Anti-Estrogens and Aromatase Inhibitors

Because of their ability to reduce risk of gynecomastia (abnormal growth of breast tissue in males) and enhance recovery of natural testosterone production after a cycle, use of anti-estrogens such as Clomid (clomiphene citrate) Cytadren (aminoglutethimide) has become popular in bodybuilding. Anti-estrogens also can reduce bloating associated with anabolic/androgenic steroid use, and may avoid health risks associated with elevated estrogen levels. Medically, the drugs are used not only for treatment of breast cancer but also for improvement of fertility in both men and women, and occasionally for increasing testosterone levels in men such as endurance athletes with low testosterone. There are two categories of anti-estrogens: aromatase inhibitors and receptor blockers. Both shall be considered here.

Estrogens

As with androgens, where any hormone that has the activity of testosterone is an androgen and therefore all anabolic steroids are androgens, any hormone that has the activity of estradiol, the principal female sex hormone, is an estrogen. The most active natural estrogens in humans are estradiol and estrone.
These hormones are related to each other rather similarly to how the andro prohormones are related to each other. Just as androdiol has a hydroxy (or –ol) group at both the 3- and 17- positions, estradiol likewise has a hydroxy group at those positions. Estrone, like androstenedione, has keto (or –one, pronounced “oan”) groups at those positions.
Estradiol is the most potent (effective per milligram) of the natural estrogens. It is produced either from testosterone via the aromatase enzyme, or from estrone via the estrogenic 17b-HSD enzyme.
Estrone is less potent, but all this means is that one needs more of it to accomplish the same job. It is produced either from androstenedione via aromatase, or from estradiol via the same 17b-HSD enzyme working in reverse.
From the standpoint of the bodybuilder using anabolic/androgenic steroids (AAS), if nothing is done about the situation, high estrogen levels can cause gynecomastia, will inhibit natural testosterone production, and will cause bloating. High estrogen levels also make it more difficult to lose fat, and tend to cause female pattern fat distribution even in males.

Estradiol also has carcinogenic metabolites, and a liver problem sometimes associated with AAS use, hepatic cholestasis, is caused not by androgen but by an estrogen metabolite.
It is also not unusual for bodybuilders to feel poorly on beginning a cycle of high dose testosterone without antiestrogens, and for this reason many have advocated starting with a low dose and building up. However, I strongly suspect that the real problem is estrogenic effect on mood, and the problem can be avoided with use of an aromatase inhibitor.

Aromatizable Steroids

Though most bodybuilders feel they know which steroids aromatize and which do not, sometimes the beliefs are in error. This is because progestogenic activity (activity like that of progesterone, another female hormone) is easily mistaken for estrogenic activity. Both hormones can cause bloating, and both can cause gyno. So AAS which are capable of activating not only the androgen receptor but also the progesterone receptor are often mistakenly assumed to aromatize. (Note: these androgens do not “convert to progesterone” but rather are themselves, without any change needed, able to act on that receptor.)

Nandrolone is proven to be a progestin. This fact is of clear importance in bodybuilding, because while moderate Deca-only use actually lowers estrogen levels as a consequence of reducing natural testosterone levels and thus allowing the aromatase enzyme less substrate to work with, Deca nonetheless can cause gyno in some individuals. Furthermore, just as progesterone will to a point increase sex drive in women, and then often decrease it as levels get too high, high levels of progestogenic steroids can kill sex drive in male bodybuilders, though there is a great deal of individual variability as to what is too much.

Incidentally, this progestogenic activity also inhibits LH production, and contrary to common belief, even small amounts of Deca are quite inhibitory, approximately as much so as the same amount of testosterone.
What relevance does this have to an article on antiestrogens? Well, antiestrogens can do nothing about these side effects of Deca.

The same appears to be true of oxymetholone (Anadrol)and of norethandrolone (Nilevar).
Methenolone (Primobolan), stanozolol (Winstrol), dromostanolone (Masteron), oxandrolone(Anavar), mesterolone (Proviron), stenbolone (Anatrofin), trenbolone, and DHT do not aromatize, and thus, antiestrogens are not relevant to these AAS either.

The steroids where aromatization is of particular concern are testosterone, methandrostenolone (Dianabol), boldenone (Equipoise), and to some extent fluoxymesterone (Halotestin). However the latter is usually used in doses low enough that aromatization is not an issue.

Among the prohormones, androstenedione is the principal offender with regard to aromatization, being readily converted to estrone. With androdiol, only that small portion which converts to testosterone can be converted further to estradiol, and that will occur only in the same percentage that other testosterone converts to estradiol.
Norandrodiol cannot convert directly to estrogen, and even after conversion to nandrolone is not readily converted to estrogen.

Norandrostenedione can be converted to estrone by aromatase, but is a very poor substrate for that enzyme. It can actually act as a competitive inhibitor, blocking better substrates such as androstenedione or testosterone. It is possible then, though unproven, that norandrostenedione might have some value as an aromatase inhibitor in bodybuilding. I do think, however, that the pharmaceuticals designed for the purpose should be assumed to be better choices.
Aromatase Inhibitors

(Author Note – May 2011: Years back, aromatase inhibitors such as Arimidex and letrozole were much more expensive than Cytadren and much less available, so in the past Cytadren was often used as an aromatase inhibitor. That use is today obsolete.)

