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SARMs: A Bright Future For Therapeutic Use

Selective androgen receptor modulators (SARMs) are low molecular weight drug-like compounds that act as either androgen receptor (AR) activators or suppressors depending on molecular structure. Idiosyncratic differences in AR regulating proteins among different target tissues allows SARMs to elicit highly selective anabolic benefits while mitigating the shortcomings and limitations of conventional androgen therapies, like testosterone creams (ie. for low T) and injectable anabolic steroids. SARMs have fewer adverse effects and show excellent oral and transdermal bioavailability, making them attractive alternatives to contemporary androgen therapy.

SARMs have been investigated as potential therapies for numerous indications, including osteoporosis, Alzheimer’s disease, stress urinary incontinence, prostate cancer treatment and prevention, benign prostatic hyperplasia (BPH), hypogonadism (ie. male sexual arousal disorder and low T), and sarcopenia (ie. muscle wasting). Although there are currently no approved indications for SARMs dictated by the Food and Drug Administration (FDA), various potential uses are still being investigated clinically and the ongoing support via grant funding is a testament to the inherent value of SARMs. Here at Umbrella Labs, we are very encouraged by the steady stream of clinical and preclinical research developments. In this updated 2020 review, we will explore and annotate the most recent developments exploring the use of SARMs for a wide variety of indications.

Since their discovery and rapid development at the end of the twentieth century, SARMs have been fervently discussed as the inevitable future of androgen therapy. Given the inherent limitations of conventional testosterone replacement therapy (TRT) for low T (ie. due to unwanted adverse effects and self-limiting efficacy) SARMs as an alternative to TRT are positioned to fundamentally change the landscape of androgen therapy across a wide range of clinical uses.

SARMs are biochemically designed drug-like small molecules that can potently exert varying degrees of activating and suppressive effects on the androgen receptor (AR), depending on the target tissue. Like natural androgens, SARMs can easily penetrate cellular membranes and attach themselves securely to AR. After this event, the SARM-AR complex travels to the nucleus of the cell, where it becomes a gene regulator and recruits various gene cofactors, ultimately altering the genetic response of the cell [1], [2]. While AR is produced in nearly all cell types, SARM-AR complexes display divergent effects due to tissue-specific cofactor availability as was first discovered with RAD-140 [3]. These complex binding interactions, coupled with tissue-specific differences in AR activation and regulation, enables an incredible diversity of activities.

SARMs promise new, orally-available therapies that facilitate target organ-specific benefits while minimizing off-target cellular effects [4]. Given the well-established drawbacks of testosterone replacement therapy (TRT) for low T that substantially limits its utility—which includes all currently available topical and injectable formulations—it is easy to see why there is so much interest in SARM research and development. Although still in the early stages of clinical evaluation, individual SARMs may soon be utilized in the treatment of hypogonadism (low T) in a formulation that is orally bioavailable with simple dosing frequency which will yield the beneficial effects of TRT without side effects.

In addition to their potential use for the treatment of low T [5]–[7], SARMs are being actively researched as a candidate therapy for osteoporosis [8]–[13], neurological disorders including Alzheimer’s disease [14], prostate cancer proliferation [15], [16], benign prostatic hyperplasia (BPH) [17], lean muscle loss [18], muscular dystrophy [19], [20], and chronic disease-associated muscle weakness [21]–[26]. While SARMs present a new route for therapy in several chronic ailments, there are important research milestones that need to be met especially with respect to their utility in prostate cancer prevention.

Despite their potential to address significant unmet medical needs, regulatory roadblocks and poorly defined clinical study endpoints have tempered interest in the potential of SARMs for the first time since their discovery. Indeed, just like other drug-like molecules, the approval process of SARMs will be lengthy [27]. More recently, the focus of using SARMs to combat muscle wasting has shifted to other clinical applications for SARMs such as LGD-4033 Ligandrol, RAD-140 Testolone, MK-2866 Ostarine, S-4 Andarine, and S-23, in addition to the SARM-like compounds including MK-677 Ibutamoren and GW-501516 Cardarine.

