Fluoxymesterone
Introduction
To people who are familiar with the compound, fluoxymesterone is probably better known as Halotestin, its brand name as produced by the pharmaceutical company Upjohn. Fluoxymesterone was and is immensely popular among power- and weightlifting athletes and for a while among endurance athletes as well. Although well known in the bodybuilding community, it was not a much sought after substance in that sport. That is likely because fluoxymesterone has a reputation of being a harsh steroid that produces relatively mild results. While this statement is not entirely untrue, it does deserve some nuance. Fluoxymesterone is definitely a unique and possibly useful compound.
The main problem with the compound is its relatively high toxicity. Some toxicity is logically expected, since fluoxymesterone is a 17α-alkylated compound, generally consumed orally, but it should be considered one of the harsher products among this class of steroids as well, something that warrants some care on the part of the user. Because of this it can also not be used for prolonged periods of time. The limit is usually a good 6 weeks at 40 mg per day, which is a relatively low dose for a compound with such low affinity for the androgen receptor. Because of this and the low rate of actual muscle gained when using fluoxymesterone alone, usually causes potential users, especially beginners (and that is probably a good thing) to opt for less toxic and more effective drugs.
Fluoxymesterone is derived from methyltestosterone (and not a precursor of said compound, as was once reported in the now defunct World Anabolic Review) and differs from this product by the addition of an 11β-hydroxyl group and a halogenation with fluorine at the 9th carbon atom, both alterations commonly seen with corticosteroids, and not androgens. Both the 11β-hydroxyl1 group and the 9α-fluoro2 group are known to increase binding to the glucocorticoid receptor. This imparts on fluoxymesterone a strong affinity for the glucocorticoid (cortisol) receptor3, without activating it4, thus consistent with a model of competitive inhibition. As we will see throughout this profile, a lot of the actions that are unique to fluoxymesterone are to a large extent the direct result of this interaction. The increased affinity for the glucocorticoid receptor in mind seems to be the only logical explanation for the addition of these two specific groups, although 11β-hydroxy-testosterone has been tentatively identified as a very potent inhibitor of the 11β-hydroxysteroid dehydrogenase Type 1 enzyme22, which converts cortisone to its more active metabolite cortisol. The addition of the 9-fluoro group would likely increase its affinity for that enzyme as well, since it bends the A-ring of the steroid to the α-side2, resulting in a more glucocorticoid like structure. As such a large part of the anti-glucocorticoid action of fluoxymesterone may also be the result of a reduction of metabolism of cortisone to the more potent glucocorticoid cortisol. In support of the latter, a study conducted by Mayer and Rosen3 seem to indicate that while fluoxymesterone is more potent than testosterone in the glucocorticoid receptor inhibiting department, long term, it is not that much more potent in that regard to explain the enormous effect of fluoxymesterone on in vivo glucocortiocid activity. Also in support of this, Ojasoo and Raynaud23 report that C-1 Double bond is more potent than either of the substituents of fluoxymesterone at increasing glucocorticoid receptor affinity, yet fluoxymesterone is considerably more potent as an anti-glucocorticoid than boldenone, though both drugs share similar traits (Increase in appetite, increased stamina and endurance). This would suggest that 11β-HSD1 inhibition is a major pathway in the effect of fluoxymesterone, likely due to its 11β-hydroxy group. In short, many of the potent effects of fluoxymesterone should be seen in light of its anti-glucocorticoid properties, more than its (admittedly weak) androgenic-anabolic properties.
Characteristics
Anabolic Characteristics : As was alluded to previously, fluoxymesterone will rarely be called a potent anabolic, which doesn’t mean you should underestimate its quality as a muscle building agent. The history of figure sports has taught us that there are many way to successfully incorporate weak anabolic drugs into a successful pharmacological regimen. The anabolic effect of fluoxymesterone is, milligram for milligram, definitely not much weaker than that of popular anabolic androgenic steroids like oxandrolone or stanozolol. But where we can easily dose those drugs at 50-100 mg per day for several weeks, with monitoring of blood for hepatoxicity of course, this approach is unlikely with fluoxymesterone, since it is more androgenic and considerably more hepatoxic than the aforementioned products. As such, fluoxymesterone is definitely not a drug used often in cycles to accrue a maximum amount of muscle. It’s low anabolic activity seems to be in line with its low relative binding affinity for the androgen receptor5. And while it does seem to convert to a number of more potent metabolites via 5α-reduction6, their A-ring is not protected against metabolism by 3α-hydroxysteroid dehydrogenase in muscle, and they are therefore not active anabolic agents in skeletal muscle tissue.
