Asian Exercise and Sport Science Journal 2588-4832 www.aesasport.com Vol.5 No.1 Received: September 2020, Accepted: December 2020, Available online: January 2021

DOI: https://doi.org/10.30472/aesj.v5i1.186

Selective Receptor Modulators – Cellular, Tissue and Organ Selectivity: Review

Veselin Vasilev 1 Nikolay Boyadjiev 2 1 Department of Physiology, Faculty of Medicine, Medical University Plovdiv, Bulgaria 2 Department of Physiology, Faculty of Medicine, Medical University Plovdiv, Bulgaria

ABSTRACT: Selective modulators (SARMs) are a new class of synthesized molecules with anabolic -like effects, and unlike the latter, SARMs are dominated by anabolic over androgenic effects on the body. SARMs bind to the androgen receptor by genomic mechanism and demonstrate a pronounced tissue selectivity, which is performed regardless of their pharmacokinetic profile, and the interaction of the androgen receptor with various co- activators and co-suppressors is therefore essential. Part of the effects we found, described by different authors in over 300 articles in the literature, can be very useful. Some SARMs have been shown to stimulate osteogenesis in osseous tissue and enhance bone mineral density; reduce the weight of the prostate in benign prostatic hyperplasia; demonstrate a cytotoxic effect in hormone-sensitive prostate cancer cell lines. Some of the newly synthesized SARMs induce major myogenic regulatory factors what contributes to the realization of ligand- mediated myogenic differentiation and the increase of muscle mass. Some SARMs have been found to have a favourable effect in age-related hypogonadism and sexual dysfunction, as well as a pronounced neuroprotective effect, which in turn makes them potential agents for the treatment of neurodegenerative diseases. Others have been found to inhibit cancer growth in metastatic models of breast cancer and have an anabolic effect on protein metabolism, which helps to restore pelvic floor muscles that weaken in postmenopausal syndrome. The effects found in the test application of SARMs make them potential candidates for the treatment of a wide range of metabolic, bone, cancer and neurological diseases.

Keywords: SARMs, androgen receptor, tissue selectivity, potential treatment

INTRODUCTION

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As a new class of androgen receptor Even though at this moment there is no ligands, the selective androgen receptor approved representative of SARM as a drug, modulators (SARM) have been of particular these preparations/substances can be scientific interest in recent years, having in purchased online, but a study of Van Wagoner mind the opportunities to use these new R. et al. of 2017 г. evidences that only 52% of molecules in clinical practice. SARMs have an the 44 products offered online and tested effect similar to the widely used anabolic contained really SARM (4). On top of that, . However, their advantage is that they SARMs are also included as ingredients in demonstrate selectivity in their action, some dietary supplements what poses a expressed in the predominance of anabolic significant risk of their use in different sports. effects over the relatively limited androgenic In some cases, as a matter of fact, consumers ones. This makes it possible, in some cases, to are misled by masking the presence of SARM use them as substitutes of anabolic-androgenic on the label. A coded name is used instead of steroids, in order to avoid some of the side the trade name of the substance (for example, effects of the latter, such as acne, liver damage, MK-2866 or GTx-024 or is testicular atrophy, thickening of vocal cords, indicated as an ingredient, instead of Ostarine). hair growth, menstrual disorders in women, To the extent that both above- etc. Al this establishes a need for studies on the mentioned groups of modulators have a possible potential use of SARMs in patients pronounced anabolic effect, their popularity is with a number of diseases: amyotrophic lateral rapidly growing among sports sector in sclerosis (Lou Gehrig’s disease), relation to their potential to enhance exercise dermatomyositis, , breast cancer, performance. This, in return, led to their sarcopenia, various types of cachexia, benign inclusion in the World Anti-Doping Agency prostatic hyperplasia and hypogonadism (1). (WADA) list of prohibited substances in The first newly synthesized molecules 2008(5). With the help of various methods, that belong to the group of SARMs were such as gas chromatography, liquid created as early as the end of the last century chromatography and mass spectrometry, they as SARMs can be divided into two main themselves or their metabolites can be detected groups: steroidal and non-steroidal (2). The in the blood and urine(6);(7);(8). Some of the non-steroidal SARMs were presented in 1998 most commonly used SARMs at the moment and since then there has been an increasing list include Ostarine and (9). of substances of this group. Most of them are also candidates for registration as therapeutic METHODS products, but are still under clinical trials(3). Non-steroidal SARMs are grouped into The main criteria for articles to be different classes: aryl propionamide included in our review was to be connected analogues, bicyclic hydantoin analogues, with SARMs. Other criteria was the articles to quinolones, tetrahydroquinoline analogues, provide information about SARMs in general, butanamides, benzimidazoles. The first their mechanism of action, effects in different discovered class is that of aryl propionamides. tissues and their adverse side effects no matter The steroidal types of SARMs are synthesized in animals or in humans. We only used articles through structural changes in the molecule of which were available in English and which . By removing the 19-methyl were open access. group, an increased anabolic effect of We examined over 300 articles testosterone is achieved. Replacement of 7- connected with SARMs for the period 1998 - alpha alkyl group in testosterone molecule 2020 years to collect the needed information reduces the interaction with the enzyme 5-α for this article. Studies were identified by reductase and increases its tissue selectivity. searching electronic databases. The search was The half-life of testosterone is increased by applied to ScienceDirect, PubMed, Elsevier, replacing the 17-alpha alkyl group in its Google Scholar. We used the following search molecule. terms in the different databases: - selective androgen receptor modulators, SARMs, Asian Exercise and Sport Science Journal, official journal of AESA 21