Before SARMs were discovered, research had already revealed the existence of Selective Estrogen Receptor Modulators (SERMs), which are analogous to SARMs yet used for breast cancer treatment (ie. tamoxifen). The successful R&D of SERMs laid out a course for the experimental manipulation of nuclear receptor signaling which then opened the door to the discovery of SARMs, Selective Progesterone Receptor Modulators (SPRMs) [28], Selective Glucocorticoid Receptor Modulators (SGRMs) [29], Farnesoid X receptor modulators [30], and others classes of modulators.

Tissue selectivity is a critical distinction between classic steroid hormone therapy like TRT and AR modulation. While TRT offers benefits including gains in muscle mass and strength, it is associated with an unfortunately high degree and frequency of adverse effects, partially due to off-target activation of AR in several tissues, and TRT currently lacks a highly effective oral dosage formulation, which is a major barrier to therapy for men with low T. TRT also carries risks including atrophy of the testicles (ie. shrinkage), erythrocytosis, dyslipidemia, gynecomastia, liver toxicity, and virilization in women [31], [32]. Meanwhile, SARMs target AR function in specific tissues and cell types while minimizing effects elsewhere.

SARMs can be administered orally or via transdermal application (which is still in development) [7]. For all intents and purposes, SARMs are non-steroidal, yet fully able of activating the AR in both muscle tissue and bone tissue. However, because they are not metabolized to dihydrotestosterone (DHT), the risk of androgenic effects such as is reduced [33]. Furthermore, SARMs are not metabolized to estrogen by aromatase, limiting estrogenic effects [34]. While the benefits of first-generation SARMs appear modest compared to those of androgens, the ability of SARMs to preferentially stimulate bone and muscle growth, shrink the prostate, and inhibit breast cancer growth without significant systemic side effects is encouraging [35]–[37]. Given that the treatment of many chronic, debilitating diseases for which SARMs have been considered requires extended exposure, the apparent lack of substantial adverse effects or toxicity with SARMs relative to TRT gives SARMs a clear and unambiguous advantage, especially in the context of low T.

Osteoporosis

While existing therapies for osteoporosis are anti-resorptive (ie. prevents the breakdown of bone mineral), multiple SARMs have shown the ability to promote new bone growth and increase matrix strength in preclinical models [8], [12], [38], [39]. Recently, four SARMs—BA321, YK-11, Ostarine, and LY305—have shown great potential in the therapy of pathological osteoporosis. BA321 can reverse bone loss without androgenic effects by binding to both AR and estrogen receptors (ER) in preclinical models. YK-11 can accelerate bone cell proliferation via AR-mediated non-classical activity [13]. When mouse bone cells were treated with YK-11, it also enhanced bone formation activity, increased bone-specific stem cell markers, and increased bone enzyme activity (a marker of bone cell maturation).

Another research group investigated the bone-strengthening properties of Ostarine (Enobosarm) in a preclinical model of osteoporosis [10]. Eight weeks after rats were treated daily with low, intermediate, or high doses of MK-2866 Ostarine for 5 weeks, with the low dose group showing no benefit, yet the intermediate and high dose groups showing comparable improvements in microstructural indices including bone volume, bone density, and bone mineral composition. These improvements were more significant in the large leg bones than in the vertebral column, although no significant improvements were observed in biomechanical parameters.

In a different study, LY305 reversed skeletal muscle atrophy and demonstrated increased bone formation in a bone fracture mouse model. LY305 was subsequently administered transdermally to humans in a phase I clinical trial in order to circumvent high first-pass liver metabolism concentrations, which may contribute to dose-dependent suppression of high-density lipoprotein (HDL) observed with other oral SARMs. Utilizing transdermal delivery to limit or prevent alterations in HDL is a significant step forward for the utility and safety profile of SARMs, given that changes in HDL levels are the most significant adverse effect of SARMs observed as of yet.

