Clomid is the anti-estrogen of choice for improving recovery of natural testosterone production after a cycle, improving testosterone production of endurance athletes, and is also effective in reducing risk of gynecomastia during a cycle employing aromatizable steroids.
While it has been claimed that Clomid “stimulates” production of luteinizing hormone (LH) and therefore of testosterone, in fact Clomid’s activity is achieved not by stimulation of the hypothalamus and pituitary, but by blocking their inhibition by estrogen.
Clomid is a mixed estrogen agonist/antagonist (activator/blocker) which, when bound to the estrogen receptor, puts it in a somewhat different conformation (shape) than does estradiol. The estrogen receptor requires binding of an estrogen or drug at its binding site and also the binding of any of several cofactors at different sites. Without the binding of the cofactor, the estrogen receptor is inactive. Different tissues use different cofactors. Some of these cofactors are able to bind to the estrogen receptor/Clomid complex, but others are blocked due to the change in shape. The result is that in some tissues Clomid acts as an antagonist — the cofactor used in that tissue cannot bind and so the receptor remains inactive — and in others Clomid acts as an agonist (activator), because the cofactors used in that tissue are able to bind.
Clomid is more precisely referred to as a “selective estrogen receptor modulator.” This is because its mode of action is not so simple as merely blocking the estrogen receptor. Estrogen receptors require not only hormone but also activation of regions of the receptor called AF-1 and AF-2. AF-1, to be activated, requires phosphorylation, while AF-2 can be activated by any of a number of cofactors, such as IGF-1.