Many orally absorbed medicines pass through the liver before entering the general bloodstream. For most steroid hormones, this pathway is fatal: liver enzymes destroy them before they have time to act. Methasterone is an example of a molecule specifically "engineered" to survive this pathway. The editors explain how it works, what is known about the drug's metabolism, and why the price of oral activity falls precisely on the liver.
First pass effect
Substances that we swallow are absorbed in the intestine and enter the liver through the portal vein and then the general bloodstream. The liver is the main "chemical factory" of the body, and its enzymes are able to change or destroy a significant part of the substance even before it reaches the target tissues. This phenomenon is called the first pass effect.
For testosterone, the first-pass effect is very pronounced. When regular testosterone is taken orally, most of the dose is inactivated by the liver, so oral replacement therapy uses special forms, such as testosterone undecanoate, which is absorbed through the lymphatic system.
Bioavailability is the fraction of a dose that enters the systemic circulation unchanged. Intravenous administration has 100% bioavailability; other injectable formulations differ, for oral steroids without protective modifications, it is very low.
That is why pharmacologists of the middle of the 20th century were looking for chemical "shields" that would allow steroids to survive the first encounter with the liver.
The role of the 17-alpha-methyl group
One of the main ways of inactivation of testosterone and DHT in the liver is the oxidation of the 17-beta-hydroxyl group to the 17-keto group. The 17-ketosteroids formed have much weaker androgenic activity and are quickly excreted.
When a methyl group is added to the 17-alpha position, 17-beta-hydroxyl becomes a tertiary alcohol that enzymes cannot oxidize. The molecule is "insured" from the main path of destruction and leaves the liver in an active form in a much larger amount.
Methasterone has just such a 17-alpha-methyl group. The second modification, 2-alpha-methyl, is more important for muscle metabolism, but probably also further slows some of the hepatic transformations of the A ring.
The exact bioavailability of methasterone in humans has not been measured: this requires pharmacokinetic studies, which no one has conducted for an unregistered compound. Therefore, any specific percentages found on the Internet are guesswork.
Metabolism and excretion
Although 17-alpha-methyl blocks the main inactivation pathway, the liver has other tools. Enzymes reduce the 3-keto group, hydroxylate the molecule in various positions, and then add glucuronic acid or sulfate to it, which makes the metabolites water-soluble and allows them to be excreted in the urine.
Methasterone metabolism was studied mainly in anti-doping laboratories. The work of Gauthier et al. (2009) on cryopreserved human hepatocytes described metabolites of drostanolone and 17-methyldrostanolone (ie, methasterone), which became the basis for reliable detection of the drug in urine samples.
As with other 17-alpha-methylated steroids, in the metabolism of methasterone, compounds with an altered structure of the D ring are formed, which are characteristic of this class. They help anti-doping laboratories to identify the drug even after some time after administration.
The exact half-life of methasterone in humans is unknown. For other oral 17-alpha-methylated androgens, it is usually hours, not days, but it is incorrect to extrapolate this data to methasterone without research.
| Parameter | Methasterone | Editorial comment |
|---|---|---|
| Route of administration | Oral | Possible due to 17α-methyl |
| Bioavailability in humans | Not measured | Figures from the Internet are guesswork |
| Half-life | Not established | No pharmacokinetic studies |
| Metabolism | Hepatic | Metabolites were described in vitro on hepatocytes |
| Elimination | Mostly with urine in the form of conjugates | Basis for doping control |
The hepatic cost of oral activity
The same property that allows methasterone to survive the first pass makes the liver the organ with the highest exposure. The concentration of the drug in the portal vein and hepatocytes is higher than in peripheral blood, and the slowed metabolism means a longer interaction with liver cells.
17-alpha-alkylated steroids are believed to disrupt bile acid transporters in hepatocyte membranes. When bile is not removed from the cell properly, cholestasis develops, the most characteristic type of liver damage for this class of substances.
For methasterone, such lesions have been documented in several clinical case series. Shah et al (2008) described five patients with cholestatic jaundice associated with methasterone-containing products. Nasr and Ahmad (2009) reported a case of severe cholestasis with renal failure.
In addition, oral androgens have a stronger effect than injectable androgens on the hepatic synthesis of lipoproteins, which is manifested by a decrease in HDL. This effect is also associated with high liver exposure after oral administration.
Factors that change the load
The burden on the liver when taking oral androgen depends not only on the molecule. Additional factors, which are often underestimated, play a significant role.
- Alcohol. Independently loads the liver and increases the risk of damage.
- Other drugs and supplements. Paracetamol in high doses, some antibiotics, herbal extracts and "fat burners" can have their own hepatotoxicity.
- Existing liver diseases. Fatty liver disease, viral hepatitis, hereditary disorders of bilirubin metabolism.
- Duration of use. The risk of cholestasis increases with time of exposure.
- Unknown product composition. The actual content of illegal pills often differs from the declared content.
The widespread opinion in the amateur community that "hepatic protectors" neutralize the hepatotoxicity of 17-alpha-alkylated steroids has no convincing clinical confirmation. The only sure way to reduce the risk is not to expose the liver to this strain.
Any signs of cholestasis—jaundice, itchy skin, dark urine, light-colored feces—need immediate medical attention.
Editorial conclusions
Methasterone is active when taken orally due to the 17-alpha-methyl group, which blocks the main pathway of its hepatic inactivation.
Exact pharmacokinetic parameters of the drug in humans — bioavailability, half-life — have never been measured; primarily its metabolism, studied by anti-doping laboratories, is known.
The price of oral activity is high liver exposure, as manifested by documented cases of severe cholestasis.
We also recommend that you read our materials on the complete review of the risks of methasterone, on the hepatotoxicity of mesterolone, and on liver tests in athletes.
References
- Gauthier J, Goudreault D, Poirier D, Ayotte C. Identification of drostanolone and 17-methyldrostanolone metabolites produced by cryopreserved human hepatocytes. Steroids. 2009;74(3):306–314.
- Shah NL, Zacharias I, Khettry U, Afdhal N, Gordon FD. Methasteron-associated cholestatic liver injury: clinicopathologic findings in 5 cases. Clin Gastroenterol Hepatol. 2008;6(2):255–258.
- Nasr J, Ahmad J. Severe cholestasis and renal failure associated with the use of the designer steroid Superdrol (methasteron): a case report and literature review. Dig Dis Sci. 2009;54(5):1144–1146.
- Kicman AT. Pharmacology of anabolic steroids. Br J Pharmacol. 2008;154(3):502–521.
- LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Androgenic Steroids. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases.
- Robles-Diaz M, Gonzalez-Jimenez A, Medina-Caliz I, et al. Distinct phenotype of hepatotoxicity associated with illicit use of anabolic androgenic steroids. Aliment Pharmacol Ther. 2015;41(1):116–125.
