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Old 11-04-2016, 12:57 PM
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Battle of the Aromatase Inhibitors

Battle of the Aromatase Inhibitors
by Mike Arnold

There has been considerable debate as to which of the 3rd generation aromatase inhibitors (anastrozole, exemestane, and letrozole) possesses the most ideal risk to benefit ratio; a question which has thus far been difficult to answer due to significant diversity in individual needs, circumstances, and priorities. While most bodybuilders tend to focus on factors such as potency and cardiovascular health when selecting their A.I of choice, there are several other factors which should be taken into consideration when attempting to make this determination. But before we explore these differences, let’s cover the basics.

There are two classes of aromatase inhibitors (A.I.’s)—irreversible steroidal inhibitors and non-steroidal inhibitors. Exemestane, being an androstenedione derivative, is an example of an irreversible steroid inhibitor. Drugs in this class form an irreversible bond with the aromatase enzyme, deactivating it permanently. This eliminates the possibility of experiencing estrogen rebound upon cessation of use. On the other hand, non-steroidal inhibitors like anastrozole and letrozole bind to aromatase only temporarily, opening up the possibility of estrogen rebound upon discontinuation of A.I. therapy.

Whether or not estrogen rebound becomes an issue will depend on the circumstances. For example, if an individual is using anastrozole as part of their post-cycle therapy regimen, the estrogen rebound that occurs at the conclusion of PCT will have a suppressive effect on testosterone production—the exact opposite of what the individual was trying to accomplish during PCT. Furthermore, estrogen rebound at this time is likely to result in a poor estrogen to androgen ratio; a situation which can lead to the development of estrogenic side effects, such as gynecomastia. This is not uncommon, with many individuals having reported the appearance of gyno during the time period immediately following PCT.

On the other hand, should estrogen rebound occur mid-cycle, particularly if the cycle is high in androgens, it is much less likely to cause any issues, as androgens are antagonistic to estrogen. In laymen’s terms, androgens have an anti-estrogenic effect on the body. So long as the ratio of androgens to estrogens is sufficiently in favor of androgens, any increase in estrogen levels that occurs as a result of estrogen rebound is unlikely to cause any serious issues.

While exemestane’s permanent deactivation of the aromatase enzyme makes it ideal for avoiding estrogen-mediated testosterone suppression in the post-PCT period, what are the other pros and cons of each A.I. that might convince someone to choose one over the other? One factor that might be taken into consideration is the drug’s half-life, as it is often a major factor in determining how frequently a drug needs to be administered in order to continue providing the desired effect. With letrozole and anastrozole having a much longer half-life than exemestane, most believe that a less frequent dosing schedule is permissible. Therefore, it is not uncommon to see some advising that these drugs be administered only 2-3X/weekly, while EOD dosing schedules are extremely common. In contrast, exemestane is more commonly administered once daily, although EOD dosing schedules are still regularly employed.

Although some of the above recommendations may appear logical when considering the half-lives involved, recent research suggests otherwise. In one particular study designed to examine the effects of the 3 primary AI’s on aromatase activity, letrozole, anastrozole, and exemestane were all administered for 18 hours, after which time they were removed from the target tissue. Shortly after cessation of use, both letrozole and anastrozole increased aromatase activity (i.e. estrogen rebound), while estrogen levels remained fairly low in the exemestane group. Given the much longer half-lives of letrozole and anastrozole, one might have expected to see the opposite occur, yet the explanation for these results is simple. As a suicide inhibitor, exemestane permanently deactivates the aromatase enzyme, while letrozole and anastrozole bind only temporarily.

Therefore, when letrozole and anastrozole are discontinued, the prisoners (aromatase) are “set free”, so to speak, resulting in a surge in aromatase activity and subsequent estrogen rebound. In contrast, due to exemestane’s ability to permanently deactivate aromatase, the body must first manufacture additional aromatase enzymes before estrogen conversion can resume normally. This is a time consuming process, which explains why exemestane, despite its shorter half-life, was able to keep estrogen levels stabilized for a longer period of time after discontinuation of use.

Some might argue that all this is meaningless—that these A.I. induced fluctuations in aromatase and estrogen levels have a negligible impact on the rate or intensity of estrogen-mediated side effects. They may then cite their experience and the experiences of others, in which every other day dosing (or even less frequently) has proven sufficient to ward-off estrogenic related side effects. While it is true that these less frequent dosing schedules may allow the user to avoid external side effects such as gyno or excess water retention, the goal of A.I. therapy should not be limited to the prevention of cosmetic side effects alone. Namely, we need to consider the effect that irregular fluctuations in estrogen levels can have on cardiovascular health.

