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Drugs targeting the AR has the potential to be used in prostate cancer, benign prostatic hyperplasia (BPH), osteoporosis, breast cancer, hypogonadism, conditions where cachexia is a consequence of the disease state (HIV, cancer, immobilization), urinary incontinence, muscle wasting conditions as Duchenne muscular dystrophy (DMD) and Alzheimer’s disease <ref name="SARMs knowledge">PMID: 30503797</ref><ref name="NR">PMID: 23457206</ref><ref name="SARMs therapy">PMID: 32257854</ref><ref name="SARMs">PMID: 28624515</ref>. | Drugs targeting the AR has the potential to be used in prostate cancer, benign prostatic hyperplasia (BPH), osteoporosis, breast cancer, hypogonadism, conditions where cachexia is a consequence of the disease state (HIV, cancer, immobilization), urinary incontinence, muscle wasting conditions as Duchenne muscular dystrophy (DMD) and Alzheimer’s disease <ref name="SARMs knowledge">PMID: 30503797</ref><ref name="NR">PMID: 23457206</ref><ref name="SARMs therapy">PMID: 32257854</ref><ref name="SARMs">PMID: 28624515</ref>. | ||
====Prostate Cancer==== | ====Prostate Cancer==== | ||
Androgen receptor is fundamental for the correct function, development of the prostate <ref>PMID: 12237244</ref> having a critical role in the control of homeostasis between prostate cells differentiation and proliferation <ref name="ARA prostate">PMID: 24639562</ref>. It's widely accepted that androgen receptor plays an important role in prostate cancer cells due to the alteration of that equilibrium, shifting the AR to a more proliferative transcriptional program <ref name="ARA | Androgen receptor is fundamental for the correct function, development of the prostate <ref>PMID: 12237244</ref> having a critical role in the control of homeostasis between prostate cells differentiation and proliferation <ref name="ARA prostate">PMID: 24639562</ref>. It's widely accepted that androgen receptor plays an important role in prostate cancer cells due to the alteration of that equilibrium, shifting the AR to a more proliferative transcriptional program <ref name="ARA prostate" />. | ||
====Alzheimer’s Disease==== | ====Alzheimer’s Disease==== | ||
Androgen depletion is considered a significant risk factor for Alzheimer’s disease and circulating testosterone levels are inversely correlated with levels of ß-amyloid (ßA) in the brains of aged men <ref name="SARMs knowledge" />. | Androgen depletion is considered a significant risk factor for Alzheimer’s disease and circulating testosterone levels are inversely correlated with levels of ß-amyloid (ßA) in the brains of aged men <ref name="SARMs knowledge" />. | ||
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==Steroid== | ==Steroid== | ||
===Natural ligand: Testosterone=== | ===Natural ligand: Testosterone=== | ||
Aging and other factors are associated with a reduction of testosterone levels which could lead to late onset hypogonadism <ref name="hypogonadism">PMID: 32737921</ref>. The decrease of the testosterone levels and therefore its active metabolite levels (DHT) are related with several symptoms such as low libido, erectile dysfunction, skeletal muscular loss <ref name=" | Aging and other factors are associated with a reduction of testosterone levels which could lead to late onset hypogonadism <ref name="hypogonadism">PMID: 32737921</ref>. The decrease of the testosterone levels and therefore its active metabolite levels (DHT) are related with several symptoms such as low libido, erectile dysfunction, skeletal muscular loss <ref name="NR" /><ref name="hypogonadism" />, increased cardiovascular risk <ref name="hypogonadism" />… To treat those symptoms is used Testosterone Restitution Therapy (TRT) which has been associated with the improve in sexual function, increase in muscle mass and bone mineral density <ref name="Testosterone">PMID: 34888506</ref>. | ||
One of the problems associated with the use of T as a therapeutic agent in TRT are the delivery method, tending to have low efficacy orally administered <ref name=" | One of the problems associated with the use of T as a therapeutic agent in TRT are the delivery method, tending to have low efficacy orally administered <ref name="NR" /><ref name="SARMs therapy” /> and having some inconvenients with intramuscular injections or implants <ref name="NR" />. Also, the use of this hormone as a treatment could triggered a lot of AR widespread around the body and a long-term exposure to a high dose could lead to related side effects like erythrocytosis <ref name="NR" /><ref name="SARMs therapy" />, dyslipidemia, hepatotoxicity <ref name="SARMs therapy" /> and in some clinical trials it has been described an increase in cardiovascular risk <ref name="Testosterone" /><ref name="hypogonadism" />. | ||
Due to all these problems, some institutions like the FDA warn about the safety issues related with this therapy assessing the reduction of its use <ref name="Testosterone" /><ref name="hypogonadism" />. However, other agencies like the EMA supported by the European Academy of Andrology establish the practical use of this therapy in men’s hypogonadism <ref name="Testosterone" /><ref name="hypogonadism" />. So, there is still some controversy about its use, and it’s still currently studied in clinical trials <ref name="Testosterone" />. | Due to all these problems, some institutions like the FDA warn about the safety issues related with this therapy assessing the reduction of its use <ref name="Testosterone" /><ref name="hypogonadism" />. However, other agencies like the EMA supported by the European Academy of Andrology establish the practical use of this therapy in men’s hypogonadism <ref name="Testosterone" /><ref name="hypogonadism" />. So, there is still some controversy about its use, and it’s still currently studied in clinical trials <ref name="Testosterone" />. | ||
