observed in studies with progestagens and estrogens alone or with other combined estrogen/progestagen compounds, suggesting that the specific ratio of estrogenic and progestagenic activity of the present steroid had played an important role in the development of ductal hyperplasia in this study. Lesions of the intercalated ducts, as described in this study, have not been reported before in the literature.

Key Words: Rat • submandibular salivary gland • hyperplasia • intercalated duct • progestagen • estrogen • histopathology • immunohistochemistry • electron microscopy.

Toxicologic Pathology, Vol. 31, No. 1, 1-9 (2003)
DOI: 10.1080/01926230390173798


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