It is not often that oral anabolic-androgenic steroids (AAS) are discussed in studies. Certainly, that’s not because they have disappeared from use by bodybuilders, athletes and others interested in building muscle. They are prominently mentioned in doping-scandal stories, prevalently used by drug-enhanced bodybuilders who purchase their AAS illicitly (i.e., illegally) and are often the “gateway” form of AAS used by those experimenting with AAS for the first time, due to the innate anxiety most people have about needles. Yet, there is little research published about oral AAS, as they are very limited in terms of approved indications (i.e., diseases or conditions that are acceptable reasons to treat with the specific drugs), and have recognized adverse (harmful) effects. Elevated Liver Enzymes Oral AAS are known to be toxic to the liver if they are C17-alpha alkylated, which means that a side chain has been attached at a specific point on the molecule to protect it from being cleared or degraded.1,2 Potentially, they may cause tumors in the liver, including deadly forms of malignant cancers— not just in frail people with chronic conditions, but in young, healthy bodybuilders.3,4 While many, possibly the majority of individuals can tolerate C17-alpha alkylated drugs, it appears that 20 percent to 40 percent will experience elevated liver enzymes in blood tests, even on the lowest replacement dose. The liver effect of oral AAS does not appear to be dose-related, but either does or does not occur. This increase in liver enzymes may be due to a “backup in bile” or drug-induced liver injury, resulting in tissue death.5 The hepatotoxic (meaning liver-injuring) effects of C17-alpha alkylated AAS are not fully understood, but appears to involve more than the effect of these AAS on processes involved in cellular maintenance, such as protecting the cell membrane, vital functions or antioxidant status.6 As well, oral AAS appear to interfere with the processing of cholesterol, and impede protective effects of glucocorticoids (e.g., cortisol).6,7 When cells cannot respond to injury, suffering worsens until it reaches a point where function deteriorates or even cell death occurs. In susceptible individuals, this may result in the promotion of a cancerous growth, much like oxidative damage appears to trigger cancer cells (e.g., sunburns in skin) or toxins from tobacco smoke in lungs. For the bodybuilder who is committed to his/her choice to misuse oral AAS, bodybuilding lore has suggested a number of strategies to reduce liver toxicity. Some of these have sufficient science supporting these suggestions to merit discussion. Reducing Cholesterol As the common injury is related to “bile backup” due to cholestasis— meaning that the gallbladder gets sludgy and the bile is not secreted into the intestines, but backs up like bad plumbing— strategies to reduce cholesterol or increase the bile acid content may be of benefit. The most effective may be the use of bile acid resin drugs, such as cholestyramine. This drug binds bile acids in the intestines, preventing them from recycling through the liver. While this may sound like it would worsen the situation, instead the liver sees the lack of bile acids as a signal to increase the production of new bile acids from cholesterol. This provides both a reduction in cholesterol within the liver, and an increase in bile acids that “loosen” the consistency of bile, making it easier for the gallbladder to secrete bile in response to a meal. Note, it is important not to be on a low-fat diet, as there is less of a signal to the gallbladder when dietary fat is low. Alternatively, bile acid supplementation, such as the use of ox bile extract, may offer relief, but does not offer the secondary benefit of lowering liver cholesterol. Cell Membrane Repair The cell membrane is not only a “wall” that protects the insides of a cell, but is also the “home” for a variety of enzymes, receptors and transporters. If the cell membrane is damaged, then the entire cell is at risk. Early signs of membrane damage include an increase in various enzymes (e.g., LDH, ALT, AST) as the cell becomes “leaky.” Thus, providing the components that aid in membrane repair and support are vital. This includes phospholipids and antioxidants. Phospholipids are prevalent in a variety of common foods, such as egg yolk and soy lecithin. Thus, it is important to include these food sources in the daily diet. Membrane antioxidants include vitamin E, estradiol and even cholesterol. However, many oral AAS reduce estradiol, as they are non-aromatizable. A study published in the journal Clinical Toxicology reported positively on the protective effect of a product called “Compound N” against elevations in enzymes associated with liver damage in AAS misusers.8 Compound N contains phospholipids and vitamins. Cell death was noted in a test-tube study, and may be a consequence of what is called the integrated stress response. This is basically an overload of the protein-making function of the cell, resulting in “bad” protein output, like a factory putting out cars that won’t start or even move. The production line halts, and the factory is shut down until the problem is solved. If the problem is unsolvable, the factory shuts down permanently. A surprising amount of research supports the potential for a product that is used by a number of AAS misusers to protect against this integrated stress response. This product is called TUDCA, the acronym for tauroursodeoxycholic acid. Acting as a “chaperone,” TUDCA prevents various stress responses from occurring, preventing the assembly line failure.9,10 TUDCA is being investigated in a variety of clinical conditions, and appears to be effective.11 Intracellular Antioxidants Previously, the protective effects of membrane-bound antioxidants were mentioned. Antioxidants within the liver cell are also depleted with prolonged exposure to oral AAS. Among the most potent intracellular antioxidants is glutathione. While glutathione can be taken as a supplement, it is relatively inefficient, as it is “digested” and must be reformed inside the affected cell. A more practical approach in the prevention of oxidative damage may be supplementation with the precursor N-acetylcysteine (NAC), which is widely available as a dietary supplement.12,13 If pronounced oxidative damage is occurring, combinining glutathione and NAC may have a place if glutathione synthesis is impaired by the degree of damage in the affected cells. While little of the glutathione may be delivered intact, it may aid a liver that is suffering functionally from oral AAS exposure, or other causes of drug-induced liver injury (e.g., alcohol, NSAID drugs, iron overload, etc.). Milk thistle has long held a place as a liver-protectant in bodybuilding lore, and science appears to support this based on animal studies.13,14 In fact, it may be a more powerful option than NAC, though NAC is unquestionably of value in this setting. Berberine is another common supplement that may aid in protecting the liver from drug-induced liver injury.15 Advice for Bodybuilders There is little doubt that bodybuilders are too often informed they have liver injury, as the lab test used to detect this is not liver-specific.16 In fact, the skeletal muscle releases the same enzymes, so following an intensive training session, it is not unusual to see an elevation in AST and ALT for several days after a single workout. Imagine if one trains daily or almost daily, the enzyme levels remain elevated to a degree that requires a bit more work to determine the cause. However, numerous drugs can cause drug-induced liver injury, and oral AAS are a well-known cause. The liver is a vital organ, and chronic damage may lead to fibrosis (scarring), necrosis (cell death) and even develop into tumors. Do not be falsely assured by the potential excuse of exercise being the cause of elevated liver enzymes, especially if oral AAS, excess drinking or other causes are present. Inform your physician of your lifestyle so he can order additional tests that are more specific to the liver, to assess its state of health.