Ora steroids and their Hepatoxicity

Once testosterone is ingested orally it is readily absorbed into the hepatic circulation, yet the catabolism of testosterone by the liver is really fast, therefore normal testosterone is not able to reach the target organs before being “destroyed”. Therefore most testosterone preparations are designed to bypass hepatic metabolism. [1]

Decades ago, scientists found that adding an alkyl group to the 17α position of testosterone retarded its hepatic catabolism. Consequently, 17α-alkylated androgens are androgenic when administered orally; however, they are less androgenic than testosterone itself, and they cause hepatotoxicity, whereas native testosterone does not. [1]

Alkyl substitution prevents deactivation of the steroid by first-pass metabolism. In the next figure we can see the testosterone molecule and the different modifications made to it, including the 17alfa-alkyl group added. [2]

Extracted from: Br J Pharmacol. 2008 Jun; 154(3): 502–521. Pharmacology of anabolic steroids. A T Kicman [2]

In the following figure we can see the different anabolic androgenic steroids that have been 17alfa alkylated and therefore are active in their oral form:

Extracted from: Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition. [1]

This modification to the molecule making it resistant to hepatic metabolism, is the exact cause of the hepatotoxicity described in these agents (as liver toxicity is extremely rare or maybe even not existent with parenteral steroids).

Several diseases have been described with these agents, including elevations of liver enzymes, cholestatic jaundice, hepatic neoplasms, and peliosis hepatis. [4]

It can be difficult to eliminate the risk of liver toxicity with parenteral agents, as physical activity can increase liver enzymes (AST, ALT), but liver dysfunction is extremely rare with parenteral agents. [4]

So there you go, this is what makes oral agents oral, the very same reason that makes them hepatotoxic, and therefore, the very same reason why combination of these agents in the same cycle is extremely discouraged as the hepatotoxicity can be exponentially increased.

Bibliography

1-. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 12th Edition.
by Laurence Brunton and Bruce Chabner.
2-. Br J Pharmacol. 2008 Jun; 154(3): 502–521. Pharmacology of anabolic steroids. A T Kicman
(http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2439524/ )
3-. Regul Toxicol Pharmacol. 2010 Jun;57(1):117-23. doi: 10.1016/j.yrtph.2010.02.001. Epub 2010 Feb 12. Adverse health effects of anabolic-androgenic steroids. van Amsterdam J, Opperhuizen A, Hartgens F.
(http://www.ncbi.nlm.nih.gov/pubmed/20153798 )
4-. J Strength Cond Res. 2009 Aug;23(5 Suppl):S1-S59. doi:10.1519/JSC.0b013e31819df2e6. Position stand on androgen and human growth hormone use. Hoffman JR, Kraemer WJ, Bhasin S, Storer T, Ratamess NA, Haff GG, Willoughby DS, Rogol AD.
(http://www.ncbi.nlm.nih.gov/pubmed/19620932 )