Neonatal Coadministration of Testosterone With Diethylstilbestrol Prevents Diethylstilbestrol Induction of Most Reproductive Tract Abnormalities in Male Rats

Authors

  • Ana Rivas,

    1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom
    2. Laboratory of Medical Investigations, Department of Radiology, School of Medicine, HUSC-University of Granada, Granada, Spain
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  • Chris McKinnell,

    1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom
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  • Jane S. Fisher,

    1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom
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  • Nina Atanassova,

    1. Institute of Experimental Morphology & Anthropology, Bulgarian Academy of Science, Sofia, Bulgaria.
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  • Karin Williams,

    1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom
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  • Richard M. Sharpe

    Corresponding author
    1. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom
      MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Chancellor's Building, The University of Edinburgh, 49 Little France Crescent, Old Dalkeith Rd, Edinburgh EH16 4SB, United Kingdom (e-mail: r.sharpe@hrsu.mrc.ac.uk).
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MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, Chancellor's Building, The University of Edinburgh, 49 Little France Crescent, Old Dalkeith Rd, Edinburgh EH16 4SB, United Kingdom (e-mail: r.sharpe@hrsu.mrc.ac.uk).

Abstract

ABSTRACT: The primary purpose of this study was to evaluate whether the coadministration of testosterone (TE; 200 μg) with 10 μg of diethylstilbestrol (DES) between days 2 and 12 postnatally could prevent the adverse gross reproductive tract changes and associated loss of androgen receptor (AR) expression induced by DES treatment alone. Various endpoints (rete testis area, efferent duct lumen area, epithelial cell height of efferent ducts, and vas deferens) were quantified to check for the abnormal changes that have been shown to occur after neonatal treatment with a high dose (10 μg) of DES. Additionally, DES induction of an aberrant pattern of estrogen receptor alpha (ER-α) immunoexpression in the vas deferens and seminal vesicles was evaluated. The coadministration of DES with TE prevented the induction of all but one of the abnormalities induced by DES treatment on its own, coincident with the restoration of normal/supranormal TE levels and normal immunoexpression of the AR and ER-α in the tissues studied. The exception was DES-induced lumenal distension of the efferent ducts, which was only partially prevented by the coadministration of DES with TE. These evaluations were made on day 18, but the described abnormalities were already somewhat evident by day 8 in DES-treated animals. It was therefore tested whether a delay of TE replacement until days 8–12 was still able to reverse the abnormalities already induced by DES treatment alone. A delayed treatment with TE reversed the adverse changes in epithelial cell height and in ER-α and AR immunoexpression in the same tissues by day 18; however, rete testis overgrowth was only partially prevented, and efferent duct distension was not prevented at all. These results provide further evidence that DES-induced disorders of reproductive tract development in the male result from a disturbance of the androgen-estrogen balance rather than from estrogen action alone.

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