===Antagonist: Steroid ARA=== | ===Antagonist: Steroid ARA=== | ||
The development of these drugs were one of the first approaches to treat prostate cancer, targeting AR activity by having a structure with an steroidal skeleton <ref name="ARA | The development of these drugs were one of the first approaches to treat prostate cancer, targeting AR activity by having a structure with an steroidal skeleton <ref name="ARA prostate" />. | ||
This kind of antiandrogens have another steroid receptor affinity (glucocorticoids receptor, progesterone receptor…) having low efficiency and some side effects like hepatotoxicity and increased cardiovascular risks <ref name="ARA | This kind of antiandrogens have another steroid receptor affinity (glucocorticoids receptor, progesterone receptor…) having low efficiency and some side effects like hepatotoxicity and increased cardiovascular risks <ref name="ARA prostate" />. Some examples are cyproterone acetate (CPA) <ref name="ARA prostate" /><ref name="bicalutamide">PMID: 15833816</ref><ref name="nonsteroidal">PMID: 16841196</ref> or megestrol acetate <ref name="ARA prostate" />. | ||
===Agonist: Anabolic Androgen Steroids (AAs)=== | ===Agonist: Anabolic Androgen Steroids (AAs)=== | ||
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Steroid androgens can be associated with a high rate of adverse effects, which limits their widespread clinical use. To overcome these side effects, SARMs were developed. | Steroid androgens can be associated with a high rate of adverse effects, which limits their widespread clinical use. To overcome these side effects, SARMs were developed. | ||
SARMs are small molecule drugs that manipulate the AR function in different tissues <ref name="SARMs knowledge" />. They can act as both agonist and antagonist, making them potential to treat AR-related diseases. | SARMs are small molecule drugs that manipulate the AR function in different tissues <ref name="SARMs knowledge" />. They can act as both agonist and antagonist, making them potential to treat AR-related diseases. | ||
These non-steroidal drugs normally can be administered orally or using a transdermal injection <ref name=" | These non-steroidal drugs normally can be administered orally or using a transdermal injection <ref name="NR" /><ref name="SARMs therapy" /> having better compliance and there are not affected by 5α-reductase (limiting its androgenic risk effects) and aromatase (limiting its estrogenic risk effects) <ref name="NR" /><ref name="SARMs therapy" />. Those characteristics help to the reduction of side effects related with the use of natural androgens and the tissue selectivity of these drugs make them a suitable option to treat a great group of diseases skipping the risk related with the use of TRT <ref name="NR" /><ref name="SARMs therapy" /><ref name="SARMs" />. | ||
Also, some SARMs could be a suitable option to achieve the improvement in anabolic activity and muscular density obtained by the use of AAs without the unwanted side effects associated with their androgenic action of those drugs <ref name="Steroids" />. | Also, some SARMs could be a suitable option to achieve the improvement in anabolic activity and muscular density obtained by the use of AAs without the unwanted side effects associated with their androgenic action of those drugs <ref name="Steroids" />. | ||
====Mechanism of SARMs==== | ====Mechanism of SARMs==== | ||
Currently SARMs tissue selectivity is still under research <ref name="SARMs" /><ref name="Steroids" />. There is no consensus on SARMs mechanisms of action. However, there are two hypotheses that could explain it: | Currently SARMs tissue selectivity is still under research <ref name="SARMs" /><ref name="Steroids" />. There is no consensus on SARMs mechanisms of action. However, there are two hypotheses that could explain it: | ||
It could be related with their non-steroidal composition and with the fact that they are unaffected by 5α-reductase <ref name="SARMs | It could be related with their non-steroidal composition and with the fact that they are unaffected by 5α-reductase <ref name="SARMs therapy" /><ref name="SARMs" /><ref name="Steroids" /> which promotes the interaction of AR with tissue-specific coactivators. | ||
The way SARMs bind to the AR is what primarily enhances or represses their effect. Each SARM-AR complex has a different conformation and tissues have unique patterns of AR expression, co-regulatory proteins levels and transcriptional regulation <ref name="SARMs knowledge" />. | The way SARMs bind to the AR is what primarily enhances or represses their effect. Each SARM-AR complex has a different conformation and tissues have unique patterns of AR expression, co-regulatory proteins levels and transcriptional regulation <ref name="SARMs knowledge" />. | ||
When a ligand promotes interactions between the N- and C-terminal AR domains, the AR is maximally active. The ability to reduce N/C interactions is the hallmark of SARMs that display antagonisms in androgenic tissues <ref name="SARMs knowledge" />. | When a ligand promotes interactions between the N- and C-terminal AR domains, the AR is maximally active. The ability to reduce N/C interactions is the hallmark of SARMs that display antagonisms in androgenic tissues <ref name="SARMs knowledge" />. | ||