The most commonly used aromatase inhibitor in bodybuilding is aminoglutethimide (Cytadren). This drug also inhibits an enzyme (desmolase) necessary for synthesis of cortisol, but fortunately, aromatase can be inhibited with levels of drug that cause only limited inhibition of desmolase.

Contrary to popular belief, it is generally not desirable to inhibit cortisol production. Doing so will likely lead to joint problems, and furthermore once the inhibition ends, the price of above-normal cortisol production must usually be paid.

For an average male, a dose of 250 mg/day (one tablet) appears optimal. The half-life is 8 hours, so the drug is better taken in divided doses. The best plan seems to be to take half a tablet on arising, and quarter tabs six and twelve hours later. This keeps levels generally fairly constant, but allows a small drop in the hours shortly before arising, which is then compensated for by the higher dose on arising. With this scheme, inhibition of cortisol production is generally too low to be noticed, and generally there is no rebound effect on discontinuance. However it is not a bad idea nonetheless to taper off, first omitting the midday quarter tab dose for a few days, then omitting both quarter tab doses, then reducing the initial dose to one quarter tab, and then ending completely. A week is sufficient for the taper.
Some people suffer a degree of lethargy or sedation from aminoglutethimide, even at this low dose, but most do not.
Anastrozole (Arimidex) is a superior aromatase inhibitor which does not have the above side effects. It is, however, very expensive. With moderate doses of testosterone it seems that 1 mg/day is sufficient, and some have claimed half a tab to be sufficient. I do not have blood test data to verify that, however.

Receptor Blockers

Clomiphene (Clomid) and tamoxifen (Nolvadex) are the most popular drugs of this class. They are more precisely referred to as “selective estrogen receptor modulators.” This is because their mode of action is not so simple as merely blocking the estrogen receptor. Estrogen receptors require not only hormone but also activation of regions of the receptor called AF-1 and AF-2. AF-1, to be activated, requires phosphorylation, while AF-2 can be activated by any of a number of cofactors, such as IGF-1.

As it happens, clomiphene and tamoxifen are estrogen receptor antagonists (blockers) in cells that depend on activation of the AF-2 region, while in cells which activate AF-1, these compounds are estrogens.
In some cells these drugs activate one of the types of estrogen receptor (ERa) but are antagonists of the other type (ERb).

The result is that these compounds are antiestrogenic in breast tissue, fat tissue, and in the hypothalamus, which is what we want in bodybuilding, but are estrogenic in bone tissue and with respect to favorable effect on blood lipid profile, both of which are, again, desirable. They also appear to have some estrogenic effect on mood, though this may be in only parts of the brain (the matter is not studied.)

Cyclofenil is a similar drug to the above two. Clomiphene will do everything that the other two will do, but for some unknown reason, has been found more effective than tamoxifen both medically and in bodybuilding for increasing LH production.

Raloxifene (Evista) is a new selective estrogen receptor modulator that, for women, has the advantage of being an antiestrogen in the uterus, whereas clomiphene and tamoxifen are estrogens in that tissue. For this reason, the latter two drugs can promote uterine cancer, while raloxifene actually should help prevent it, and is therefore a superior drug for women. It is not known how effective it may be in increasing LH production.

While on high dose androgens it is impossible to maintain LH production in any case, and clomiphene can do no good in that regard. As androgen levels return to normal, however, a dose of 50 mg/day of clomiphene if estrogen levels are reasonable, or 100 mg/day if estrogen levels are high, is usually effective in restoring natural testosterone production.
Because the drug has a long half-life, when one takes 50 mg/day the amount in the system is not only the 50 mg just taken, but also approximately another 250 mg from previous days. Thus, to immediately arrive at the therapeutic level, one would take 300 mg (50 mg six times) on the first day, and then continue with 50 mg/day.

A small percentage of individuals suffer vision problems from use of clomiphene, which is generally reversible upon discontinuance. These persons, of course, should not use the drug after discovering the problem.

It also must be pointed out that these are prescription drugs, and should be obtained and used only by precription with medical advice, though the selective estrogen receptor modulators have excellent safety records.

After a cycle, it is reasonable to continue clomiphene use until at least four weeks after the last injection of long acting ester, or at least two weeks after the last use of an oral, or until natural testosterone production is clearly back to normal, whichever comes last.

Conclusion

Other than acne and accelerated hair loss, the two most common problems of AAS use are gynecomastia and difficulty in recovering natural testosterone production. Antiestrogenic drugs can effectively address both problems and are safe for most individuals. Ideally, if aromatizable drugs are used, the problem is corrected at the source by limiting production of estrogen by using an aromatase inhibitor. However, it is also effective to use a selective estrogen receptor modulator such as Clomid. The latter drug is also of particular use in helping to restore natural testosterone production after a cycle.