Aromatase inhibitors and their potential clinical significance.

Estrogen biosynthesis occurs not only in reproductive tissues of the female but also in such diverse sites as testes, adipose and muscle. Our rationale for the clinical use of aromatase inhibitors is that compounds interacting with aromatase in all tissues could provide both selective and effective inhibition of estrogen production. The most potent inhibitor identified by us to date is 4-hydroxyandrostene-3,17-dione (4-OHA). This compound causes rapid competitive inhibition followed by irreversible inactivation of aromatase. Treatment of rats with 4-OHA results in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen induced mammary tumors. Using rhesus monkeys, marked inhibition of peripheral aromatization by 4-OHA was also demonstrated. The first clinical study with a selective aromatase inhibitor was recently carried out using once weekly injections of 500 mg 4-OHA in 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors. The mean serum estradiol level reduced to 36% of pretreatment values for at least 4 months. No effect of treatment on gonadotropin levels occurred indicating that the reduction in estrogen levels was due to inhibition of peripheral aromatization. In spite of the fact that all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. Although the optimum dose of 4-OHA has not yet been established, this aromatase inhibitor appears to be of value in treating postmenopausal breast cancer and may be beneficial in other diseases associated with estrogens.