Selective Androgen Receptor Modulators: An Emerging Liver Toxin

Abstract

Selective androgen receptor modulators (SARMs) are a class of nonsteroidal drugs that are favored over anabolic androgenic steroids (AASs) for their tissue-selectivity and improved side-effect profile. These drugs have been evaluated for treatment of various diseases including muscle-wasting disorders, osteoporosis, and breast cancer. Despite lacking approval for therapeutic use, SARMs are widely used recreationally as performance enhancing drugs by bodybuilders and athletes. In recent years, cases of drug-induced liver injury (DILI) secondary to SARMs have begun to emerge, but little is known regarding their hepatotoxicity. In this review, we provide current knowledge regarding DILI from SARMs. A literature search was conducted regarding SARMs and liver injury to evaluate relevant cases and information. SARMs have been associated with a cholestatic syndrome congruent with that of DILI from AASs, and it consists of a bland cholestasis in which there is minimal bile duct injury, inflammation, or necrosis. Patients present with an insidious onset of jaundice with marked hyperbilirubinemia and mild hepatic enzyme elevations. No clear treatment exists, although patients typically show improvement with cessation of the offending SARM. Given the novelty of these drugs, further study is necessary to understand diagnosis, management, and complications of SARM-related DILI.

Keywords: Anabolic steroids; Androgen receptor agonist; Cholestasis; Drug-induced liver injury.

Fig. 1. Proposed mechanisms of bland cholestasis associated with SARMs.

(A) SARM binding to bile salt exporter pumps and disrupting bile acid transport from the hepatocyte to the bile duct. (B) SARM molecules interact with the hepatocyte lipid bilayer which decreases the permeability of osmotic factors (e.g. glutathione) that facilitate bile flow. (C) Canalicular microvilli damage seen in hepatocytes metabolizing SARMs with associated biliary stasis and canalicular dilation. (D) SARM induction of hepatocyte and canalicular injury resulting in canalicular contraction and decreased bile flow. SARM, selective androgen receptor modulator.