Noble first demonstrated that testosterone is carcinogenic for the rat prostate, and he established that sequential treatment with testosterone and estrogens was even more effective than testosterone per se. Noble used the Noble (or NBL) rat strain which he developed . Long-term treatment of NBL rats with a combination of testosterone and 17^-estradiol leads to a high incidence of adenocarcinomas, that develop from the periurethral ducts of the dorsolateral and anterior prostate [205-207]. The development of these tumors is preceded by the appearance of epithelial dysplasia in these ducts and in the acini of the dor-solateral prostate [206-208]. Carcinomas developing from the acinar dysplasia in the periphery of the prostate gland have not been reported, and the malignant potential of these lesions, which are morphologically similar to human prostatic intraepithelial neoplasia (PIN), is not certain [206,207]. Treatment of NBL rats with diethylstilbestrol (DES) combined with testosterone resulted in wide spread dysplasia in the ventral prostate but less dysplasia in the dorsolat-eral prostate . Long-term treatment of NBL rats with DES and testosterone induced a low carcinoma incidence in the dorsolateral prostate and some early-stage carcinomas in the ventral lobe . In summary, the addition of estrogen to testosterone treatment of NBL rats markedly increases the incidence of prostate cancer from 35-40% to 100%.
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