Side Effects
Compared with steroidal androgens, SARMs appear to be much better tolerated with few incidences of severe adverse effects. In addition, many of these pre-clinical agents can be administered as oral therapies. This helps to reduce the risk of accidental exposure, as can be seen with topical testosterone, and can significantly improve ease of administration compared to currently available forms of TTh. Enobosarm treatment led to small increases in hemoglobin in certain subjects, increases in ALT, and decreased serum HDL levels. Other early clinical studies have investigated the safety profiles and pharmacodynamics and kinetics of several candidate SARMs.
SARM being investigated by GlaxoSmithKline for muscle growth and strength in subjects with muscle wasting, was tested in a two part, randomized, double-blind, placebo-controlled dose-escalation Phase 1 study to assess safety, pharmacokinetics and pharmacological effects in a small cohort of young men and postmenopausal women.Overall the treatment was well tolerated, with the most common adverse events being constipation, dyspepsia, and nausea (3 of 89). One female subject developed a maculopapular rash with biopsy consistent with a drug reactions, two female subjects developed elevated ALT values 2–2.5 time the upper limit of normal during treatment, and two male subjects experienced muscle soreness and elevated CK levels weeks into the follow up period.GSK2881078 was also associated with reductions in HDL.
Clinical testing has shown SARMs to be well tolerated with mild and infrequent adverse effects. Several of the trials showed no increases in AEs compared to placebo. The most consistent biological alteration shared between most of the tested compounds were decreases in HDL levels and transient increases in ALT. Anabolic androgenic steroids (AAS) like testosterone are known to increase liver transaminase levels, and there have been reports of peliosis hepatis, cholestasic jaundice, and liver malignancies associated with their use. None of the subjects in the above trials had alterations in their bilirubin levels to suggest cholestasis, but several had elevations in ALT, suggesting hepatocellular injury. Liver damage from AAS was initially thought to be due to an idiosyncratic hypersensitivity reaction, but has been shown to be due to intrinsic direct hepatotoxicity of AASs depending on individual susceptibility with genetics playing a role. Thus, it remains to be seen if SARMs may pose a risk of significant hepatotoxicity and further studies are needed to examine the relationship between theses transient ALT elevations and pathologic hepatic changes.
Continued investigation and development of these agents is called for given their novel mechanisms of action and potential to address and complement conditions with a lack of effective therapies or therapies with unacceptable side effects. Additionally, to date SARMs have consistently been shown to be well tolerated, easily administered via an oral route, and overall lacking in significant drug interactions which can only further increase their future applicability. Like the SERMs before them, the next decades could herald the approval and widespread use of SARMs for an array of indications. However, further studies are currently needed to determine the safety and efficacy of these medications before they are approved for clinical use.
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