SARMs can be agonists, antagonists, or partial agonists of the AR depending on the tissue, which can enable targeting specific medical conditions while minimizing side effects. These antagonists work by binding to the AR to prevent androgenic action; this class of chemicals dates to the 1970s. The chemical starting point for AR mixed agonist/antagonists were nonsteroidal AR antiandrogens such as flutamide, nilutamide, bicalutamide. Interest in nonsteroidal AR mixed agonists/antagonists increased after the therapeutic uses of selective estrogen receptor modulators (SERMs) became evident. These have increased metabolic stability and are orally active, but are not tissue selective. SARMs are more selective, affecting androgen receptors in muscle and bone, and their structure is nonsteroidal. Similarly, two phase III trials with anamorelin, a non-peptide, orally-active, centrally-penetrant, selective agonist of the ghrelin/growth hormone secretagogue receptor, in subjects with lung cancer and cachexia showed that it increased muscle mass but failed to improve hand grip strength (104). The dissociation of anabolic from androgenic effects is proposed to result from tissue-selective actions. In this paper we critically evaluate the evidence for the purported enhanced tissue selectivity of SARMs compared with traditional steroidal androgens, and assess their results in clinical research. In 1999, the term "selective androgen receptor modulator" or "SARM" was introduced, as the mixed agonist–antagonist and tissue-selective activity of these nonsteroidal androgen receptor agonists had similarities with selective estrogen receptor modulators (SERMs). Phase II trials of enobosarm for stress urinary incontinence—considered promising, given that the levator ani muscle in the pelvic floor has a high androgen receptor density—did not meet their endpoint and were abandoned. Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate. The pharmaceutical industry invested billions in their development precisely because they represent a more targeted approach to treating muscle wasting, osteoporosis, and age-related sarcopenia with fewer side effects than testosterone. Selective androgen receptor modulators have been almost universally condemned in the fitness and health space. Our cross-sectional data imply that these compounds might alter intramuscular androgenic hormone and receptor concentrations along with promoting muscular strength, when compared with previously published data from trained males. MK-677 increases growth hormone and IGF-1 through ghrelin receptor agonism, complementing the AR-mediated anabolic effects of RAD-140. Preclinical data suggest RAD-140 is anabolically potent per milligram, comparable to moderate testosterone doses ( mg/week). The combination of anabolic activity without estrogenic water retention makes RAD-140 a compound of interest for simultaneous fat loss and lean mass gain. The theory is that at these lower doses, you get tissue-selective anabolic signaling without triggering meaningful HPTA suppression. Selective androgen receptor modulators (sometimes called specific androgen receptor modulators or SARMs) have been looked at as popular supplements among fitness enthusiasts and chiseled athletes. SARMs have less activity in the prostate and skin than anabolic steroids. Since the levator ani muscle is enriched in the AR, it responds quickly when exposed to androgens. While the results from ER-positive breast cancer trials (one completed and another ongoing) were largely positive, the TNBC trial is still recruiting patients. Currently, to the best of our knowledge, the only SARM that is in clinical trials is enobosarm (GTx, Inc., Memphis, TN). SARMs capable of selectively building pelvic floor muscles with reduced virilizing and uterine proliferative side-effects would be preferred and better tolerated for SUI. The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. This lack of approval notwithstanding, the purported improved safety profile of SARMs over conventional steroidal androgens has garnered the attention of both professional and recreational athletes. Although such high-dose regimens are less acceptable today, these results suggest that older nonaromatizable androgens can be highly effective. In a recent phase 2 trial, 29–32% of patients receiving enobosarm experienced clinical benefit (defined as complete response, partial response, or stable disease) at 24 weeks (67). SARMs, by contrast, may offer a promising re-emerging therapy lacking virilization for treatment of breast cancer. The AR also plays an important role in breast cancer, hence the AR can be included in molecular breast cancer classification (77, 78). In one 12-week placebo-controlled trial in healthy elderly men and postmenopausal women, the highest-dose enobosarm group increased LBM by 1.3 kg and reduced fat mass (FM) by 0.6 kg compared with the placebo group (64). Other androgen-synthesizing enzymes 17-β HSD types 3 and 5 are highly expressed in testes and prostate and they play important roles in synthesizing testosterone from precursor androstenedione (55,56). Expression of other enzymes belonging to hydroxysteroid dehydrogenase (HSD) class regulates the availability of steroidal androgens to the AR in a variety of tissues. Several mechanisms such as the coactivator-corepressor ratio and tissue-selective modulation of signaling pathways that have been established as mechanisms for the tissue-selectivity of SERMs are also applicable to the SARMs (50,51). While insights into AR structure and differential coregulator recruitment offer theoretical avenues for achieving enhanced tissue selectivity, robust evidence linking these mechanisms to meaningful clinical outcomes is still lacking. Despite decades of research and development, SARMs have yet to fulfill the promise of providing truly tissue-selective effects. This hepatotoxicity is likely linked to increased activation of the AR in hepatic tissue and may be an unavoidable consequence of orally bioavailable androgens administered at sufficiently high doses (85). Future research should assess whether lower, less virilizing doses of such nonaromatizable androgens can match SARMs like enobosarm in both efficacy and safety. Indeed, historically, androgens such as testosterone propionate, methenolone and fluoxymesterone demonstrated tumor regression in up to 30% of patients with advanced disease. These findings support the notion that nongenomic pathways may also provide a potential mechanism for tissue selectivity, although its clinical relevance remains unclear. This suggests that the SARMs form a complex in the prostate cellular environment comprised of both coactivators and corepressors that will prevent maximal activation of the AR in this androgenic tissue. The molecular mechanisms underlying the separation of the detrimental androgenic activities (e.g., virilization/prostatic hypertrophy) from the desired anabolic effects remain unknown. In addition to their effects on muscle, enobosarm and other arylpropionamide SARMs also demonstrated beneficial effects on bone (42). Although the use of levator ani muscle as a surrogate end point for anabolic activity in skeletal muscle is criticized due to its unparalleled expression of the AR, it provides a sensitive and rapid assessment of anabolic effects.
