EFFECT OF CGS-20267 ON OVARIAN AROMATASE AND GONADOTROPIN-LEVELS IN THE RAT

Aromatase catalyzes the rate limiting step that converts androgens to estrogens. Postmenopausal women with hormone dependent breast cancer r espond to first generation aromatase inhibitors such as aminoglutethim ide with a marked suppression of circulating estradiol levels. In cont rast, premenopausal women appear to be resistant to first generation a romatase inhibitors. The inability to block ovarian aromatase results from the low affinity of first generation inhibitors for the active si te of the enzyme. Under these circumstances, the high substrate levels in the premenopausal ovary compete effectively with these inhibitors and do not allow binding of inhibitor to the active site of the enzyme . Second and third generation aromatase inhibitors with higher affinit y for aromatase have now been developed and potentially could block ov arian aromatase. To test this possibility, we administered CGS 20267 ( letrozole), a highly potent aromatase inhibitor, to cycling female rat s. A dose dependent inhibition of uterine weight occurred with maximum effects produced by the 5 mg/kg/day dosage. During a period of 4 week s, uterine weight was reduced to levels induced by ovariectomy. Ovaria n tissue estradiol levels were inhibited by approximately 80%. As a re flection of inhibition of ovarian aromatase activity, the levels of an drostenedione in the ovary increased by an order of magnitude. Both LH and FSH plasma levels increased but not to those observed after ovari ectomy. The rise in gonadotropin levels induced a statistically signif icant but relatively small increase in ovarian weights. These results demonstrate the ability to persistently block ovarian aromatase activi ty in cycling rats with a potent aromatase inhibitor. This study provi des a rationale for clinical trials of potent aromatase inhibitors in pre-menopausal women with breast cancer.