SELECTIVE ANDROGEN RECEPTOR MODULATORS VOL. 5 (1) selective androgen receptor modulators - rats. There was no restriction regarding to the RESULTS representative of SARMs used. Also there were no restrictions for the type of the SARMs perform their effects after experiment performed with SARMs – on binding to the androgen receptor by genomic humans or on animals. mechanism. The androgen receptor (AR) is coded by a gen which is located on the Х- There were about 100 articles chromosome (10) and acts as a transcription connected with SARMs that were not included factor. It consists of three principal domains, in our review. The main reason for them not to and after binding to the ligand, conformational be included is that they do not provide the type changes occur in it and the resulting complex of information we were looking for. They give moves to the cell nucleus. There, an interaction detailed information about the chemical with the nuclear DNA occurs, and as a result, structure and development of SARMs and the target genes are activated which take part in the process of their synthesis and discovery. As we regulation of a number of physiological already said this is not the focus of our review processes. Other SARMs also exist, e.g. YK11, and such articles were considered irrelevant by which can realize their effects by non-genomic us. mechanism, as well (11).

Fig.1 Diagram of the domains of the androgen receptor and of the gene that codes it (12) enzyme which action is associated with the effects of the intake of AAS is aromatase. It SARMs demonstrate a pronounced converts into female sex tissue selectivity, which mechanisms are hormones (estrogens), which in turn explained by various hypotheses. This demonstrate their specific effects. selectivity is supported by their However, non-steroidal representatives of insusceptibility to the enzyme 5-α reductase SARMs are insusceptible to aromatase (13). By contrast, testosterone and (14). DHT and SARM, after their binding anabolic-androgenic steroids (ААS), under to AR, enhance the phosphorylating the action of this enzyme are converted into activity of various kinases (2). For example, (DHT) and other a non-steroidal SARM representative of the metabolites, which have a greater aryl propionamide class mediates its effects biological activity and more pronounced the pathways of kinases MEK, ERK, р38 effects on the genitals. Another similar Asian Exercise and Sport Science Journal, official journal of AESA 22