Neurological Disorders

Androgen depletion is implicated in the development of Alzheimer’s disease and related neurological disorders, as circulating testosterone levels in aging men are inversely correlated with levels of amyloid β (Aβ) plaques in grey matter brain slices [14]. Men with low T also experience a decrease in cognitive processes including episodic memory, working memory, processing speed, visual-spatial processing, and executive function [40], [41], while a higher free testosterone index is associated with improved visual and verbal memory, spatiotemporal functioning, visual-motor scanning, and a lower rate of decline in visual memory [42]. Given that these functions are regulated by AR-controlled parts of the brain [43], the potential impact of SARMs as a treatment for cognitive disorders associated with low T is significant. In fact, in 2012, a new SARM was found to increase the activity of an Aβ plaque-degrading enzyme without adverse effects on the prostate [14]. However, researchers are eagerly awaiting further studies to continue investigation of this compound.

Benign Prostate Hyperplasia

Another obvious use of SARMs will be as a treatment for BPH via acting as an AR antagonist. Numerous groups have observed that because SARMs are not metabolized to DHT by alpha-reductase, the risk of prostatic hyperplasia is comparably reduced. While previous studies have observed that SARMs can decrease prostatic weight in rat models, a single phase II clinical trial (NCT03297398) was recently begun to investigate the efficacy and safety of OPK-88004 in men with BPH. In this trial, men were given either a placebo, 15, or 25 mg of OPK-88004 for 4 months. Regular visits evaluated drug safety and plasma level profiles, in addition to prostate weight determination and lower urinary tract symptoms. Unfortunately, this trial has since been terminated, and a press release disclosed that while serum PSA analysis has yet to be completed, the utilization of transrectal ultrasound for measuring prostate volume proved to be too imprecise to reliably determine the effect of the drug. Anticipation builds for another shot at addressing BPH with SARMs, perhaps with the use of YK-11, another excellent candidate.

Sexual Medicine & Low Libido

Most excitingly, SARMs may offer a superior alternative to testosterone replacement therapy (TRT) for men with low T, which has been the mainstay of the treatment of hypogonadism. While the libido improvements of TRT are well established using injected testosterone, SARMs are orally-active, non-steroidal, do not undergo aromatization to estrogen, and are inherently tissue selective, with a more agreeable side effect profile than testosterone replacement therapy (TRT). Previous studies have demonstrated the potential benefit of SARMs for libido in both female and male animals [44], [45]. In the latter study, treatment of male rats with the SARM LGD-2226 resulted in an increased number of sexual mounts, sexual attempts, and ejaculations compared with a control group [45]. These results were not statistically different from a group treated with the synthetic androgen, fluoxymesterone, suggesting that SARMs may represent a viable alternative to TRT in promoting male libido for men with low T. Repurposing SARMS for improvements libido has encouraged research specifically into S-4 Andarine, LGD-4033 Ligandrol, RAD-140 Testolone, and MK-2866 Ostarine.

As discussed above, many SARMs demonstrate the ability to treat male hypogonadal (low T) symptoms such as loss of muscle mass and bone mineral matrix density. Among others, the SARMs Ostarine MMK-2866 and LY305 have shown the greatest capacity to reverse the low T-related deterioration of muscle mass and skeletal strength. LY305 did so while simultaneously avoiding adverse effects demonstrated by other SARMs such as decreased HDL and increased hematocrit. However, approval for SARMs in the treatment of low T likely hinges upon clinical agreement on what constitutes a legitimate deficiency in these low T symptoms, and determining what qualifies as a clinical benefit in mitigating them [27].

Lean Muscle Mass Maintenance

The use of SARMs as a potential alternative to TRT for cancer-related muscle loss or age-related strength loss has been desirable since their inception [46]. Owing to their selective anabolic capacity without androgenic adverse effects, SARMs may treat muscle wasting associated with many chronic conditions including heart failure, chronic obstructive pulmonary disease (COPD), chronic infection, immobilization, and chronic glucocorticoid use [47]. Studies have demonstrated that survival of cancer patients correlates directly with muscle mass [48] and that sarcopenia is associated with increased risk of death [49]. As such, TRT is approved for the treatment of these conditions. However, recent clinical trials have suggested that the cardiac risks of TRT outweigh its therapeutic benefits [50], [51]. Although this controversy has not been resolved, SARMs are being considered instead of TRT to combat the problem of muscle atrophy in men with low T, irrespective of the underlying etiology. While early preclinical models showed SARMs to be effective in preventing muscle weakening by increasing proportional lean body mass, more recent clinical studies have cast doubt on their outlook and suggest optimal dosing has yet to be established.

