The androgen receptor is part of the steroid hormone nuclear receptor superfamily, and binding of its endogenous hormones (such as testosterone and dihydroxytestosterone) modulates its function as a transcription factor (proteins that regulate gene transcription).
while the Androgen receptors Widely known for its role in male sexual development and maintenance, it also has important effects on bone density, strength, muscle mass, blood formation, clotting, metabolism, and cognition. .
Testosterone and synthetic steroid hormones have many clinical applications.
Its effects can broadly be categorized as anabolic (increased bone density, muscle mass) or androgenic (impaired fertility, virilization, acne). Despite its potential benefits, therapeutic use is often curtailed due to potential side effects, including erythrocytosis, prostatic hypertrophy, hepatotoxicity, estrogen aromatization and testicular atrophy. .
Selective androgen receptor modulators (SARMs) are small molecule drugs that can exert varying degrees of agonist (agonist) and antagonist (inhibitory) effects on androgen receptors in different tissues.
Their actions can be understood by looking at the selective estrogen receptor modulators (SERMs) that preceded them.
Tamoxifen is widely used to treat breast cancer, acting as a breast antagonist, a bone stimulator and a partial stimulator in the uterus. It is precisely the tissue-specific effects of these agents that make them attractive, as they can be tailored to treat specific medical conditions while minimizing off-target effects.
SARMs are chemically engineered to more specifically target androgen receptor function in specific tissues while minimizing off-target effects. .
For example, animal models of muscular dystrophy have shown encouraging results using SARMs .
SARMs have begun to be studied in preclinical and clinical phases as treatment options for cachexia associated with cancer, breast cancer, benign prostatic hyperplasia, and hypogonadism. .
Background and mechanisms of SARMs
An improved understanding of selective estrogen receptor modulators (SERMs) and their mechanisms of action in the 1990s, combined with the increasing use of tamoxifen in the treatment of breast cancer, has stimulated interest in similar drugs to modulate the androgen receptor.
Tissue specificity is the main feature underlying the therapeutic potential of SARMs.
Steroid though Hormone replacement therapy Offering many benefits, it can be associated with a high rate of adverse effects, due in part to the widespread and non-specific activation of the androgen receptor in many different tissues.
Essentially, there are different cofactors and cellular effects downstream between the hormone and SARMs.
This has been experimentally proven with SARMs, TSAA-291, and dihydrotestosterone (DHT). Despite binding to androgen receptors in the same tissues, TSAA-291 showed a different cellular response than DHT in the prostate.
This suggests that there are conformational differences in ligand (hormone)-androgen receptor complexes that are partly responsible for unique cellular responses. .
Below is a simplified signaling pathway generated by SARM:
appearance: SARM signaling mechanism. Like androgens, SARMs enter the cytoplasm, where they displace the androgen receptors from heat shock proteins. Once bound, they translocate to the nucleus and act as transcription factors by binding to androgen response elements (AREs). Depending on the tissue type and the regulatory environment of the cell, different co-regulatory proteins help determine and modulate the transcriptional response. HSP = heat shock protein. AR = androgen receptor. ARE = androgen response element. Adapted from Solomon et al 2019 
Given the complex biological actions of the steroid hormones and SARMs depending on their binding affinity, degree of morphogenesis, and androgen receptor antagonism in different tissue types, high-throughput screening methods are used to discover SARMs with favorable biological and pharmacological profiles.
Although there are currently no FDA-approved indications for SARMs, researchers are studying potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a paucity of drug interactions.
Early clinical studies have indicated potential uses for SARMs in the treatment of cachexia associated with cancer, benign prostatic hyperplasia, hypogonadism, and breast cancer, with positive results. .
Potential for abuse
The anabolic effects of SARMs and their lack of androgenic side effects have sparked a lot of interest in bodybuilders. community and create the potential for abuse among competing athletes. Unfortunately, despite not being approved by the Food and Drug Administration, many of the SARMs mentioned in the studies above are available for purchase online, though it’s unclear how verifiable their sources are. .
There are forums complete with getting started guides for first-time users (on topics like getting and interpreting blood work) and easily accessible purchase links.
In 2008, the World Anti-Doping Agency banned SARMs in sport, citing their potential for abuse .
A study sponsored by governmental anti-doping organizations in Europe used mass spectrometry to identify S-4 (andarine) and chemically related impurities in supplements sold online, indicating that online retailers offer bioactive SARMs in their supplements. .
The androgen receptor is a complex signaling organ that has critical effects on Tissue development, growth and maintenance. Although steroidal hormones have beneficial clinical applications, their broad activation of the androgen receptor leads to treatment-limiting side effects.
SARMs and tissue selectivity have the potential to revolutionize the treatment of many debilitating diseases.
Recent clinical trial results have shown mixed but promising results, and basic research continues to fuel the idea that SARMs can be powerful and effective treatments for a wide variety of conditions, from Alzheimer’s disease and osteoporosis to male contraceptives and benign prostatic hyperplasia (BPH).
These agents will continue to be investigated and developed given their novel mechanisms of action and potential to treat and supplement cases with lack of effective therapies or therapies with Unacceptable side effects.
To date, SARMs have always proven to be well tolerated, easy to administer, and generally lack significant drug interactions which will only enhance their future applicability. However, more research studies are needed to confirm the safety and effectiveness of these medications before they are approved for clinical use.
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2. Unwalla, R., et al., Structural-Based Approach to Identification 5-[4-Hydroxyphenyl]Pyrrole-2-carbonitrile derivatives as effective androgen receptor modulators and histology. J Med Chem, 2017. 60 (14): p. 6451-6457.
3. Handlon, AL, et al., Improving Ligand Efficiency of Selective Androgen Receptor Modulators (SARMs). ACS Med Chem Lett, 2016. 7(1): p. 83-8.
4. Ponnusamy, S., et al. Androgen receptor agonists increase lean mass, improve heart and lung function and prolong survival in preclinical models of Duchenne muscular dystrophy. Hum Mol Genet, 2017. 26 (13): p. 2526-2540.
5. Hikichi, Y., et al., Selective androgen receptor modulator activity of the antiandrogen TSAA-291 and cofactor recruitment profile. Eur J Pharmacol, 2015. 765: p. 322-31.
6. Solomon, ZJ, et al., Selective androgen receptor modulators: current knowledge and clinical applications. Sex Med Review, 2019.7(1): p. 84-94.
7. Thevis, M., et al., Detection of selective arylpropionamide derived from the androgen receptor (SARM) S-4 (Andarine) in a black market product. Anal Drug Testing, 2009. 1 (8): p. 387-92.