What are anti-estrogens?
As the name suggests, anti-estrogens are a class of compounds that counteract estrogen and estrogenic activity in the body.
Anti-estrogens can be naturally occurring (such as plant or herbal extracts) or synthesized (created in a laboratory), and are organized into two sub-families: aromatase inhibitors and selective estrogen receptor modulators (SERMs).
Aromatase inhibitors and SERMs are used to mitigate and control estrogen where estrogen is a concern, as well as as hormone restoration compounds in men, in this case after the end of an anabolic steroid cycle during post cycle therapy (PCT) to restore endogenous testosterone production.
Over time, it has been found that some of these anti-estrogens can also be used in men with conditions such as hypogonadism, but it is useful to know that almost all anti-estrogens developed and marketed are designed to treat estrogen-responsive breast cancer in women.
SERMs and AIs are two types of anti-estrogens that are very different in the way they address estrogen issues.
In general, there is considerable confusion (especially among beginners to anabolic steroid use) about the differences between the two.
On the surface, AIs work by lowering the total circulating plasma levels of estrogen in the body.
SERMs work by blocking the activity of estrogen in specific tissues in the body.
The specific mechanisms of action will be discussed later.
Aromatase inhibitors (AIs)
Aromatase inhibitors include the following compounds Arimidex (Anastrozole), Femara (Letrozole), and Aromasin (Exemestane) are the three most widely used aromatase inhibitors.
While a variety of aromatase inhibitors exist, ranging from synthetic to naturally occurring compounds, the first three remain the most popular and most effective aromatase inhibitors medically.
Aromatase inhibitors are anti-estrogenic drugs that work by inhibiting the aromatase enzyme, the enzyme that converts androgens into estrogen.
Every enzyme has a substrate binding site, which is the site where the substrate (the enzyme's target molecule) binds in order for a chemical reaction to occur.
In the case of aromatase, testosterone (or any aromatizable anabolic steroid) is the substrate for aromatase.
Aromatase inhibition can be achieved through two methods: allosteric inhibition and competitive inhibition.
In allosteric inhibition, an aromatase inhibitor (in this case, aromatase) binds to the allosteric site of the enzyme, changing the shape of the substrate binding site so that the substrate cannot bind successfully.
Competitive inhibition is achieved by an aromatase inhibitor binding to the substrate binding site, effectively occupying the site so that the substrate cannot bind to the enzyme.
There are also two types of inhibition: reversible inhibition and irreversible inhibition (also known as suicidal inhibition).
While the terms irreversible and suicidal may raise concerns, these terms only refer to the activity of the inhibitor.
Aromasin (exemestane) is a suicidal (irreversible) inhibitor, meaning that once it binds to the aromatase enzyme, it doesn't come off and the enzyme remains permanently inactive.
Eventually, the body will produce more of the aromatase enzyme to replace it (hence the term 'suicidal', which refers to the suicidal nature of 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 it free to aromatize androgens.
Coincidentally, Aromasin is a steroidal aromatase inhibitor, while Letrozole and Arimidex are not.
AIs are anti-estrogens that can and do decrease circulating plasma levels of estrogen in the body because they neutralize the root cause of estrogen production in the body.
Selective Estrogen Receptor Modulators (SERMs)
SERMs are a large group of anti-estrogens that includes Nolvadex (tamoxifen citrate), clomiphene citrate (Clomid), raloxifene, and toremifene, and SERMs are the oldest anti-estrogenic drugs used in medicine.
While aromatase inhibitors are a much more modern and recent discovery, some SERMs (e.g., Toremifene and Raloxifene) are fairly recent, while others (e.g., Nolvadex) have existed and been used for nearly 50 years.
SERMs selectively modulate estrogen receptor sites located throughout various tissues in the body.
Interestingly, although SERMs are categorized as anti-estrogens, these compounds have agonistic as well as antagonistic actions at estrogen receptors located in multiple tissues and sites in the body [1].
Many SERMs actually bind to estrogen receptors located in the liver and increase estrogenic activity there (in this case, acting as receptor agonists), while the same SERMs may have antagonistic activity at other receptor sites (such as the hypothalamus and breast tissue) and decrease estrogenic activity in these locations.
Within tissues where a SERM acts as an estrogen antagonist, such as the hypothalamus and breast tissue, the SERM binds to the estrogen receptor and remains inactive.
Circulating estrogen is unable to bind to the estrogen receptor because it is occupied by the SERM.
In breast tissue, this prevents (and possibly reduces) estrogen-driven gynecomastia.
Testosterone production increases due to an increase in the negative feedback loop that results in the release of GnRH from the hypothalamus and ultimately acts as an estrogen antagonist in the pituitary gland [2].
SERMs are anti-estrogens that do not reduce circulating plasma estrogen levels, but instead work to block estrogenic activity in certain tissues.
This is why SERMs do not reduce various estrogen-related side effects, such as bloating and water retention.
Medical references
[1] Riggs BL, Hartman 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. Hormonal effects of the antiestrogen, tamoxifen, in normal and sperm-deficient men. Fertility Steril. 1978 Mar 29(3):320-7.