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MAPK, etc. While DHT uses the pathways vesicles, for example, total activation of AR of completely different kinases: PI3K, is required (19). By this manner of action, PKC, ERK, etc. (15). This indicates that the the SARMs representative TFM-4AS-1 two groups of ligands use different signal demonstrates anabolic effects in bone and pathways. muscle tissue, however it does not exhibit The mechanisms of tissue activity in the prostate (20). selectivity are performed regardless of the SARMs can also modulate the pharmacokinetic profile of SARMs (16). activity of the androgen receptors by The interaction of the androgen receptor inhibiting their transport to the cell nucleus with various co-activators and co- (21). suppressors is essential. When binding With regard to the effects of DHT, testosterone or AAS to AR, the SARMs, described in the literature, in induced conformational change of the various tissues and organs of the human receptor leads to interaction with some co- body, it can be considered that in the future regulators, and when binding SARMs to they could be used in the treatment of a AR, the conformational change and the co- number of diseases and conditions, such as activators, with which AR interacts, are osteoporosis, cachexia, sarcopenia, benign others (14);(9). Other authors deliver prostatic hyperplasia, neurological similar data as well (17). They found that in pathology with cognitive deficit, an osteopenic model in female rats, DHT, hypogonadism, sexual dysfunction, breast after binding to AR, led to interaction of the cancer, as well as for effective receptor with the co-regulators TIF2, contraception in men. SRC1, β-catenin, NCoA3, gelsolin and PROX1. After binding S-101479 to АR, the 1. Effects on bone tissue. selection of co-regulators is different, and SARMs show effects on bone tissue the receptor interacts only with the co- and its metabolism. Thus, for example, regulators gelsolin and PROX1, what is YK11 stimulates the proliferation of sufficient for the performance of tissue MC3T3-E1 osteoblast cells in mice. It was selectivity. More than 200 co-regulators are found to increase significantly the specific known and used to activate or suppress markers for osteoblast differentiation various target genes. (osteoprotegerin and ostecalcin) compared The conformational change induced to the markers in untreated cells (11). On by classical AR agonists (testosterone or the other hand, the selective S-4 modulator AAS) favours the well-known can reduce the expected loss of bone intramolecular N-terminal/С-terminal substance in an osteopenic model in rats interaction (N/C interaction). It is important maintaining bone mineral density and for the selection of certain co-regulators, for enhancing bone strength (22). In another the transcriptional activity of AR and for study, once again in an osteopenic model in the modulation of target genes. The female rats, it was found that taking S-4 synthesis of new SARMs molecules is after the ninetieth day of ovariectomy aimed to cause conformational change, resulted in almost complete restoration of which, however, does not stimulate this N- bone parameters compared to those of terminal/С-terminal interaction, which intact rats. Bone anabolism is stimulated would determine the performance of the and bone resorption is suppressed (23). desired tissue selectivity by choosing other Another modulator, i.e. JNJ-28330835, also co-regulators and activating other target suppresses bone resorption (24). In a model genes (18). Antagonizing N-terminal/С- of osteoporosis in rats, the representative of terminal interaction leads to incomplete tetrahydroquinolone analogues S-40503, activation of the receptor, and to exert the after intake for 4 weeks, increases the bone effects on the prostate and the seminal mineral density of the femur and the

