AROMATASE INHIBITORS AND THEIR USE IN CONTROLLING ESTROGEN-DEPENDENT PROCESSES

The goal of this work is to develop potent in vivo inhibitors to the aromatase (oestrogen synthetase) enzyme system and to evaluate them for controlling oestrogen-dependent processes. To date, the most potent compounds in vitro are 4-hydroxy-4-androstene-3,17-dione (4-OH-A), 4-acetoxy-4-androstene-3, 17-dione (4-acetoxy-A) and 1,4,6-androstatriene-3,17-dione (ATD). In antifertility studies, rats were treated from dioestrus 1 of the cycle with aromatase inhibitors. The oestrogen surge and subsequent LH surge normally occurring during pro-oestrus were inhibited and mating and ovulation prevented. These effects were counteracted when oestradiol was administered concomitantly with aromatase inhibitors. The compounds also retarded implantation, an oestrogen-dependent process in the rat, and ovarian oestradiol secretion was reduced on day 4 of pregnancy. In contrast, hamsters do not require oestrogen for implantation and aromatase inhibitors were without effect. The compounds were also highly effective in causing regression of dimethylbenzanthracene-induced, hormone-dependent, mammary tumours of the rat. Ovarian oestrogen secretion measured at the end of treatment with 4-acetoxy-A was reduced compared with controls, and when supplemental oestradiol was given, together with aromatase inhibitors, tumour regression was prevented. Our studies indicate that aromatase inhibitors act in vivo to reduce oestrogen production by aromatase inhibition. They thus have potential for treating oestrogen related disorders, for fertility control and as tools for investigating the role of oestrogen in physiological and pathological processes. © 1979.