Interaction of spironolactone with oestradiol receptors in cytosol

The role of spironolactone in the etiology of gynecomastia was examined in terms of its ability to bind to the estrogen receptor in cytosol, to cause specific estrogenic effects in the absence of endogenous estrogen and to be antiestrogenic in the presence of estradiol. Tamoxifen, a non-steroidal antiestrogen, was chosen as an internal standard for comparison. Spironolactone and tamoxifen competitively inhibited the binding of estradiol-17β to its receptor in uterine and mammary cytosol, with inhibition constants of 2 x 10^-5 and 1 x 10^-7 mol/l respectively. To measure estrogenic or antiestrogenic effects of the drugs 5 indices believed to be specific markers for estrogen action were studied: uterine to body weight ratio, uterine protein content, estradiol receptor in cytosol, progesterone receptor in cytosol and uterine peroxidase activity. Spironolactone, when administered for 3 successive days (40 μg/day) to immature female rats, increased all of the 5 indices of estrogen agonistic activity. The estrogen-antagonistic properties of the drug were evaluated by comparing the estradiol-injected group (5 μg) to the estradiol + spironolactone-injected group. A decrease was noted in all indices measured except for progesterone receptors in cytosol. Spironolactone appeared to be very similar to tamoxifen in its action both as an estrogen and as an antiestrogen. The antiestrogenic effect of spironolactone cannot be explained by previously proposed mechanisms of action for the drug such as decreased synthesis of testosterone or inhibition of dihydrotestosterone binding to its receptor. The results suggest that spironolactone-induced gynecomastia may be modulated by its action at both the estrogen and dihydrotestosterone receptor in cytosol.