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deposition of minerals in the periosteum of bone resorption and stimulates bone the same bone, what shows its direct formation in an osteopenic model in rats stimulating effect on bone formation (25). (32). Some of the carboranes which are Ostarine helps the formation of callus and carbon-containing compounds, derivatives healing of the bone after osteotomy. It of the chemical element boron, may have increases the concentration of serum effects on bone tissue such as those of alkaline phosphatase, raises the serum level SARMs. It was found that the of phosphorus and reduces the serum representative of this group, BA321, cholesterol (26). Unlike Ostarine, the restores the lost bone density in castrated anabolic-androgenic steroid male and female rats. In male rats, it decanoate, after intake for twenty eight increases the weight of the seminal vesicles, days in rats with induced femoral fracture, and in females reduces the induced atrophy stimulated to a less extent the formation of of the uterus (33). callus and had no effect on the intact part of the bone (27). The combined application of 2. Effects on prostate gland. the selective androgen receptor LGD-3304, In a study of intact rats, (34) together with a representative of compared the effects of SARM (S-1) with bisphosphonates (alendronate) leads to the drugs used to treat benign prostatic potentiation of the effects of both hyperplasia (BPH) – substances and obtaining a better total () and inhibitors of the effect which is suitable for the treatment of enzyme 5-α reductase (finasteride). S-1 osteoporosis (28). S-101479 enhances the reduces the weight of the prostate, and activity of the alkaline phosphatase, the unlike hydroxyflutamide, it does not transcriptional activity of the androgen increase the plasma concentration of receptors in the osteoblast cell line, and testosterone, FSH, LH, and does not reduce increases the bone mineral density without the weight of m. levator ani. In a model of stimulating the proliferation of the benign prostatic hyperplasia in rats, S- endometrium in an osteopenic model in 40542 dose-dependently reduced the female rats (17). Another study, once again weight of the prostate, and again, unlike in an osteopenic model in rats, compared antiandrogens, it did not alter the plasma the effects of S-101479 with other drugs for levels of testosterone and LH (35). JNJ- treatment of osteoporosis – 28330835 reduces the weight of the bisphosphonates, selective estrogen prostate by up to 30% in intact rats (24). receptor modulators (SERM) and synthetic SARMs also have advantages in analogues of parathyroid hormone. All comparison to DHT. In a model of substances increased the bone mineral androgenic deficit in rats, DHT causes a density. Only S-101479 increased the size significant increase in the weight of the of the bone. Potentiation of their effects is prostate (25). The selective androgen observed in combined application (29). The receptor modulator MK-4541 inhibits the preparation 4c has an osteoanabolic effect enzyme 5-α reductase and suppresses the in female rats with induced osteoporosis, androgen-dependent growth of the prostate and has a sparing effect on uterus compared in intact rats. It also suppresses the growth with DHT (30). Another representative of of some prostate tumors by inhibiting SARMs, i.e. 1d, also used in a model of proliferation and enhancing apoptosis of the osteoporosis in female rats, increases the expressing androgen receptor, androgen- bone mineral density of the femur, without dependent prostate cancer cells. Another any side effects on the uterus and clitoris advantage is that it does not cause the side (31). LGD2226 is also a non-steroidal effects of therapy related to representative of SARMs, which prevents a the musculoskeletal system and behaviour decrease in bone density, suppresses the (36). MK-4541 induces the activity of

