January 22, 2023 5 min read
The androgen receptor is part of the superfamily of steroid hormone nuclear receptors, and the binding of its endogenous hormones (i.e. testosterone and dihydroxytestosterone) moderates its function as a transcription factor (proteins that regulate transcription of genes).
While the androgen receptor is widely known for its role in male sexual development and maintenance, it also has important effects on bone density, strength, muscle mass, hematopoiesis, coagulation, metabolism, and cognition .
Testosterone and synthetic steroid hormones have many clinical applications.
Their effects can be broadly categorized as anabolic (increased bone density, muscle mass) or androgenic (impaired fertility, virilization, acne). Despite their potential benefits, therapeutic use is often curtailed due to potential side effects, including erythrocytosis, prostate hypertrophy, hepatotoxicity, aromatization to estrogen and testicular atrophy .
Selective androgen receptor modulators (SARMs) are small molecule drugs that can exert varying degrees of both agonist (activates) and antagonist (inhibits) effects on the androgen receptor in different tissues.
Their actions can be understood by considering the selective estrogen receptor modulators (SERMs) that preceded them.
One SERM widely used to treat breast cancer, tamoxifen, acts as an antagonist in the breast, an agonist in the bone and a partial agonist in the uterus. The tissue-specific effects of these agents are precisely what makes them attractive, as they can be tailored to address specific medical conditions while minimizing off-target effects.
SARMs have been chemically engineered to more specifically target androgen receptor function in certain tissues while minimizing off-target effects .
For example, animal models of muscular dystrophy have demonstrated encouraging results utilizing SARMs .
SARMs have begun to be studied in the pre-clinical and clinical phases as treatment options for cancer related cachexia, breast cancer, benign prostatic hyperplasia, and hypogonadism .
An improved understanding of selective estrogen receptor modulators (SERMs) and their mechanisms of action in the 1990s, as well as the growing use of tamoxifen in the treatment of breast cancer, stimulated interest in analogous drugs to modulate the androgen receptor.
Tissue specificity is the key characteristic underlying the therapeutic potential of SARMs.
Although steroid hormone replacement therapy offers many benefits, it can be associated with a high rate of adverse effects, partly due to widespread and nonspecific activation of the androgen receptor in many different tissues.
Essentially, there are different cofactors and cellular downstream effects between a hormone and SARMs.
This was experimentally demonstrated utilizing an experimental SARM, TSAA-291 and dihydrotestosterone (DHT). Despite binding to androgen receptors in the same tissues, TSAA-291 displayed a different cellular response than DHT in the prostate.
This suggests that there are conformational variations in ligand (hormone)-androgen receptor complexes which are partially responsible for the unique cellular responses .
Below is a simplified SARM-induced signaling pathway:
Figure: Mechanism of SARM signaling. Like androgens, SARMs enter the cytoplasm, where they displace the androgen receptor from heat shock proteins. Once bound, they translocate to the nucleus and act as transcription factors by binding androgen response elements (AREs). Depending on the tissue type and 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 steroid hormones and SARMs depending on binding affinity and degree of agonism and antagonism at the androgen receptor in different tissue types, high throughput screening methods are being utilized to discover SARMs with favorable biological and pharmacokinetic profiles.
While there are currently no FDA-approved indications for SARMs, researchers are investigation the potential uses for these compounds. Basic research has focused on the pharmacokinetics and pharmacodynamics of these agents, demonstrating good availability with a scarcity of drug interactions.
Early clinical studies indicated potential uses for SARMs in the treatment of cancer-related cachexia, benign prostatic hyperplasia, hypogonadism, and breast cancer, with positive results .
The anabolic effects of SARMs and their lack of androgenic side effects have generated great interest in the bodybuildingcommunity and create the potential for abuse among competitive athletes. Unfortunately, despite the lack of FDA approval, many of the SARMs mentioned in the studies above are available for purchase online, though it is unclear how verifiable their sources are .
There are forums complete with starter guides for first time users (on subjects like obtaining and interpreting blood work) and links for purchase that are easily accessible.
In 2008 the World Anti-doping Agency banned SARMs in sports, 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 being sold online, suggesting that these online retailers are providing biologically active SARMs in their supplements .
The androgen receptor is a complex signaling apparatus with crucial effects on tissue development, growth, and maintenance. Although steroidal hormones have useful clinical applications, their vast activation of androgen receptors give rise to treatment-limiting side effects.
SARMs and their tissue selectivity have the potential to revolutionize the treatment of many debilitating diseases.
Results from recent clinical trials have shown mixed but promising results and basic research continues to raise the idea that SARMs could be powerful and effective treatments in a wide variety of conditions, from Alzheimer’s disease and osteoporosis to male contraception and Benign Prostatic Hyperplasia (BPH).
Investigation and development of these agents will continue 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.
To date, SARMs have consistently shown to be well tolerated, easily administered and overall lack significant drug interactions which will only further enhance their applicability in the future. However, further research studies are needed to ascertain the safety and efficacy of these medications before they are approved for clinical use.
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2. Unwalla, R., et al., Structure-Based Approach To Identify 5-[4-Hydroxyphenyl]pyrrole-2-carbonitrile Derivatives as Potent and Tissue Selective Androgen Receptor Modulators. J Med Chem, 2017. 60(14): p. 6451-6457.
3. Handlon, A.L., et al., Optimizing 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 cardiopulmonary functions and extend 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 a steroidal antiandrogen TSAA-291 and its cofactor recruitment profile. Eur J Pharmacol, 2015. 765: p. 322-31.
6. Solomon, Z.J., et al., Selective Androgen Receptor Modulators: Current Knowledge and Clinical Applications. Sex Med Rev, 2019. 7(1): p. 84-94.
7. Thevis, M., et al., Detection of the arylpropionamide-derived selective androgen receptor modulator (SARM) S-4 (Andarine) in a black-market product. Drug Test Anal, 2009. 1(8): p. 387-92.