Metabolites of Masteron Propionate: How the Body Breaks Down the Drug

To understand how any steroid works and how long it “leaves a trace” in the body, one must trace its path from injection to excretion. The editorial team examines the biotransformation of drostanolone propionate: what happens to the ester, which enzymes change the molecule, which metabolites appear in the urine and why exactly they interest anti-doping laboratories.

The starting molecule and the role of the ester

Drostanolone is 2α-methyl-5α-androstan-17β-ol-3-one, that is, a derivative of dihydrotestosterone (DHT) with a methyl group at position 2α. This small modification increases the molecule’s resistance to inactivation by the enzyme 3α-hydroxysteroid dehydrogenase in muscle tissue compared with DHT itself, which explains its higher anabolic activity.

Propionate is the residue of propionic acid attached to the 17β-hydroxyl group. The ester itself has no hormonal action: it only makes the molecule more lipophilic, thanks to which it is released more slowly from the oil depot in the muscle.

Propionate is a short ester with only three carbon atoms. Therefore the depot empties faster than in the case of enanthate, and the concentration of the substance in the blood rises and falls faster. This is exactly what determines the pharmacokinetic difference between the two forms of masteron, while the active molecule in them is the same.

After entering the bloodstream, the ester is quickly split off by nonspecific esterases of the plasma and tissues. From this moment the drug is no longer “propionate” — free drostanolone circulates in the body, and all subsequent metabolism is identical for any ester form.

Phase I: enzymatic transformations

The main organ of androgen biotransformation is the liver, although certain reactions also occur in peripheral tissues. For drostanolone the key reactions are redox reactions involving hydroxysteroid dehydrogenases.

The first important reaction is oxidation of the 17β-hydroxyl group to a 17-keto group by the enzyme 17β-hydroxysteroid dehydrogenase. The resulting 17-ketosteroid has significantly weaker androgenic activity.

The second is reduction of the 3-keto group to a 3α-hydroxyl. As a result, 2α-methyl-5α-androstan-3α-ol-17-one is formed — a compound that classic works on the metabolism of anabolic steroids describe as the main urinary metabolite of drostanolone. 3α,17β-dihydroxy derivatives and hydroxylation products may also form.

Importantly, the molecule is already 5α-reduced, so the enzyme 5α-reductase does not act on it, and thanks to the absence of a double bond in ring A it is not a substrate for aromatase. Thus drostanolone is not converted into estradiol — this is a fundamental difference from testosterone.

• Hydrolysis of the ester by esterases → free drostanolone.
• Oxidation of 17β-OH → 17-keto derivatives.
• Reduction of 3-keto → 3α-hydroxy derivatives.
• Aromatization and 5α-reduction — do not occur.

Phase II and excretion

The products of phase I remain fairly lipophilic, so to be excreted in the urine they must be made water-soluble. This function is performed by conjugation — the attachment of glucuronic acid (by UGT enzymes) or a sulfate group (by sulfotransferases).

Glucuronides of the main metabolite make up a significant share of what is excreted by the kidneys. That is why in classic urine analysis the sample is first treated with the enzyme β-glucuronidase to “release” the steroid before chromatography.

Sulfated metabolites long remained less studied, since standard procedures did not hydrolyze them. The development of liquid chromatography with mass spectrometry made it possible to analyze conjugates directly, and in anti-doping science works appeared on long-term metabolites of a number of anabolic steroids.

Part of the substance and its metabolites is also excreted with bile, but for practical diagnostics the main significance belongs to urine.

Metabolites in doping control

Anti-doping laboratories look not only for the parent substance but above all for the metabolites, since it is they that persist in the urine the longest. For drostanolone the marker is the already-mentioned 3α-hydroxy-17-keto metabolite, as well as other specific products.

The methods GC-MS and GC-MS/MS, and in recent years LC-MS/MS, allow these compounds to be detected at very low concentrations. Sensitivity is constantly increasing, so the detection window that was considered typical a few years ago may today be significantly longer.

The fact that the ester — propionate or enanthate — does not change the set of metabolites has practical significance: a “short” ester does not guarantee a short detection window, since the metabolites of the active molecule can be detectable long after the substance has stopped acting.

The editorial team does not provide exact universal detection times: they depend on the dose, the duration of use, individual enzyme activity and the laboratory’s method. Any “clearance tables” from the internet have no scientific basis.

Individual differences and the load on the liver

The activity of steroid-metabolizing enzymes differs among people because of genetic variants. A well-studied example is the polymorphism of the UGT2B17 gene, the deletion of which substantially affects the excretion of testosterone glucuronide. For drostanolone the specific data are limited, but the very principle of individual variability is obvious.

Drostanolone is administered by injection and is not a 17α-alkylated steroid, so its direct hepatotoxicity is considered lower than that of oral drugs like methandienone or oxandrolone. Still, “lower” does not mean “absent,” especially against the background of other substances and alcohol.

Changes in liver enzymes in people who use injectable steroids may also be related to muscle damage after training, since AST and ALT are also present in muscle tissue. Therefore interpreting the tests requires assessment of the clinical picture by a doctor.

The metabolism of other drugs against the background of androgens may also change: for example, anabolic steroids can enhance the action of indirect anticoagulants. This is one more reason why a doctor should be informed about taking any hormonal substances.

For more on this topic, read our articles “The legal status of masteron propionate in Ukraine and the EU,” “How to recognize a counterfeit of masteron propionate” and “Masteron enanthate and the kidneys: what is known about the load.”

Editorial conclusions

Propionate is only a “transport”: after the ester is split off, it is free drostanolone that works and is metabolized in the body.

The main transformations are oxidation at position 17 and reduction at position 3 with subsequent glucuronidation and sulfation; aromatization does not occur.

The metabolites, primarily 2α-methyl-5α-androstan-3α-ol-17-one, are the target of anti-doping laboratories and can be detected longer than the drug’s action lasts.

Individual variability of enzymes makes any universal predictions about clearance unreliable.

References

1. Schänzer W. Metabolism of anabolic androgenic steroids. Clin Chem. 1996;42(7):1001–1020.
2. Kicman AT. Pharmacology of anabolic steroids. Br J Pharmacol. 2008;154(3):502–521.
3. Thevis M, Schänzer W. Mass spectrometry in sports drug testing: structure characterization and analytical assays. Mass Spectrom Rev. 2007;26(1):79–107.
4. Jakobsson J, Ekström L, Inotsume N, et al. Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism. J Clin Endocrinol Metab. 2006;91(2):687–693.
5. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; актуальна редакція.
6. Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.