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caspase-3 (a key enzyme for the tissue what ranks them among the accomplishment of apoptosis) and candidates for the treatment of cachexia and accordingly induces the apoptosis of the sarcopenia of various origin. YK11, for androgen-independent and androgen- example, which activates AR without dependent prostate cancer cells. It also performing the N/C-terminal interaction, inhibits the effect of DHT on the prostate, induces the differentiation of the С2С12 but not on m. levator ani. The preparation myoblast cell line. DHT demonstrates the does not impact the androgen-independent same effect, but YK11 more effectively and androgen-dependent non-malignant induces the key myogenic regulatory prostate cells (37). It was found that another factors (myogenic differentiation factor, SARM, i.e. S-42, suppresses the growth of myogenic factor 5, and myogenin). YK11 the prostate cancer cell line LNCaP. This also stimulates the expression of Follistatin, effect is not achieved by inducing cellular which plays a major role in the realization apoptosis, but through inhibition of the of YK11-mediated myogenic expression of proliferation-related differentiation (42). receptors – insulin-like growth factor The JNJ 28330835 modulator, 1(IGF-1R), insulin and androgens. S-42 alternately, reduces by half the loss of lean also inhibits the activation of the body mass caused by orchidectomy in rats. extracellular signal-regulated kinase It mediates the restoration of 30% of the (ERK), a mitogen-activated protein kinase already lost muscle body mass in older (MAPK) that is important for the prostate castrated rats and stimulates the growth of cancer proliferation (38). FL442 also m. levator ani (24). JNJ 37654032 is a inhibits the androgen-dependent prostate similar agent with identical effects (43), and cancer cell line LNCaP and demonstrates the MK-4541 modulator preserves lean efficiency equivalent to that of the most body mass in female rats after ovariectomy common antiandrogen - . (36). Unlike bicalutamide, FL442 does not Muscle atrophy caused by stimulate the VCaP cell line, which hypogonadism or administration of expresses elevated AR levels (39). S-11 и glucocorticoids in rats may be favourably R-9 exhibit stronger cytotoxic effect than affected by the use of SARMs. The atrophy bicalutamide in the hormone-sensitive is due to the enhanced expression of prostate cancer cell lines LNCaP and MAFbx and MuRF1, which are ubiquitin LNCaP-AR. Within the hormone-resistant ligases and form a part of the ubiquitin prostate cancer cell lines LNCaP-AR and proteasome system that is responsible for VCaP, R-9 exhibits stronger cytotoxic the decomposition of proteins and the effect than S-11. Both representatives of decreased IGF-I function. SARMs inhibit SARM decrease PSA and suppress the the activity of the ubiquitin ligases and synthesis of DNA by blocking the enhance that of IGF-I (44). In a model of androgen-dependent increase in the protein muscle atrophy in mice, GLPG0492 proto oncogene cyclin D-1 (40). Another partially prevents the development of representative of SARM (JNJ 26146900), atrophy and causes hypertrophy of muscle in a model of prostate cancer in rats, also fibers in a dose-dependent manner. The inhibits the tumor growth (41). All this data efficiency of the SARM representative in of SARM makes them candidates for the this model is comparable to that of treatment of BPH and prostate cancer, , and the effect is including in castration-resistant forms. achieved by affecting the signal pathways which regulate the homeostasis of the 3. Effects of SARMs on muscle tissue. muscles (45). Ostarine (S-22), another non- SARMs also have a number of steroidal selective androgen receptor pronounced beneficial effects on muscle modulator, has also been shown to reduce

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muscle loss and decrease total fat hypogonadism and sexual dysfunction. percentage, with minimal side effects on the These two conditions can aggravate the prostate (46). In a double-blind study in quality of life, and the main reason for their postmenopausal women and older men, development is the decreased secretion of Ostarine increased lean body mass and also testosterone and estrogen with aging. In this had a favourable effect on insulin prospect, SARMs could be applied as a resistance. Like the other selective replacement therapy in older men and modulators, in another study in women with hypogonadism because of postmenopausal women and men over the their anabolic effect on muscle and bone age of forty-five, Ostarine caused a tissue, and their ability to maintain and significant increase in the reduced lean restore the libido (32). For example, the body mass (47). An increase in muscle representative of SARM – LGD 2226, in strength and endurance in mice treated with addition to exhibiting an anabolic effect on the GLPG0492 modulator was observed in bone and muscle tissue, is efficient in a a Duchenne muscular dystrophy model model examining the sexual behaviour in (48). The intake of МК-0773 for a period of rats, which measures the number of 6 months by 170 women with sarcopenia penetrations, ejaculations, and leads to a significant increase in muscle effectiveness of copulation (54). According mass and physical strength (49). to the authors (55) SARMs enhances sexual Transdermal SARM (LY305) has also been motivation in female rats following found to restore muscle mass in a model of ovariectomy to the same extent as the effect muscle atrophy in test animals. Moreover, of testosterone. In relation to these this modulator has been found not to cause established effects of SARMs, it is significant changes in the values of important to note that they do not respond haematocrit and high-density lipoproteins to the action of the enzyme aromatase. LGD (HDL) (50). 3303 in female rats after ovariectomy Another non-steroidal SARM that is increases sexual desire to male rats. considered suitable for the treatment of Interestingly, this effect occurs only in sarcopenia and cachexia is SARM2f. It has females which were sexually active before been used in various models of malignant the test. Moreover, LGD 3303 stimulates cachexia in rats, restoring the body mass behaviour in female rats which predisposes and increasing the weight of m. levator ani to copulation (56). This SARM may be without enlarging the prostate or seminal used as a potential therapy in women with a vesicles (51). SARM2f demonstrates its decreased libido. JNJ 28330835 enhances anabolic effects in muscle tissue and the preference of female rats subject to decreases the lipid levels in monkeys as ovariectomy for intact male rats over the well (52). preference for castrated rats. This non- Measurement of the rate of steroidal representative of SARM also fractional synthesis of proteins from reduces bone decomposition (24). different muscles on the tenth day of SARM2F restores the lost sexual desire in administration of selective androgen castrated male rats while increasing the receptor modulators may provide early voluntarily run distance and the locomotor biomarkers for the expected increase of activity (57). The combined administration lean body mass and muscle weight of the of SARM(S-23) and benzoate in corresponding muscles (53). four of six male rats had a reversible contraceptive effect decreasing the 4. Effects of SARMs in hypogonadism concentration of FSH and LH, suppressing and sexual dysfunction. the testis spermatogenesis and reducing the SARMs have been found to have a occurrence of gestations to 0%. One beneficial effect on age-related hundred days after cessation of intake,

