Letrozole Side Effects
Side effects associated with decreased estrogen
Almost all letrozole side effects are caused by the inhibition of the aromatase enzyme, which contributes to a decrease in total circulating estrogen levels in the body.
This is a phenomenon common to all aromatase inhibitors. The following are the main potential letrozole side effects associated with decreased estrogen.
Joint and bone pain:
Anecdotally, bone and joint pain has been commonly reported as a side effect of letrozole, and is actually more commonly reported as a side effect of letrozole than other aromatase inhibitors.
This may be due to Letrozole's ability to reduce serum estrogen levels to much lower levels than all other aromatase inhibitors.
In fact, estrogen is an important hormone in promoting and maintaining bone mineral content, which promotes bone strengthening.
That's why postmenopausal women are more likely to develop osteoporosis as their estrogen levels naturally decline with age.
Even the information pamphlet for generic APO-manufactured letrozole created by Health Canada clearly states “Long-term use of APO-letrozole may cause a decrease in bone density and an increased risk of osteoporosis and fractures"[1] .
Studies have also shown that letrozole severely reduces bone strength in subjects[2].
Although short-term use does not show extreme changes in bone strength, many male users report an increase in bone and joint pain when letrozole use causes estrogen to drop well below normal physiologic levels.
These bone and joint pains invariably subside when letrozole is discontinued (or when the dose of letrozole is adjusted so that estrogen levels return to normal physiologic levels).
Fatigue:
Similar to the problem of bone and joint pain in anabolic steroid users who lower their estrogen levels too much, persistent fatigue is also a commonly reported Letrozole side effect.
This is due to the aforementioned lowered estrogen levels.
Estrogen is well known to play an important role in the proper functioning of the central nervous system (CNS), and when estrogen is reduced below normal physiological levels through aromatase inhibitors, it can lead to chronic fatigue, a symptom that can only be properly treated by restoring circulating estrogen levels to normal.
Negative effects on cholesterol:
This is a side effect common to all aromatase inhibitors or any substance that reduces total circulating estrogen levels in the body.
Letrozole side effects are no exception, and this is probably the most important side effect to understand.
This side effect is also why we emphasized controlling estrogen levels rather than eliminating them completely in this profile.
Estrogen is known to play a very important role in the liver, where it works to produce good cholesterol levels (increasing HDL, the good cholesterol, and decreasing LDL, the bad cholesterol).
When estrogen levels decrease below normal physiological levels, cholesterol changes occur, resulting in a decrease in HDL, the good cholesterol, and an increase in LDL, the bad cholesterol, which increases the risk of cardiovascular disease.
For this reason, studies of almost all aromatase inhibitors have generally produced inconsistent results (some studies have shown dramatic changes in cholesterol levels, while others have shown no change).
In general, one particular study stands out, involving the use of anabolic steroids in conjunction with an aromatase inhibitor.
This study found that 300 mg of testosterone enanthate per week for 20 weeks without the use of an aromatase inhibitor resulted in a 13% reduction in HDL cholesterol, while increasing the testosterone dose to 600 mg per week resulted in a further 21% reduction in HDL cholesterol [3].
Thus, the data examined shows a very clear increase in estrogen via aromatization and hepatic metabolism, which actually helps to offset the negative cholesterol changes caused by the use of supraphysiological amounts of anabolic steroids.
This is not surprising considering that estrogen itself is known to have a positive effect on cholesterol levels.
Therefore, the use of aromatase inhibitors and their impact on the cholesterol profile should always be kept in mind by any user considering the addition of an aromatase inhibitor during a cycle or for PCT.
It is recommended to use the lowest dose of an aromatase inhibitor during a cycle with the goal of controlling estrogen rather than eliminating total estrogen levels.
The idea in this case is to keep estrogen levels within a normal range, preventing them from spiking due to aromatization, while at the same time preventing them from dropping to near zero due to the use of a full dose of an aromatase inhibitor.
Estrogen Rebound:
This is one of the most serious letrozole side effects of the two non-lethal aromatase inhibitors (letrozole itself and Arimidex).
While Arimidex has been shown to have estrogen rebound issues, letrozole has been shown to have a much more severe rebound upon discontinuation.
It is very important to understand this side effect.
This is a side effect commonly seen with both Arimidex and Letrozole (Femara).
Aromasin (Exemestane), the third major aromatase inhibitor, does not show estrogen rebound.
This is because Arimidex and Letrozole are known as non-lethal aromatase inhibitors.
Aromasin (Exemestane) is a suicidal aromatase inhibitor.
Suicidal aromatase inhibitors (such as aromasin) bind to and inhibit the aromatase enzyme, which means that the inhibited enzyme permanently binds to the aromatase, rendering the enzyme inactive forever.
The body will eventually produce more aromatase enzyme, but the currently bound enzyme will remain bound indefinitely and there is no risk of estrogen rebound.
However, non-lethal aromatase inhibitors, such as Arimidex and Retro, are only bound to the aromatase enzyme for a limited time before natural metabolism or competition from other substrates causes the aromatase inhibitor to unbind.
If a non-lethal aromatase inhibitor is discontinued too abruptly, circulating inhibited aromatase enzymes that have not been metabolized in vitro will become free again and begin to aromatize androgens to estrogens at a rapid rate.
Therefore, it is recommended that the dose and/or number of doses be reduced gradually when tapering or discontinuing letrozole.
It is often necessary to administer a SERM such as Nolvadex a few days before and a few days after discontinuing letrozole to ensure that the breast tissue receptor sites are shielded from estrogenic activity due to rebound, and then discontinue Nolvadex as estrogen levels slowly return to baseline.
Medical References:
[1] Fact sheet apo-letrozole. Pharmaceutical Sciences Agency. Health Canada.
[2] Effects of the steroidal aromatase inhibitor exemestane and the non-steroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Paul E. Goss1, Shangli Qi, Angela M. Cheung, Haiqing Hu, Maria Mendez, Kenneth P. H. Pritzker. September 1, 2004; 10; 5717.
[3] Testosterone dose-response relationship in healthy young men. Bassin S, Woodhouse L. et al. Am J Physiol Endocrinol Metab 281:E1172-81, 2001
