Letrozole Explored


by Mike Arnold

With most of the focus on Aromasin these days, I wanted to bring some of the attention back to our other AI’s. While Aromasin has rightly earned its place on the most popular list, each AI has its own unique set of characteristics which makes it ideal under various circumstances, but before we start discussing these differences, let’s begin with a brief history of letrozole in medicine. Brought to market by Novartis in 1997, Letrozole’s original indication was for the treatment of receptor-positive or unknown advanced breast cancer in postmenopausal women. A few years later, fertility specialists began employing letrozole for the purpose of ovarian stimulation after clinical studies demonstrated several advantages over Clomid, such as an improved side effect profile, a reduced risk of multiple gestation (twins, triplets, etc), and increased rates of conception.

It didn’t take long for BB’rs to become aware of this potent anti-estrogen, but as a patented drug and without any peptide/research chemical companies in existence at the time, not many BB’rs couldn’t afford or even find the drug. This all changed a few years later, with an abundance of UGL’s and chemical research companies offering the drug at reasonable prices. At this point letrozole has been widely available on both the black & grey markets for close to a decade.

Prior to the arrival of AI’s most BB’rs relied in Nolvadex and to a lesser extent Clomid, in order to combat the estrogenic side effects associated with the use of aromatizable drugs. As SERMs, they were able to prevent receptor mediated side effects such as gynecomastia, but they were completely ineffective at managing systemic estrogen levels. This left the BB’r prone to water retention, increased blood pressure, female fat pattern distribution, reduced libido, sexual dysfunction, emotional disturbances, and other undesirable side effects.

AI’s were also largely responsible for the change in PED habits that occurred among BB’rs over the last 15 years, particularly in regards to testosterone usage. While large dosages were certainly in use prior to that, AI’s allowed BB’rs to not only use greater amounts of testosterone without fear of estrogenic side effects, but it allowed them to run these large doses right into contests—a practice I am adamantly opposed to for several reasons, the most important of which is related to its negative effect on conditioning. With aromatization having such potentially negative effects on a BBr’s contest appearance, this was not something which was done previously with any regularity.

Out of all the AI’s currently available (anastrozole, letrozole, and exemestane are the most commonly used), Letrozole is probably the strongest. It comes out on top when compared directly against anastrozole and while exemestane has shown an equal rate of suppression, real-world use tells a different story. This is likely due to letrozole’s much longer half-life in the body. With a half-life of roughly 2 days, letrozole will maintain near maximum blood concentrations with EOD dosing, allowing the drug to exert its full effects 24/7 with a minimal number of weekly applications. On the other hand, with a half-life of only 8.9 hours, exemestane requires twice daily dosing just to maintain full effectiveness for a single 24 hour period. When taken only once daily, which is often the case, declining blood levels of the drug will allow aromatization to increase during the second half of the day. Needless to say, EOD dosing (a practice many people ignorantly engage in) provides comparatively little protection and is therefore incompatible with this particular AI.

As long as exemestane is administered properly, its short half-life is inconsequential, but the problem is that is that few people are willing to engage in twice daily dosing. Hell, if BB’ing forum posts are any indication, many people can’t even seem to take their AI once per day, let alone twice daily (note: once daily dosing with exemestane is generally sufficient for estrogen control when the dose is sufficient). The point here is that letrozole has the advantage of less frequent dosing, whereas missing doses of exemestane will lead to erratic fluctuations in estrogen blood levels.

Letrozole has the added benefit of being highly selective in its actions. Selectivity can be defined as the ability of a drug to affect a particular population (i.e. gene, enzyme, signalling pathway, protein, etc) in preference of others. Selective drugs discriminate in their actions, where as non-selective, or promiscuous drugs, affect more than just the intended target. A good comparison would be letrozole and Cytadren (aminoglutethimide). Cytadren can be used as an anti-estrogen similarly to letrozole, although the drug is highly promiscuous, resulting in a variety of unwanted side effects. This is because Cytadren’s primary job is to inhibit the conversion of cholesterol to pregnenolone, which starts a chain reaction of events within the body that eventually leads to the interference of estrogen synthesis, but not before it interferes with the production of adrenal glucocorticoids (i.e. cortisol), and mineralocorticoids (i.e. aldosterone).
Instead of making several pit stops along the way, letrozole affects the aromatase enzyme only. Pregnenolone, progesterone, cortisol, aldosterone, etc, remain unaffected. This makes letrozole not only much safer, but also provides a significantly greater degree of control over the rate of estrogen conversion.

Among the various AI’s, letrozole has built a reputation as the best drug for preventing/reducing gynecomastia. In my own experience, I have to say this seems to be the case. With a higher potency than anastrozole, the reasons are obvious, but with an equal potency to exemestane, it is bit more of a mystery. As stated above, it may be due, at least in part, to letrozole’s longer half-life and subsequent blood level stability. Regardless of the cause, letrozole has been shown to not only stop the progression of gyno, but in some cases it can even reverse it.

Letrozole has also built a reputation as being the best pre-contest AI for drying out (reducing sub-q water retention); an observation I have been able to personally confirm, although the difference is slight. Still, even small improvements in conditioning matter, so you may want to consider it for your next prep.

As with all AI’s there are a few disadvantages, as well. Letrozole is what’s known as a non-suicidal inhibitor, which means it deactivates aromatase temporarily. So long as the product continues to be used, this is a non-issue, but estrogen rebound becomes a possibility upon discontinuation. Estrogen rebound occurs when previously bound aromatase is suddenly liberated from the A.I., which, when combined with currently unbound aromatase, can result in an elevated estrogen conversion rate. However, it should be noted that estrogen rebound is often blow out of proportion, as the majority of people don’t experience any side effects upon cessation of letrozole, but for those that are concerned, a gradual reduction in one’s AI dose should ameliorate any potential problems.

Like some other AI’s, letrozole also has the ability to negatively affect the lipid profile. For this reason, the regular use of this AI probably isn’t a good idea, especially for those with currently damaged lipid profiles, but short-term use, such as when trying to deal with gyno or dropping water a few weeks before a competition, doesn’t pose much of a problem.

There are a few misconceptions regarding the use of AI’s in men, the first of which is the fear of “crushing” estrogen. This unfounded fear has led numerous BB’r to under-dose their AI, which can lead to an insufficient degree of aromatase inhibition. Arising from the misinterpretation of clinical data, in which male response was extrapolated from female test results, some think that even small doses of AI’s will lead to a near obliteration of estrogen levels. However, while AI’s like letrozole may be able to decrease circulating estrogen levels up to 98% in female test subjects, that same dose used in men will achieve only about a 60% reduction.

Typical doses of letrozole range from about 1 mg/EOD to 2.5 mg/daily. It is impossible to recommend an exact dosage which corresponds with a given amount of aromatizable AAS, as multiple variables influence the body’s proclivity towards aromatization.

In conclusion, letrozole is a selective, exceptionally potent inhibitor of aromatase which in my opinion finds its niche in the treatment/alleviation of gynecomastia and drying out before bodybuilding competitions.