Recent research has shown that having estrogen levels even slightly outside the normal range, regardless of whether it is a matter of excess or deficiency can have a negative impact on cardiovascular health, significantly increasing the likelihood of developing atherosclerosis. Furthermore, most researchers now believe that we must do more than simply maintain a normal estrogen level if we want to enjoy optimal cardiovascular health. More specifically, there is a small range within normal where optimal cardiovascular benefits are realized. Although the exact numbers have not yet been determined, most agree that it falls somewhere between the upper-20’s and low 30’s, with even slight deviations from this range having a negative affect on cardiovascular health. So, while you may be able to avoid external side effects with an infrequent A.I dosing schedule, maintaining internal health necessitates a more finely tuned approach to estrogen management.

In order to maintain ideal estrogen levels, one must not only dose their A.I properly, but they must maintain even blood levels of the drug, as this is the only way to prevent spikes in aromatization that occur with irregular dosing schedules. Therefore, letrozole and anastrozole should both be dosed once daily, while exemestane should be dosed twice daily at roughly 12 hour intervals, but doesn’t this recommendation conflict with my prior statement that exemestane maintains stable estrogen levels longer than letrozole or anastrozole? Yes and no. In the above-mentioned study, letrozole and anastrozole were only active for 18 hours, after which they were removed from target tissue. This means that none of the drugs were administered long enough to reach steady-state concentrations in the bloodstream, especially letrozole, which takes far longer than either exemestane or anastrozole. Neither did the study take in account differences in tissue build-up, which can vary significantly depending on how long an A.I is administered.

When looking at the bigger picture, it becomes obvious that the irregular dosing schedules employed by the majority are not ideal, regardless of which A.I is used, as irregular dosing schedules leave the user susceptible to significant fluctuations in estrogen levels. When attempting to maintain one’s estrogen reading within that small, optimal range, more frequent dosing intervals are mandatory.

Without trying to overcomplicate things, there is one more factor to consider when attempting to maintain stable estrogen levels. AAS dosing frequency. To get right to the point, maintaining even blood AAS levels is crucial, as large swings in blood AAS levels leads to varying rates of aromatization, making any attempt to maintain stable estrogen levels through A.I. management alone a vain proposition. Obviously, if you are using 1 gram of test prop weekly and inject all of it on Monday, aromatization rates will vary drastically throughout the week, due to the rapid release rate of the prop ster. So, regardless of the steroid you use, your dosing schedule should ensure that blood levels remain as even as possible.

Lastly, all of this would be futile without lab work, as it is the only sure-fire way to confirm the effectiveness of your efforts. Ideally, anytime you make significant changes to your steroid cycle in terms of dosage or compound selection, it should be followed by lab work to ensure that you’re A.I regimen is providing the desired result.

Another area of interest which has received quite a bit is discussion as of late, but which clinical research has failed to bring any clarity to, is the effect of A.I.’s on lipids. Still, we are not completely in the dark on this subject, as both clinical and anecdotal evidence is strong enough to draw some limited conclusions. To cut right to the chase, many of the studies which have been conducted for the purpose of ranking the various A.I.’s according to their effects on lipid health have provided contradictory results. However, after scouring study after study, reviewing one meta-analysis, and taking in account the opinions of respected researchers, it appears that the worst offender is letrozole, followed by anastrozole and exemestane. It should be said that the difference between exemestane and anastrozole, at least according to the research, appears to be negligible. But we need to take into consideration that most of these studies were performed using women and oftentimes post-menopausal women, which may not apply directly to men, particularly steroid using men.

Although the clinical research is a bit muddied, anecdotal evidence (user bloodwork) appears to confirm these findings, with letrozole being the worst offender and exemestane being the least injurious, but again, it is important to point out that anastrozole, like exemestane, has often had a neutral effect on lipids according to user bloodwork. At this juncture the general consensus among most bodybuilders is that exemestane is the safest A.I. in terms of cardiovascular health. Although this claim cannot be substantiated 100%, the evidence does appear to support this position, especially when compared to letrozole.

Another seldom considered aspect of A.I. use is their effect on brain function. While all A.I.’s affect the level of estrogen exposure in the brain, both letrozole and exemestane demonstrate an increased aptitude for crossing the blood-brain barrier, making them capable of adversely affecting neurosteroid balance to a greater degree than anastrozole. Along with enhanced blood-brain permeability, letrozole also suffers from a reduced clearance rate, allowing concentrations within the brain to climb even higher. While exemestane clears more quickly, its permanent deactivation of aromatase makes it equally problematic in this regard, as the body must first produce additional aromatase before proper neurosteroid balance can be restored.

