Since the last issue of Trans Health I have fielded several biochem questions from trans and non-trans people alike. One of the most interesting came from a trans guy and was regarding a new supplement called 6-OXO™. 6-OXO™ is a compound that reportedly inhibits the conversion of testosterone to estradiol. This conversion is a concern for trans men who are using testosterone, because the last thing that most of them want is more estrogen in their bodies. I decided to write an article on this new compound. In this article I will ask the following questions:
- What is 6-OXO™ and how does it work?
- Where does it come from?
- Does it work at all?
What is 6-OXO™ and how does it work?
Your body is efficient at converting some compounds to other compounds. One of the conversions that happens is the conversion of testosterone to estradiol; another is the conversion of androstenedione to estrone. We will concern ourselves primarily with the conversion of testosterone to estradiol, since these compounds are the most potent of their respective families. This conversion is an undesirable conversion for many trans men.
If we can get nerdy for a minute: your body is a very complex system. Substances called enzymes effect the conversion of one chemical to another.
An enzyme is a typically complex molecule that receives another molecule and structurally manipulates it to create a third molecule. The enzyme has an active site, which is a location into which a precursor molecule (called a “substrate” in relation to the enzyme) fits like a key in a lock. Once the substrate binds to the active site, the shape of the enzyme/substrate complex changes, and the enzyme turns the substrate into another molecule by performing chemical actions upon it. The resultant product is a molecule that we (and many other people, for that matter!) will call a metabolite; this molecule is released from the complex, and the active site on the enzyme is again open to receive another substrate molecule. This conversion happens incredibly quickly— in a fraction of a second— so one enzyme molecule can convert oodles of substrate molecules to their metabolites in a very short period of time.
The primary mechanism for the conversion of testosterone to estradiol is an enzyme called aromatase. Aromatase changes the physical structure of testosterone to estradiol. As you can see in figures 1 and 2, testosterone and estradiol have the same fundamental ring structure; the primary differences between estradiol and testosterone are that estradiol has an aromatic (fully double bonded) ring in the lower left of the figure, while testosterone has no such aromatic ring; in addition, testosterone has a keto (=O) group at the bottom left, while estradiol has a hydroxyl (-OH) group. These seemingly small differences make a big practical difference between the activities of the molecules in question.
fig. 1: testosterone
fig. 2: estradiol
An inhibitor is a compound that blocks the action of an enzyme. Competitive inhibitors, for example, are structurally similar to the substrate such that they bind to the active site of the enzyme, but cannot themselves be converted to the same metabolite by the enzyme. Sometimes inhibitors completely block the action of the enzyme; sometimes they can themselves act as a substrate and be converted by the enzyme, but to a different (usually less potent) metabolite.
6-OXO™ is the product name for a compound chemically known as 4-androstene-3,6,17-trione. ErgoPharm reports that 6-OXO™ is a “suicide inhibitor” of the aromatase enzyme, which means that it is a substrate that permanently bonds to the active site of the aromatase molecule but is not itself converted. This effectively blocks the enzyme from acting on testosterone or other androgen substrates, rendering that particular molecule of the enzyme inactive.
Where does 6-OXO™ come from?
4-androstene-3,6,17-trione, and similar compounds, have been a subject of research since at least the 1960s, and their effects in humans have been known since the 1970s at the latest. They are naturally occurring metabolites of androgens, and have been shown to inhibit aromatase in humans and other animals.
As a product, 6-OXO™ was developed for a bodybuilding audience by a company called ErgoPharm, whose head researcher is a biochemist named Patrick Arnold. If I can be allowed to editorialize for a moment: Pat has a reputation in bodybuilding communities for having a low bullshit tolerance for supplements. Though I have not spoken with him for years, I know Pat personally. He is scrupulously honest to the point of often being a bad marketer, because in my experience he does not want to be seen as a scam artist, and will tell the truth about drugs even if it means that his company will sell fewer products. Pat is one of the few researchers that I trust in the bodybuilding world. The fact that he came up with the product speaks well of it, and the fact that there is independent research to back up his claims makes 6-OXO™ worth a closer look.
Does it work at all?
Your body is well tuned to notice these sorts of changes, and will produce more of the aromatase enzyme to make up for the ineffective enzyme that already exists; therefore, once one stops taking an inhibitor, aromatase levels will increase and the conversion of estrogen will start again. If one is taking doses of testosterone that are greater than the body normally produces, this could be an issue. If you are taking replacement doses— i.e., doses that are the same as a healthy body would produce— aromatization is probably not something to worry about, as some amount of estrogen is required for normal functioning of all bodies.
There are a few studies, performed in the last 25 years, that demonstrate that 4-androstene-3,6,17-trione has the effect of inhibiting aromatization in human bodies. It remains to be seen whether it is an effective compound for trans guys, but I do think that it is worth a try, especially under your physician’s supervision. In fact, if anybody wants to be a guinea pig, have your doctor test your testosterone and estrogen levels before you take the drug, then start a 4-6 week cycle of it, and have the same levels tested halfway through the cycle and at the end of the cycle, but before you stop using it. I would love to hear about the results!
UPDATE: On June 18, 2008, Health Canada issued a warning that 4-AT and 6-OXO had a health risk related to blood clotting and recommended all users immediately cease use. However this warning is based on a single domestic adverse reaction case report “in which an individual with no known predisposing medical conditions developed seizures and blood clots in his brain”.