Several phase I studies have recently evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various SARMs. In one such clinical trial (NCT02045940), a dose range of oral SARMs was administered to healthy men for either 1 or 2 weeks and was associated with decreases in high density lipoprotein, similar to what has been observed with other SARMs [52]. Side events were noted in half of the study population, yet these were distributed equally between the placebo and SARM treatment groups, indicating that the dose range was very well tolerated. These early trials demonstrate a potential role for SARMs in therapy to prevent loss of muscle mass.

In another phase I clinical investigation of GSK2881078 which is structurally similar to MK-2866 Ostarine, gains in lean mass were evaluated at various doses [25]. While both male and female patients on all doses of GSK2881078 experienced greater lean mass gains than those on placebo, lower doses resulted in greater lean mass responses in females than in males. Crucially, these dose-dependent mass gains occurred without any required resistance training. Fleeting elevations in alanine aminotransferase liver enzymes were observed yet retuned to baseline after discontinuing the SARM, and minor, reversible reductions in testosterone levels were observed in all men. Finally, a phase II trial (NCT03359473) evaluating the efficacy and safety of GSK2881078 in chronic obstructive pulmonary disease is still ongoing. In addition to safety and toxicity parameters, this trial is evaluating the role of this MK-2866 analog in modulating physical strength and function in both postmenopausal female and older male subjects with chronic obstructive pulmonary disease, fatigue or fibromyalgia, and muscle weakness. These test participants will participate in a baseline period of 1 month, after which they will strictly adhere to an exercise regimen and SARM treatment for 3 months, followed by a 1.5 month reassessment period during which participants’ physical performance in various metrics will be recorded and analyzed independently, including readouts of leg press strength and core strength.

Another recent trial examined the impact of a novel SARM, S-42, which is similar in structure to S-23. This study utilized the common human muscle cell line in culture, and the SARM was observed to have both anabolic and anti-catabolic effects on the actin structures of stem-cell derived muscle cells [18]. The anti-catabolic effects consisted of inhibition of the degradation pathway in human muscle cells and decreased gene activation of skeletal muscle enzymes. The anabolic effects of S-42 included activation of the mTOR signal transduction pathway, independent of Insulin-like growth factor signaling, which was unexpected. S-42 may selectively encourage muscle growth while simultaneously minimizing adverse effects such as prostate hyperplasia. These in vitro results hint at the capacity of SARMs to prevent muscle loss and simultaneously induce muscle gains in patients who suffer from various muscle wasting conditions which share a common etiology.

It should be noted that the results of recent clinical trials of the MK-2866 Ostarine have reduced the sky-high expectations for its use as a therapy for age-related muscle loss. Early on, Ostarine appeared to demonstrate particularly strong potential to combat pathological muscle weakness. Preliminary clinical trials also demonstrated that Ostarine could significantly improve lean body mass and augment physical function without androgenic side effects [23]. Failure to satisfy the primary study endpoint of “stair climb power” is ultimately what led to a hiatus on approval granted by the Food and Drug Administration (FDA), despite the fact that lean body mass improved. This unfortunately cast doubt on the previously uncharted course for SARMs clinically and extended the timeline to future FDA approval. Nevertheless, Men everywhere who are seeking to gain muscle strength and muscle mass are rightfully excited about SARM R&D, and the evidence thus far points to a myriad of therapeutic benefits, both for men with normal levels of testosterone and for men suffering from low T. In particular, there is justifiable excitement for particular SARMs, including LGD-4033 Ligandrol, RAD-140 Testolone, MK-2866 Ostarine, S-4 Andarine, and S-23, in addition to the SARM-like compounds including MK-677 Ibutamoren and GW-501516 Cardarine.

*The information herein is for educational and informational purposes only. THE PRODUCTS DESCRIBED ARE FOR RESEARCH USE ONLY. For use in animal studies, all research must be conducted with oversight from the appropriate Institutional Animal Care and Use Committee (IACUC) following the guidelines of the Animal Welfare Act (AWA)

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