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incidence of gestations is restored to 100% The effects of SARMs have also (58). In this respect, it has been established been related to possible use in androgen by other researchers that the JNJ-37654032 receptor-expressing breast cancer (63). modulator decreases the levels of the Some authors (64) administer SARM to cell elevated LH concentration in castrated rats, cultures of triple-negative breast cancer and in intact rats – reduces the size of the (lack of estrogen receptors, progesterone testicles (43). receptors and epidermal growth HER2 factor receptors), which expresses mutated 5. Neuroprotective effect of SARMs. androgen receptors. SARMs inhibit the SARMs also have a neuroprotective AR-dependent growth of the tumor. This effect. For example, the RAD140 occurs by blocking the intratumor modulator has been shown to delay the expression of genes which while acting on programmed nerve cell death in various AR stimulate the growth of the breast neurodegenerative models in rats. The cancer. SARMs also block paracrine mechanisms of this neuroprotective effect factors (IL-6, MMP 13), which stimulate are related to MAPK (mitogen-activated the development of metastases. In a model protein kinase)-signal pathways (59). It can of xenograft from patients with breast be speculated that this effect of RAD140 cancer expressing androgen and estrogen could be used in the treatment of receptors (AR+, ER+), the isolated Alzheimer’s and other neurodegenerative application of RAD140 (testolone), as well diseases. as in combination with palbociclib, inhibits The selective androgen receptor cancer growth. The non-steroidal SARM modulators also have a favourable effect on acts as an AR agonist in breast cancer cells age-related cognitive deficit. It is believed and provides androgen-dependent that they increase the levels of androgen suppression of the activity of the estrogen receptors in our brain and have an receptors (ЕSR1) (65). RAD140 also antagonistic effect on disorders of inhibits cancer growth in metastatic models hippocampus-dependent exploration of of breast cancer, which also express AR and new locations (60). Moreover, the selective estrogen receptors while exhibiting an androgen receptor modulator АC-105 acceptable safety profile as well (66). improves the condition of anxiety in mice. Its combined use with the selective estrogen 7. Metabolic effects of SARMs. receptor modulator (AC-186) enhances the SARMs can also affect metabolism. activity of amyloid-β degrading enzymes, The non-steroidal representative of SARM thus reducing the concentration of this S-42, in addition to increasing the weight of group of peptides that are associated with m. levator ani, without increasing the the development of Alzheimer’s disease. weight of the prostate, also exhibits Another effect of the combined application metabolic effects. In contrast to the of these substances is the improvement of negative effect of DHT, it does not alter the cognitive abilities and elevated levels of concentration of gonadotropic hormones AR in the brain. This suggests that such a and adiponectin, but decreases the plasma combination could be used in the treatment concentration of triglycerides, as this effect of patients with Alzheimer’s disease (61). is associated with the suppression of the NEP 28 is another representative of SARM, SRBP-1c mediated lipogenic and insulin- which in addition to its favourable effects desensitizing pathway in the liver and on bone and muscle tissue, also has a adipose tissue of internal organs (67). In the neuroprotective effect (62). myoblast cell culture of mice (С2C12), S- 42 probably exerts its anabolic effect by 6. Effects from the use of SARMs in enhancing the activity of p70S6K-kinase, breast cancer. which is essential for stimulating the

