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

Synthetic androgens exhibit estrogenic/antiestrogenic and progestational ac tivities in addition to their androgenic effects. To investigate the pharma cological action of the synthetic androgen, 7 alpha-methyl-19-nortestostero ne (MENT), we examined its action in female rodents. The criteria employed for estrogenic/antiestrogenic effects were, uterine weight increase, vagina l cornification, induction of progesterone receptors (PR) synthesis and sti mulation of peroxidase activity in the uteri of ovariectomized rats and mic e. MENT increased uterine weight in a dose dependent manner, but did not ca use vaginal cornification or stimulate PR synthesis in the uterus. The uter otropic activity of MENT was 200-fold lower than that of estradiol. Estroge n receptor (ER) bound [H-3]-E-2 was displaced by E-2 and MENT with ED50 val ues of 70 pg and 250 ng, respectively, a 3,500 fold difference in their bin ding affinity. The low binding of MENT to ER, in contrast to its relatively high uterotropic action, suggested that receptors other than ER may be inv olved in its action on the uterus. The progestational activity of MENT in i mmature rabbits using the McPhail index assay was comparable to that of pro gesterone. Binding affinities of MENT and progesterone to PR were also comp arable. However, the action of MENT on the uterus does not seem to be a pro gestational effect since mifepristone, an antiprogestin, had no effect on M ENT-induced uterine growth. Specific androgen receptors (AR) in uterine cyt osol were demonstrated. The involvement of AR in MENT action was confirmed by using an antiandrogen (flutamide) and an antiestrogen (ICI-182) in ovari ectomized 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 ova riectomized rats. The antiestrogenic effect of MENT was also blocked by flu tamide. These results suggest that the uterotropic and antiestrogenic effec ts of androgens are mediated via AR. It is concluded that the increase in u terine weight caused by MENT is attributable to its anabolic effects. (C) 1 998 Elsevier Science Ltd. All rights reserved.