Non-aromatase related estrogenic effects from androgen use
In the past we've been pretty uniform about estrogen. Despite theories flying around about progestins, prolactin and what have you not, none showed evidence of having an effect on the development of gyno in the absence of estrogen. Therefor, the use of an anti-estrogen was sufficient to treat problems of this kind.
Gyno is a fairly infrequent problem on proper cycles, and of the number that did have problems a very few people reported it when non estrogenic drugs were used. Of those we need to take into account a lot of them probably couldn't recognize gyno and were overreacting.
Nonetheless, reports of this nature have been around for a long time and continue to persist, begging us to ask the question over and over if there is a factor we are overlooking. Here I would like to present two.
Case number 1 : The appearance of estrogenic effects with testosterone in aromatase negative mice (Ishikawa et al, 2005). This study reported the presence of estrogenic effects in the absence of aromatization, and this effect was blocked by a 5-alpha-reductase inhibitor. Meaning a metabolite of DHT is acting as an androgen. Since we already know that saturated A-ring steroids with a 3-hydroxyl group act as estrogens since 5AD is a every potent estrogen, the likely culprits include the neuroactive steroids 3alpha and 3beta androstanediol. Steckelbroeck et al (2004) demonstrated that 5beta-androstanediol is indeed and ER ligand. Now your question will likely be what the relevance of this is to gyno. Its likely less active than estrogens themselves. This is true, but estrogens are produced by aromatase and dumped into circulation and have to make their way to mammary tissue. Mammary tissue itself contains no aromatase (
http://www.ncbi.nlm.nih.gov/UniGene...glist=Hs.511367). 3beta-androstanediol is produced by AKR1C, and this gene is expressed directly in mammary tissue, leading to direct local conversion if DHT is present in the tissue. 5AR is also present in mammary tissue. This means despite weaker activity, the presence of the product in the tissue is likely higher.
Not only can effects of this nature not be blocked by aromatase inhibitors, they are likely worsened by aromatase inhibitors, which would increase the substrate for 5AR. This also opens the door for ER binding of 3beta derivatives of other A-ring saturated androgens. They can be treated with SERMS.
Another important issue pointed out in that study is that unlike the 3-alpha isomer, 3-beta hydroxyl are NOT converted back to DHT.
CASE 2 : the binding of Androgen receptor to estrogen response elements induced by certain ligands. I won't go into detail on this too much as I know I adressed this before. For nandrolone it has been demonstrated that it can bind the AR and cause the AR to activate estrogen-responsive genes. Nandrolone is 60% as estrogenic as estradiol itself and Aromatase inhibitors and ER-blockers and RU486 did not significantly change that number, showing that nandrolone's strong estrogenic effects are caused entirely by the androgen receptor.
Natural nandrolone is a by-product of aromatisation. Likely other 19-Nor-3-oxo steroids are capable of inducing a similar change, to a different extent.
This effect, which is androgen receptor mediated, cannot be blocked by either aromatase or SERMS.