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Inhibition of Aromatase With CGS 16949A in Postmenopausal Women^*

Departments of Medicine and Pathology, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey Pennsylvania 17033
the Department of Clinical Chemistry, University of Helsinki, Meilahati Hospital 00290 Helsinki, Finland

Address requests for reprints to: Dr. R. J. Santen, Department of Medicine, Milton S.Hershey Medical Center, Pennsylvania State University, P.O. Box 850, Hershey, Pennsylvania 17033.

Potent, specific, and nontoxic inhibitors of aromatase would be useful for experimental studies and for use in the treatment of breast cancer and other disorders. We evaluatedthe effects of CGS 16949A, a nonsteroidal inhibitor of aromatase activity, in 12 postmenopausal women with breast cancer by measuring plasma and/or urinary androgens and estrogens after oral administration of CGS 16949A at doses ranging from 0.6– 16 mg daily; each dose was given for 2 weeks. The 0.6-mg daily dose partially lowered estrogen levels, and maximum reduction occurred at doses of 2–16 mg daily. The fall in plasma and urinary estrogens without a concomitant fall in plasma androgens confirmed the blockade of aromatase activity. The degree of estrogen reduction was greatest for urinary estrone [to 27 ± 3± (±SE) of basal], followed in order by plasma estrone sulfate (30 ± 4%), plasma estrone (32 ± 6%), urine estradiol (45 ± 5%), andplasma estradiol (65 ± 5%). Use of gas liquid chromatography- mass spectrometry techniques revealed similar patterns of reduction in catechol estrogens, estriol, and total urinary estrogens,estrogens, suggesting that CGS 16949A does not alter the pathways of estrogen metabolism. The degree of estrogen reduction was remarkably similar to that caused with aminoglutethimide. At doses of 4–16 mg daily, CGS 16949A inhibited the C₂₁-hydroxylase enzyme as well, based on concomitant rises in plasma androstenedione, testosterone, and 17-hydroxyprogesterone. This effect was insufficient to lower urinary cortisol excretion during the study. However, a statistically significant blunting of plasma cortisol responsesto ACTH occurred with the 16-mg daily dose. No changes in plasma dehydroepiandrosterone sulfate levels or in thyroid, hematological, liver, or renal parameters were found. No significant side-effects of the medication were encountered.

CGS 16949A appears to be a specific inhibitor of aromatase at doses below 4 mg daily and tolack apparent side-effects or toxic actions at doses up to 16 mg daily. This agent showspromise as a potent aromatase inhibitor for physiological and clinical studies.

^* This work was supported by the Ciba-Geigy Corp. (Summit, NJ).

Received April 25, 1988.

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