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protein synthesis. Moreover, it decreases androgenic steroids is their tissue the expression of the musculoskeletal selectivity which mechanisms are still ubiquitin ligase (MuRF1), which would being examined. Nevertheless it is exactly reduce the protein catabolism (68). Ostarine the selectivity that allows SARMs to have (enobosarm) has a pronounced effect on the almost missing or very weak androgenic intensity of lipid metabolism. It decreases effects, concerning the prostate the most, the expression of mRNA, adiponectin and and equal or even better anabolic effects, leptin, and correspondingly reduces their concerning bones and muscles the most, release from adipocytes (69). S-4 can lower compared to testosterone and androgenic the percentage of body fat (22). steroids. Ostarine is the SARM which is in the most advanced phase of research. There 8. Impact of SARMs on urinary tract are some side effects of SRAMs reported by system. different authors in the literature in both GTX-027 and GTX-024, in a humans and animals. The most common postmenopausal model in rats, restore the include elevated liver enzymes (ALT, AST) weight of the pelvic floor muscles. These or changes in the levels of different effects of SARM may rank them among the lipoproteins (HDL, LDL). However these candidates for potential treatment of urinary side effects are with low frequency, stress incontinence where damage and reversible after quitting the use of the weakening of the pelvic floor muscles with modulators and will not decrease aging in women constitute one of the main significantly the quality of life of the reasons (70). Another non-steroidal patients. On the other hand anabolic representative of SARM (GSK2849446A), androgenic steroids cause increased in a model of urinary stress incontinence frequency of sudden cardiac death, liver induced by bilateral ovariectomy in rats, diseases, benign prostatic hyperplasia, has favourable effects. It restores the low prostatic cancer, testicular atrophy, values of urethral baseline pressure, the infertility and many other significant amplitude of urethral response during disorders. SARMs are also a temptation for sneezing and the sneeze-induced leak point both amateur and professional sportsmen as pressure. GSK2849446A also stimulates they tend to increase the physical working the hypertrophy of the muscles of the capacity. Despite this fact sportsman have urethra, without affecting the function of to bear in mind that SARMs are included in the bladder. (71); (72). the list of prohibited substances of WADA. There are various methods to detect ostarine or other representatives in both CONCLUSION blood and urine during doping tests. Also there is no data about the long term effects Despite not having an approved of SARMs. Whether they will pose some representative by FDA at the moment risks in such conditions or not is still SARMs tend to be a big promise for difficult to give definitive response. The improving the treatment process in various interest in this group of substances remains types of diseases – breast cancer, very high and in the near future hopefully osteoporosis, benign prostatic hyperplasia, new positive data will be available. A cachexia, hypogonadism, sexual further examination is needed regarding the dysfunction and others. They can replace mechanisms of action, unreported side anabolic androgenic steroids and improve effects and the effects of SARMs when the quality of life of a lot of patients. The combined with physical exercise. big advantage of SARMs over anabolic

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