Retrozole, being the most potent among the three aromatase inhibitors, should be used with the goal of estrogen modulation, not estrogen elimination.
A decrease in bodily estrogen can cause negative changes and issues for the body, especially when estrogen is suppressed for extended periods using aromatase inhibitors.
Retrozole side effects are generally manageable, and due to differing endocrine physiology, it has a greater impact on men than on women when taken, as previously demonstrated in this profile that Retrozole affects women less than men.
Side Effects Related to Estrogen Reduction
Almost all Retrozole side effects occur as a result of the reduction in total circulating estrogen levels in the body due to the inhibition of the aromatase enzyme.
This is a phenomenon common to all aromatase inhibitors.
The following are the main potential side effects of Retrozole related to estrogen reduction.
Joint and Bone Pain:
Anecdotally, bone and joint pain has been a commonly reported side effect of Retrozole, and in fact, it is reported more frequently as a side effect with Retrozole compared to other aromatase inhibitors.
This may be because Retrozole has the ability to lower serum estrogen levels to a much lower level than any other aromatase inhibitor.
In fact, estrogen is a crucial hormone for promoting and maintaining bone mineral content, thereby promoting bone strengthening.
This is why post-menopausal women are more likely to develop osteoporosis as they age, due to a natural decline in estrogen levels.
The information pamphlet for the generic APO-manufactured Retrozole, created by Health Canada, also clearly states: “Long-term use of APO-Letrozole may lead to a decrease in bone mineral density and an increased risk of osteoporosis and bone fractures.”[1].
Furthermore, studies have shown that Retrozole significantly reduced the bone strength of subjects [2].
While extreme changes in bone strength may not occur with short-term use, many male users report increased bone and joint pain when their estrogen drops far below normal physiological levels due to Retrozole use.
This bone and joint pain always subsides upon discontinuation of Retrozole (or upon adjusting the Retrozole dosage to allow estrogen levels to return to normal physiological levels).
Fatigue:
Similar to the bone and joint pain issues reported by anabolic steroid users who lower their estrogen levels too much, persistent fatigue is another commonly reported Retrozole side effect.
This is, as mentioned earlier, due to estrogen levels becoming too low.
Estrogen is well-known to play a vital role in the proper functioning of the central nervous system (CNS), and a reduction of estrogen below normal physiological levels via aromatase inhibitors can cause chronic fatigue, a symptom that can only be properly remedied by restoring circulating estrogen levels to normal.
Negative Impact on Cholesterol:
This is a side effect common to all aromatase inhibitors, or any substance that reduces the body’s total circulating estrogen levels.
Retrozole side effects are no exception, and this is perhaps one of the most important side effects to understand.
This side effect is also the reason why this profile emphasized modulating estrogen levels rather than eliminating them entirely.
Estrogen is known to play a very important role in the liver for generating positive cholesterol levels (increasing good HDL cholesterol and decreasing bad LDL cholesterol).
When estrogen levels fall below normal physiological levels, a shift in cholesterol occurs, resulting in a decrease in good HDL cholesterol and an increase in bad LDL cholesterol, thereby increasing the risk of cardiovascular disease.
For this reason, studies on almost all aromatase inhibitors have generally yielded inconsistent results (some studies show dramatic shifts in cholesterol levels, while others show no change).
One particular study stands out regarding the use of aromatase inhibitors alongside anabolic steroids.
A study where subjects were administered 300mg of Testosterone Enanthate per week for 20 weeks without an aromatase inhibitor resulted in a 13% decrease in HDL cholesterol, whereas increasing the testosterone dose to 600mg per week saw a further progression of HDL cholesterol reduction to 21% [3].
Thus, the data investigated shows a very clear increase in estrogen via aromatization and hepatic metabolism, which actually helps offset the negative cholesterol changes induced by the use of supraphysiological amounts of anabolic steroids.
This makes sense, considering that estrogen itself is known to positively influence cholesterol levels.
Therefore, the use of aromatase inhibitors and their impact on cholesterol profile is something every user considering the addition of an aromatase inhibitor during a cycle or for PCT must always keep in mind.
It is recommended to use the minimum effective dose of an aromatase inhibitor during a cycle with the goal of estrogen modulation rather than total estrogen elimination.
The idea in this case is to keep estrogen levels within the normal range, preventing them from spiking due to aromatization, while also preventing them from crashing to near zero from full-dose aromatase inhibitor use.
Estrogen Rebound:
This is one of the most serious side effects of Retrozole among the two non-suicidal aromatase inhibitors (Retrozole itself and Arimidex).
While Arimidex exhibits an estrogen rebound issue, Retrozole has been shown to exhibit a much more severe rebound upon discontinuation.
Understanding this side effect is very important.
This is a side effect generally seen with both Arimidex and Retrozole (Femara).
The third major aromatase inhibitor, Aromasin (Exemestane), does not exhibit estrogen rebound.
This is because Arimidex and Retrozole are known as non-suicidal aromatase inhibitors.
Aromasin (Exemestane) is a suicidal aromatase inhibitor.
Suicidal aromatase inhibitors (e.g., Aromasin) refer to the fact that when they bind to and inhibit the aromatase enzyme, the inhibited enzyme is permanently bound to the aromatase, rendering the enzyme inactive forever.
The body will eventually produce more aromatase enzyme, but the currently bound enzymes remain bound indefinitely, posing no risk of estrogen rebound.
However, non-suicidal aromatase inhibitors like Arimidex and Retrozole bind to the aromatase enzyme only for a limited time before the binding is reversed due to natural metabolism or competition with other substrates.
If a non-suicidal aromatase inhibitor is discontinued too abruptly, the circulating inhibited aromatase enzymes, not yet metabolized, become free again and begin rapidly aromatizing androgens into estrogen.
Therefore, it is advisable to taper off Retrozole administration gradually, slowly reducing the dosage and/or frequency of administration when discontinuing.
Often, a SERM like Nolvadex is administered a few days before and a few days after stopping Retrozole to ensure the breast tissue receptor sites are blocked from the estrogenic activity caused by the rebound, after which the Nolvadex can be discontinued once estrogen levels have slowly returned to baseline.
Medical References:
[1] Fact Sheet Apo-Letrozole. Pharmaceutical Sciences Section. Health Canada.
[2] Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Paul E. Goss1, Shangli Chi, Angela M. Cheung, Haiqing Hu, Maria Mendez, Kenneth P. H. Pritzker. September 1, 2004; 10;5717.
[3] The dose-response relationship of testosterone in healthy young men. Bhasin S, Woodhouse L. et al. Am J Physiol Endocrinol Metab 281:E1172-81, 2001
