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Effect of 4-Hydroxyandrostenedione on Murine Leydig Tumor Cell Steroidogenesis¹

Reproductive Sciences and Endocrinology Laboratories [S. J. Z., M. E. B., M. H. M., D. P.], Departments of Biochemistry and Molecular Biology [S. J. Z., M. E. B., M. H. M., D. P.], Medicine [D. P.], and Obstetrics and Gynecology [S. J. Z., M. H. M., D. P.], University of Miami School of Medicine, Miami, Florida 33101, and Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201 [A. M. H. B.]

The murine Leydig cell tumor (M5480A) possesses high levels of estrogen receptor and is known to produce estrogens. In these studies we examined the effects of the potent aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) on Leydig tumor cell steroidogenesis both in vitro and in vivo. The addition of 4-OHA to Leydig tumor cells in primary culture resulted in a dose- and a time-dependent decrease in media progesterone levels. The observed decrease was most likely due to impaired synthesis of progesterone, inasmuch as no alteration in progesterone metabolism was seen when progesterone levels were diminishing. However, 4-OHA inhibited progesterone conversion to testosterone following 1 h of incubation, but this effect disappeared coincident with 4-OHA metabolism. Analysis of pregnenolone production revealed a biphasic dose-dependent effect of 4-OHA. At low doses (0.01–0.1 µM), 4-OHA was found to decrease pregnenolone concentrations, while at higher doses (1–10 µM) pregnenolone levels were elevated. Therefore, the actions of 4-OHA on Leydig cell steroidogenesis in vitro appear to be multifocal. Other experiments were performed to evaluate the effects of 4-OHA on tumor-bearing male mice in vivo. In these studies, the predominant effects of 4-OHA were to act as an aromatase inhibitor and to inhibit progesterone production. Thus, while 4-OHA is a potent aromatase inhibitor, we have found that this compound may alter steroidogenesis in Leydig tumor cells at several sites prior to aromatization.

¹ Supported by NIH Research Grants DK33973 and CA43226.

² Present address: The Women's Research Institute, Department of Obstetrics and Gynecology, University of Kansas School of Medicine, 2900 E. Central, Wichita, KS 67214. To whom requests for reprints should be addressed.

³ Present address: Department of Physiology and Biophysics, University of California, Irvine, CA 92717.

⁴ Present address: Oregon Regional Primate Research Center, Beaverton, OR 97006.

Received 11/12/90. Accepted 4/30/91.