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Lack of Evidence for Aromatase in Human Prostatic Tissues: Effects of 4-Hydroxyandrostenedione and Other Inhibitors on Androgen Metabolism¹

Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland 21201

The effects of 4-hydroxyandrostenedione (4-OHA) and other aromatase inhibitors, 10-propargylestr-4-ene-3,17-dione and imidazo[1,5-]-3,4,5,6-tetrahydropyrin-6-yl-(4-benzonitrile), as well as 5-reductase inhibitors N,N-diethyl-4-methyl-3-oxo-4-aza-5-androstane-17ß-carboxyamide and 4-methyl-3-oxo-4-aza-androsta-5-ene-17-ol were investigated in prostatic tissue from six patients with benign prostatic hypertrophy and seven patients with prostatic cancer, and from normal men at autopsy. We attempted to measure aromatase activity in the tissue incubations by quantitating ³H₂O released from androstenedione or testosterone labeled at the C-1 position. High performance liquid chromatography and thin layer chromatography were used to isolate steroid products. Although the amount of ³H₂O released was at least twice that of the heat-inactivated tissue samples, no estrone or estradiol was detected on high performance liquid chromatography. The ³H₂O release was significantly inhibited by 4-OHA and N,N-diethyl-4-methyl-3-oxo-4-aza-5-androstane-17ß-carboxyamide, but not by the other aromatase inhibitors. 4-OHA also inhibited 5-reductase in both benign prostatic hypertrophy and cancer tissue, although to a lesser extent than N,N-diethyl-4-methyl-3-oxo-4-aza-5-androstane-17ß-carboxyamide. The other aromatase inhibitors were without effect on 5-reductase. Our results indicate that ³H₂O released from [1ß-³H]androstenedione and [1,2,6,7-³H]androstenedione does not correlate with estrogen formation and may be the result of other metabolic reactions. Although it appears that the prostate lacks aromatase, 4-OHA may be of benefit in patients with benign prostatic hypertrophy or prostatic cancer by inhibiting this enzyme in peripheral tissue.

¹ Supported by NIH grant CA-27440. Presented in part at the 8th International Congress of Endocrinology, Kyoto, Japan, 1988, and the American Association for Cancer Research, New Orleans, Louisiana, 1988.

² To whom requests for reprints should be addressed, at Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, 655 W. Baltimore St., Baltimore, MD 21201.

Received 3/27/89. Revised 8/ 7/89. Accepted 8/14/89.

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