Due to its greater specificity of action (less apt to interfere with non-target tissues), anastrozole has the clear advantage in this area. It does not penetrate the blood brain barrier as readily, making it much less likely to cause side effects such as sexual dysfunction, libido issues, or depression. Letrozole also appears to negatively impact cellular response to estrogen in areas of the brain that help govern mood, leaning, and memory. Lastly, exemestane and letrozole can disrupt steroid production within the adrenal cortex, while anastrozole does not. Many of the side effects associated with neurosteroid imbalance, such as sexual dysfunction, reduced libido, and depression, have been reported in those who use letrozole. Although exemestane appears to be less problematic in these areas, one could postulate that this is largely due to the infrequent dosing patterns employed by those who use the drug, rather than a diminished ability to affect neurosteroid balance.

While the exceptional potency of exemestane and letrozole can sometimes be disadvantageous, there are several instances in which it is beneficial. One example would be the treatment of gynecomastia. Of all the cosmetic side effects caused by AAS, this is definitely one of the worst, if not the worst. While all other cosmetic side effects (acne, oily skin, hair loss, etc) are undesirable, they are inherently male in nature; encountered in both steroid using and non-steroid using men alike. However, the appearance of tits on a man is wholly unnatural—feminine, if you will. Being strongly associated with woman-hood, most would prefer to avoid this side effect at all costs. However, a lack of education, inexperience, and the sourcing of illegitimate anti-estrogens presents ample opportunity for this side effect to manifest in otherwise healthy men.

Of all the A.I.’s available, letrozole has by far the greatest success rate in treating gynecomastia. Although a liability in terms of neurosteroid balance, letrozole’s greater tissue build-up and enhanced potency are the specific reasons it does such a good job at combating gynecomastia. If treated during the initial swelling phase (before the appearance of hard lumps, otherwise known as glandular tissue), it is often capable of eliminating gyno altogether. Even if hard lumps have already formed, it is frequently able to shrink them to the point where they are no longer visible. In more severe cases letrozole can be combined with antagonistic treatment, such as topical DHT. This attacks the problem from two different angles, providing potentially dramatic results.

Pre-contest preparation is another area where letrozole shines. Although anastrozole and exemestane are definitely viable alternatives for this purpose, letrozole tends to provide a slightly drier and harder look than other A.I.’s. In sport where conditioning is paramount, even small improvements can make all the difference. For this reason, letrozole should rightfully be awarded the title of pre-contest A.I of choice. However, one does not need to use letrozole throughout their entire prep in order to receive these benefits. A dose of 2-3 mg/day for the last 3-4 weeks of prep should suffice, assuming aromatizable AAS have been minimized or eliminated from the program.

Unfortunately, most bodybuilders tend to view A.I.’s as somewhat one-dimensional in nature, rather than seeing them as potential disrupters of whole-body estrogen metabolism capable of affecting numerous bodily systems. As we have seen, just because an A.I. may be advantageous in one area does not mean it is ideal in other ways. Therefore, it is incumbent on the individual to not only educate him/herself about the various A.I.’s and their effects on the body, but to make sure their selection matches their own unique needs.

Still, if we attempted to put together a general ranking system based on priorities, it would probably go something like this. If prioritizing cardiovascular health, exemestane would likely be on top, followed closely by anastrozole and with letrozole being the least desirable. This is an important consideration, especially for long-steroid users who employ A.I’s regularly in an effort to maintain normal estrogen levels. At the same time, the lack of specificity associated with letrozole and exemestane make them much more likely to interfere not only with brain chemistry (potentially resulting a number of different side effects), but other estrogen-dependent tissues as well.

In a sport littered with multiple cardiovascular risk factors, and with the end points of cardiovascular disease being heart attack and stroke, it is probably wise to prioritize cardiovascular health above all else. However, this does not mean one should ignore other aspects of their health, either. Overall, anastrozole has the least amount if side effects, so for those whose lipid profiles remain unaffected by its use, it is hard to argue against it for every-day estrogen management. For those whose lipid profiles are adversely affected by anastrozole, exemestane is likely the best candidate. At this point, letrozole’s place in a bodybuilder’s program appears to be limited, as it is not only the most likely to alter one’s lipids, but its relative lack of specificity also leaves the user vulnerable to estrogen deficiency in estrogen-dependent tissues. Potential applications include gyno treatment and use as a drying agent during the final stages of pre-contest prep. As always, bloodwork is essential in learning how these drugs affect both our estrogen levels and other relevant health markers.
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Old 11-04-2016, 01:09 PM
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I love Mike Arnold's articles! Always so well written and informative.
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