Androgenic Characteristics : Although the androgenic effect of fluoxymesterone is often exaggerated, it is a fairly androgenic steroid. The parent compound is a very weak androgen receptor agonist, and that means the same holds true for metabolites with similar structural differences, including its 5α-reduced metabolites6. So, in total, one can still state that fluoxymesterone is less potent androgenically speaking, than testosterone. But as a whole, for an anabolic steroid, it’s a very potent androgen and should be treated as such. This does of course make the compound off limits for individuals with reasons to avoid strong androgens, such as women, elderly men with prostate problems and men with a genetic tendency to male pattern hair loss, since the androgenic effect mostly outweighs the anabolic benefits. Older research using the comparison between the weight increase in seminal vesicles or ventral prostate and the levator ani muscle in castrated rats indicates that the actions of fluoxymesterone favour anabolism, but any person who has actually used the compound will testify against that. As stated, commonly the androgenic strength of this drug is wildly exaggerated, but at best it has an anabolic:androgenic dissociation close to that of testosterone (which indicates no real dissociation since testosterone is the reference drug).
Estrogenic/Progestagenic Characteristics : Fluoxymesterone does not aromatize in any way. This is likely due to the addition of the 11β-hydroxyl group. Fluoxymesterone also has no appreciable binding to the estrogen receptor. Progestagenic activity of this steroid seems somewhat unlikely as well, since the same 11β-hydroxyl group reduces progesterone binding1.
If anything fluoxymesterone has a unique estrogen lowering effect, especially when used in combination with steroids that normally aromatize. This is the result of its potent anti-glucocorticoid effects. Glucocorticoid receptor activation in tissue that produce aromatase, usually results in an increased production of aromatase. Inhibition of glucocorticoid action7 or reduction of glucocorticoid potency8 leads to reduced expression of aromatase. This provides a cumulative role for the use of fluoxymesterone with competitive inhibitors of aromatase or the estrogen receptor in reducing circulating estrogen.
Fluoxymesterone and aggression : Fluoxymesterone is a drug that is often used because it seems to increase the level of aggression in an athlete notably, and short term. This effect is often desired by power- and weightlifters, where a sudden burst of energy/aggression, seems to increase self-confidence and performance. In bodybuilders too, this effect is sometimes desirable to survive the hard, final weeks of a cutting phase, to maintain work-out intensity when energy and caloric intake are low. Some people have mistakenly attributed this characteristic to be androgenic in nature. A grave mistake, since fluoxymesterone is often used as an example of a product that causes roid rage. But the resulting aggression, of this all in all mild androgen receptor binding steroid, stem, you guessed it, from its anti-glucocorticoid action. Glucocorticoid deprivation can notably increase aggression9. Since we know aggression to be a very relative understanding, this basically means that if you already have aggressive tendencies or a short temper, using fluoxymesterone may cause you to lash out quicker, but should be less of an issue if you are not usually quick to fly off the handle. Be aware that the use of strong androgens, estrogens11 or progestins10 can augment aggressive behaviour when using fluoxymesterone.
Fluoxymesterone increases endurance : Several anabolic androgenic steroids are known for their effect on increasing hematocrit and red blood cell mass. For this reason a lot of them have been used in the past to treat various forms of anemia. Increased hematocrit, however, also increases the oxygen content of blood and oxygen delivery to tissues. This in turn increases performance. Before the appearance of synthetic erythropoietin (rhuEPO, Epogen) and its derivatives, various brands of fluoxymesterone were much sought after by professional and semi-professional cyclists and long-distance runners, because it is very potent in this regard12,13. This is of course in part to its androgen mediated effect on erythropoietin release, but it is also noted that fluoxymesterone also seemed to distinguish itself from the other steroids in that it seemed to mediate increased responsiveness to erythropoietin in cells of the erythrocyte (red blood cell) lineage14. I found this to be very interesting and set out to see if there was a link between this phenomenon and the anti-glucocorticoid activity of fluoxymesterone, and indeed there was. Glucocorticoids seem to reduce the effect of erythropoietin on these cells, most likely due to anti-inflammatory effects15 (the reduction of prostaglandin formation, since prostaglandin E2 has a stimulatory effect on erythropoietin action). In this regard, by the way, it is still a very useful compound, since this indicates a synergistic effect with the use of erythropoietin (rhuEPO, Epogen) or its derivatives. Of course in light of the mechanism behind this effect, it could easily be substituted with other anti-glucocorticoid agents that are more difficult to detect (cycling especially is a sport where thorough drug testing is prevalent) and less toxic. It also seems to plead against the common practice of using corticosteroids for endurance athletes.
Fluoxymesterone is not very suppressive of HPTA : Although suppressive of endogenous testosterone production, just like any androgen, it can be duly noted that fluoxymesterone is all in all much less suppressive than most androgens16. Again, this is likely a result of the anti-glucocorticoid action of fluoxymesterone, since the GnRH gene (which encodes for GnRH, the hypothalamic hormone that initiates the cascade to testosterone synthesis) contains a glucocorticoid response element17. Indeed, Chandran et al.18 demonstrated that dexamethasone had a direct supressive effect on GnRH release. This also means that incorporating fluoxymesterone in a stack, especially at the end of a stack, can take the edge off recovery a bit, especially if post-cycle a non-HPTA-inhibitory glucocorticoid reducing agent is used, such as arginine19,20 for example.
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