Estrogenic and progestational activity of 7 α-methyl-19-nortestosterone, a synthetic androgen

Abstract

Synthetic androgens exhibit estrogenic/antiestrogenic and progestational activities in addition to their androgenic effects. To investigate the pharmacological action of the synthetic androgen, 7 α-methyl-19-nortestosterone (MENT), we examined its action in female rodents. The criteria employed for estrogenic/antiestrogenic effects were, uterine weight increase, vaginal cornification, induction of progesterone receptors (PR) synthesis and stimulation of peroxidase activity in the uteri of ovariectomized rats and mice. MENT increased uterine weight in a dose dependent manner, but did not cause vaginal cornification or stimulate PR synthesis in the uterus. The uterotropic activity of MENT was 200-fold lower than that of estradiol. Estrogen receptor (ER) bound [ 3H]-E 2 was displaced by E 2 and MENT with ED 50 values of 70 pg and 250 ng, respectively, a 3,500 fold difference in their binding affinity. The low binding of MENT to ER, in contrast to its relatively high uterotropic action, suggested that receptors other than ER may be involved in its action on the uterus. The progestational activity of MENT in immature rabbits using the McPhail index assay was comparable to that of progesterone. Binding affinities of MENT and progesterone to PR were also comparable. However, the action of MENT on the uterus does not seem to be a progestational effect since mifepristone, an antiprogestin, had no effect on MENT-induced uterine growth. Specific androgen receptors (AR) in uterine cytosol were demonstrated. The involvement of AR in MENT action was confirmed by using an antiandrogen (flutamide) and an antiestrogen (ICI-182) in ovariectomized mice. Although MENT did not block the uterotropic effect of E 2, it inhibited the E 2-induced cornification of vaginal epithelium, induction of uterine PR synthesis and increase in uterine peroxidase activity in ovariectomized rats. The antiestrogenic effect of MENT was also blocked by flutamide. These results suggest that the uterotropic and antiestrogenic effects of androgens are mediated via AR. It is concluded that the increase in uterine weight caused by MENT is attributable to its anabolic effects.