A neat little study, and in-vivo at that, which demonstrates that DHT is a direct estrogen receptor (ER) antagonist. According to the study, so are testosterone, nandrolone and a few other steroids with demonstrated therapeutic effects on ER-positive breast cancer (BC). However, all of the other steroids mentioned by the study are aromatizable and as such suboptimal as anti-estrogens compared to DHT. This is probably one of the reasons that back in the 1960s when synthetic steroids for treatment of BC were first developed, only DHT derivatives such as Proviron and Masteron eventually made it to clinical trials and got approval for this condition. None of the aromatizable synthetic androgens (or testosterone for that matter) made it through the clinical trials despite being much more widely used (experimentally) for BC at the time. When we also consider the fact that DHT (and other 5-AR derives steroids) are also aromatase inhibitors, it becomes clear that DHT is right up there with progesterone in terms of importance for estrogen antagonism, and perhaps the main anti-estrogen in males. Another interesting finding of the study was that the anti-estrogenic effects of DHT were independent from its role as an androgen agonist. However, androgen agonists are well-known known to have anti-estrogenic effects of their own, so the effectiveness of DHT as an anti-estrogen is actually amplified by its role as a strong androgen. Finally, the study provide some information on what a physiological dose of DHT would be, which is subject to much debate in the literature and in the blogosphere. As the study states, healthy males produce about 45 mcg estrogen daily and DHT amounts need to be about 50 times higher in order to fully block the effects of a given amount of estrogen. This means that a daily physiological dose is about 2mg for healthy adult males, and that dose may need to be increased with increasing age or pathological conditions resulting in elevated estrogens such as liver disease, diabetes, prostate cancer, etc.
“…Estrogen treatment to such mice stimulates breast growth and as in other species increases the amount of progesterone receptor in the breast. Both effects of estradiol can be inhibited by dihydrotestosterone. We concluded that this might be an adequate model system for investigating the mechanism of the antiestrogenic action of androgen, and we designed experiments to assess two mechanisms that have been proposed for this action, namely that androgen acts at the genomic level via its own receptor to block estrogen action or that androgen acts as a pharmacological antagonist and/or weak estrogen agonist by competing with estradiol for the estrogen receptor. The findings in these experiments favor the latter possibility. Indeed, the fact that dihydrotestosterone was equally effective in blocking estrogen effects in tfm/Y and control mice suggests that this action of androgen is not mediated by the androgen receptor. If this interpretation is correct, then this effect of androgen is different than the antiestrogenic effect of the hormone in the embryonic mouse breast (11) and in the uterus (12). Dihydrotestosterone binds weakly to the estrogen receptor in mouse breast and like some other antiestrogens appears to anchor the estrogen-receptor in the nucleus of the cell. These effects have only been studied with pharmacological amounts of hormone, but the fact that the relative binding affinities of dihydrotestosterone, 313-androstanediol, testosterone, and Sfdihydrotestosterone correlate with their capacities to inhibit induction of the progesterone receptor is in keeping with the finding in MCF7 tumor cells (10) that androgens bind to the estrogen receptor. Unlike the situation in MCF7 cells, however, we were unable to demonstrate any estrogen-like effects of dihydrotestosterone on the mouse breast.”
“…If androgen prevents the development of gynecomastia in normal men by acting as a direct antiestrogen at the level of the estrogen receptor, this is the first androgen action recognized that is not mediated by the androgen receptor.”
“…Normal men produce ~45 mcg of estradiol each day, a sixth of which is secreted by the testes and the remainder of which is derived from the extraglandular aromatization of circulating androgens (1). Extraglandular estradiol formation takes place by two mechanisms, one from the direct conversion of testosterone to estradiol and the other from androgens of adrenal origin by the sequence of androstenedione – estrone – estradiol. The function of estradiol in normal men is unknown, but feminization, commonly manifested by gynecomastia, ensues under conditions of relative or absolute estrogen excess (2)….By this estimate estradiol binds to the estrogen receptor with an affinity that is approximately fifty times greater than that of dihydrotestosterone.”