Anti-Estrogens

What Are Anti-Estrogens?

Anti-Estrogens are a class of compounds that, as their name implies, counteracts Estrogen and estrogenic activity in the body. Anti-Estrogens can be either naturally occurring (such as extracts from plants or herbs) or synthetic (synthesized in a laboratory), and is comprised of two sub-classes: aromatase inhibitors and selective Estrogen receptor modulators (SERMs). AIs and SERMs are the cornerstones of the Estrogen concern when it comes to anabolic steroid use, as they are used to mitigate and control Estrogen when and if it becomes a concern, as well as their use as hormonal recovery compounds in men, and are in this case used after the end of an anabolic steroid cycle during post cycle therapy (PCT) in order to restore endogenous Testosterone production. It is useful knowledge that almost all anti-Estrogens developed and marketed were intended for the treatment of Estrogen responsive breast cancers in females, though over time some of these anti-Estrogens found viable use in men where conditions such as hypogonadism is concerned.

SERMs and AIs are two very different types of anti-Estrogens in the manner by which they tackle the Estrogen problems. There is usually a significant amount of confusion (especially among beginners to anabolic steroid use) over the difference between the two. Superficially, AIs serve to lower total circulating blood plasma levels of Estrogen in the body. SERMs serve to block the activity of Estrogen in specific tissues of the body. Specific mechanisms of action will be explained shortly.

Aromatase Inhibitors (AIs)

Aromatase inhibitors include the following compounds: Arimidex (Anastrozole), Femara (Letrozole), Aromasin (Exemestane), which are the three primary and most popular aromatase inhibitors. There exist plenty of other aromatase inhibitors, ranging from synthetic to naturally occurring compounds, but the previous three remain as the most popular and most effective aromatase inhibitors that are used medically. Aromatase inhibitors are anti-e’s that operate by inhibiting the aromatase enzyme, which is the enzyme responsible for the conversion of androgens into estrogens.

Enzymes all contain a site known as the substrate binding site, which is where the substrate (the enzyme’s target molecule) will bind to in order for a chemical reaction to occur. In the case of aromatase, Testosterone (or any aromatizable anabolic steroid) is the substrate for aromatase. Inhibition can be achieved through two methods: allosteric inhibition and competitive inhibition. In allosteric inhibition, the aromatase inhibitor (in this case, aromatase) binds to the allosteric site on the enzyme, which causes the substrate binding site to alter its shape as such that the substrate cannot successfully bind to it. Competitive inhibition is achieved by way of the aromatase inhibitor binding to the substrate binding site, and in effect occupies the site so that the real substrate cannot bind to the enzyme.

Furthermore, there are two types of inhibition: reversible and irreversible (also known as suicide) inhibition. Though the terms irreversible and suicide might convey a concern, as these terms merely to the activity of the inhibitor. Aromasin (Exemestane) is a suicidal (irreversible) inhibitor, meaning that once bound to the aromatase enzyme, it does not leave and the enzyme remains permanently disabled. Eventually the body will manufacture more aromatase enzymes to replace (hence the term ‘suicidal’ refers to the suicidal nature in permanent inhibition). Reversible inhibitors include Arimidex (Anastrozole) and Femara (Letrozole), which bind to and inhibit the aromatase enzyme, but eventually dissociate from the enzyme, leaving the enzyme free to aromatize androgens. Coincidentally, Aromasin is a steroidal aromatase inhibitor, while Letrozole and Arimidex are not. Because AIs disable the root source of Estrogen production in the body, they are anti-Estrogens that can and do reduce circulating blood plasma levels of Estrogen in the body.

Selective Estrogen Receptor Modulators (SERMs)

SERMs are a large group of anti-Estrogens that include the following: Nolvadex (Tamoxifen Citrate), Clomiphene Citrate (Clomid), Raloxifene, and Toremifene and SERMs are the oldest anti-Estrogen drugs used in medicine. Aromatase inhibitors are a much more modern and recent discovery, though some SERMs are fairly recent (such as Toremifene and Raloxifene) while others have existed and been used for almost 50 years (such as Nolvadex). SERMs selectively modulate the Estrogen receptor sites located throughout various tissues in the body. Interestingly enough, although SERMs are classified as anti-Estrogens, these compounds have both agonistic as well as antagonistic activity at the Estrogen receptor in different tissues and areas of the body[1]. Many SERMs will actually bind to the Estrogen receptors located in the liver and increase estrogenic activity there (acting as receptor agonists in this case), whilst at the same time the same SERMs will have antagonistic activity in other receptor sites (such as the hypothalamus gland and breast tissue), and decrease estrogenic activity in these locations.

Within those tissues where the SERM acts as an Estrogen antagonist, such as the hypothalamus and breast tissue, the SERM will bind to the Estrogen receptor and remain inert. Circulating Estrogen will be unable to bind to the Estrogen receptor, as it is occupied by the SERM. At the site of breast tissue, this results in the prevention (and possibly the decrease) of gynecomastia where Estrogen is the culprit. At the hypothalamus gland, GnRH release is achieved and ultimately results in increased Testosterone production as a result of the augmentation of the negative feedback loop in acting as an Estrogen antagonist at the pituitary gland[2].

SERMs are anti-Estrogens that do not reduce circulating blood plasma levels of Estrogen, but instead work to block the Estrogenic activity in select tissues. Hence, this is the reason as to why SERMs will not reduce various Estrogen-related side effects such as bloating and water retention.

 


References:

[1] Riggs BL, Hartmann LC (2003). “Selective estrogen-receptor modulators — mechanisms of action and application to clinical practice”. N Engl J Med 348 (7): 618–29. doi:10.1056/NEJMc030651. PMID 12584371.

[2] Vermeulen A, Comhaire F. Fertil Steril. Hormonal effects of an antiestrogen, tamoxifen, in normal and oligospermic men. 1978 Mar;29(3):320-7.