Being that Letrozole is the most powerful and potent of the three aromatase inhibitors, it must be emphasized that the use of any AI should be for the purpose of Estrogen control rather than Estrogen elimination. The reduction of Estrogen in the body can cause negative changes and problems for the body, especially when aromatase inhibitors are utilized and Estrogen is suppressed long-term. Letrozole side effects are generally manageable and are for the most part very different for males rather than females utilizing it, as it has been previously demonstrated in this profile that Letrozole will impact females in a more significant manner than in males due to different endocrine physiology.
Side Effects Associated With Estrogen Reduction
Nearly all Letrozole side effects are resultant of its effect on the body in reduction of total circulating Estrogen levels as a result of the inhibition of the aromatase enzyme. This is common of all aromatase inhibitors. The following are all of the major potential Letrozole side effects associated with Estrogen reduction.
Joint and bone pain: Anecdotally, bone and joint pain has been a commonly reported effect of Letrozole, and in fact is a more commonly reported effect resulting from Letrozole than any of the other aromatase inhibitors. This is likely due to the fact that Letrozole holds the capability to reduce serum Estrogen levels to far lower levels than all other aromatase inhibitors. The fact is that Estrogen is an important hormone in the promotion and retention of bone mineral content, and therefore the promotion of increased bone strengthening. This is why post-menopausal females exhibit increased likelihood of developing osteoporosis due to the natural decline in Estrogen levels with age. Even in the informational pamphlets created by Health Canada for the generic APO manufactured Letrozole, it clearly states: “Long term use of APO-LETROZOLE may result in a reduction in bone mineral density and may increase the risk of osteoporosis and fracture” . Additionally, studies have demonstrated that Letrozole has demonstrated severe reductions in bone strength in subjects. Short term use should present no extreme changes in bone strength; however, many male users will report increased bone and joint pain when Estrogen is reduced far below normal physiological levels due to Letrozole use. This bone and joint pain will always subside following the cessation of Letrozole (or if Letrozole doses are adjusted as such to allow Estrogen levels to return to normal physiological levels).
Fatigue: A commonly reported Letrozole side effect that is just as common as the issue of bone and joint pain in anabolic steroid users that reduce their Estrogen levels too low, persistent fatigue is also a common problem. This, as previously mentioned, is once again the result of Estrogen levels dropping too low. Estrogen is well known for playing a key role in the proper functioning of the CNS (Central Nervous System), and the reduction of Estrogen (with any aromatase inhibitor) below normal physiological levels can and does result in chronic fatigue that can only be properly remedied by allowing circulating Estrogen levels to return to normal.
Negative effects on cholesterol: This is a side effect common of any and all aromatase inhibitors or any substances that reduce total circulating Estrogen levels in the body. Letrozole side effects are no exception to this, and this is perhaps the most important side effect to understand. This side effect is also the reason why this profile has emphasized the control of Estrogen levels rather than the total elimination of them. Estrogen is known to play a very important role through its activity in the liver in generating favorable cholesterol levels (increases in HDL, the good cholesterol, and reductions in LDL, the bad cholesterol). When Estrogen levels are reduced below normal physiological levels, cholesterol changes take turns for the worse where HDL (good) cholesterol decreases and LDL (bad) cholesterol increases, creating an increased risk for CVD (Cardiovascular Diseases). With this having been said, studies on nearly all aromatase inhibitors have brought forth what are generally inconsistent results (some studies have demonstrated drastic changes in cholesterol levels while others have demonstrated no changes). In general, one particular study involving the use of anabolic steroids with aromatase inhibitors does stand out.
Studies have been conducted whereby 300mg weekly of Testosterone Enanthate was administered for a 20 week period without the use of an aromatase inhibitor which resulted in a 13% reduction of HDL cholesterol, however, when Testosterone doses were raised to 600mg weekly, reduction of HDL cholesterol had proceeded even further to 21%.
Therefore, the examined data exhibits a very evident increase in Estrogen via aromatization and liver metabolism which actually helps to offset the negative cholesterol changes from the use of supraphysiological amounts of anabolic steroids. This makes sense, considering Estrogen itself is known to promote positive impacts on cholesterol levels. Therefore, the use of an aromatase inhibitor and its impact on cholesterol profiles should always be remembered when any user is considering the addition of an aromatase inhibitor during a cycle or even for PCT. It is advisable to instead use minimal doses of an aromatase inhibitor while on a cycle for the purpose of Estrogen control rather than total Estrogen level elimination. The idea in such a case is to keep Estrogen levels within normal ranges and not allow them to skyrocket as a result of aromatization, but at the same time prevent them from dropping to near zero from the use of full doses of an aromatase inhibitor.
Estrogen rebound: This is one of the Letrozole side effects that are perhaps the worst out of the two non-suicidal aromatase inhibitors (the two being Letrozole itself and Arimidex). While Arimidex exhibits issues of Estrogen rebound, Letrozole has shown to exhibit far worse rebound upon discontinuation. This side effect is very important to understand. It is a side effect generally unique to both Arimidex as well as Letrozole (Femara). The third major aromatase inhibitor, Aromasin (Exemestane) does not exhibit Estrogen rebound. This is because Arimidex and Letrozole are what is known as non-suicidal aromatase inhibitors. Aromasein (Exemestane) is a suicidal aromatase inhibitor. A suicidal aromatase inhibitor (such as Aromasin) indicates that once it has bound to the aromatase enzyme (and thereby inhibiting it), the inhibited enzyme remains bound to aromatase permanently, rendering the enzyme inactive forever. The body will eventually manufacture more aromatase enzymes, but the current bound enzymes are bound indefinitely, eliminating any risk for Estrogen rebound.
Non-suicidal aromatase inhibitors such as Arimidex and Letro, however, are only bound to the aromatase enzyme for limited time periods before the aromatase inhibitors unbind either due to natural metabolism, or through competition with other substrates. If a non-suicidal aromatase inhibitor is halted too abruptly, the circulating inhibited aromatase enzymes that have not been metabolized out of the body will then become free again, and begin aromatizing androgens into Estrogens at an often rapid rate. This is why it is advised to slowly halt administration of Letrozole, and/or slowly reduce the dose and/or frequency of the dose when stopping. Often times the inclusion of a SERM such as Nolvadex starting several days prior to and following the cessation of Letrozole will be necessary so as to keep the breast tissue receptor sites blocked from any possible Estrogenic activity that results from the rebound, after which Nolvadex administration is halted as Estrogen levels slowly return to baseline.
 Effects of the Steroidal Aromatase Inhibitor Exemestane and the Nonsteroidal Aromatase Inhibitor Letrozole on Bone and Lipid Metabolism in Ovariectomized Rats. Paul E. Goss1, Shangle Qi, Angela M. Cheung, Haiqing Hu, Maria Mendes, and Kenneth P. H. Pritzker. Clin Cancer Res September 1, 2004 10; 5717.