The role of spironolactone in the aetiology of gynaecomastia was examined in terms of its ability to bind to the oestrogen receptor in cytosol, to cause specific oestrogenic effects in the absence of endogenous oestrogen and to be antioestrogenic in the presence of oestradiol. Tamoxifen, a non-steroidal antioestrogen, was chosen as an internal standard for comparison.
Spironolactone and tamoxifen competitively inhibited the binding of oestradiol-17β to its receptor in uterine and mammary cytosol, with inhibition constants of 2 × 10−5 and 1 × 10−7 respectively.
To measure oestrogenic or antioestrogenic effects of the drugs five indices believed to be specific markers for oestrogen action were studied: uterine to body weight ratio, uterine protein content, oestradiol 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 five indices of oestrogen agonistic activity. The oestrogenantagonistic properties of the drug were evaluated by comparing the oestradiol-injected group (5 μg) to the oestradiol + 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 oestrogen and as an antioestrogen.
The antioestrogenic 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. These results suggest that spironolactone-induced gynaecomastia may be modulated by its action at both the oestrogen and dihydrotestosterone receptor in cytosol.