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Vishal Bhoir, Marta Roldan Lazaro, Cristina Benito, Alexsandra Tifane Santos do Nascimento, Student

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 ===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="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="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" />.
+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" />.
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 These kinds of drugs were developed with the objective to avoid the secondary effects associated with cross reactivity of steroidal ARA, increasing the selectivity and the affinity to the androgen receptor, limiting the association with other steroids nuclear receptors <ref name="bicalutamide" />. Also, their non-steroidal structure improved oral bioavailability being another advantage in comparison with steroidal ARA <ref name="bicalutamide" />. Some examples are flutamide, bicalutamide <ref name="ARA prostate" /><ref name="bicalutamide" /><ref name="Bicalutamide functions">PMID: 12015321</ref><ref name="Unexpected">PMID: 21506597</ref><ref name="nonsteroidal" /><ref name="Role of AR">PMID: 30209899</ref> or apalutamide (ARN-509) <ref name="ARA prostate" /><ref name="Role of AR” />.
 ====Bicalutamide====
-R-<scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>, marketed as Casodex <ref name="ARA prostate" /><ref name="nonsteroidal" />, is one of the most stable and tolerated androgen receptor antagonists used in the treatment of prostate cancer <ref name="ARA prostate" /><ref name="bicalutamide" /><ref name="AAWS">PMID: 28971898</ref>, belonging to the first generation of antiandrogens developed <ref name="ARA prostate" /><ref name="MoA">PMID: 35245614</ref>. It is a competitive antagonist <ref name="Bicalutamide functions" /><ref name="MoA" /><ref name="AAWS" /> which binds to the LBD producing a transcriptionally inactive androgen receptor <ref name="Bicalutamide functions” />. However, it seems that the long-term use of these drugs and other first generation antiandrogens leads to withdrawal syndrome in prostate cancer resistant to castration patients <ref name="ARA prostate" /><ref name="nonsteroidal" />. In many cases associated androgen receptor mutations like W741L that can switch the mechanism of action of the drug from antagonist to agonist or partial agonist <ref name="ARA prostate" /><ref name="bicalutamide" /><ref name="MoA" /><ref name="Unexpected" /><ref name="nonsteroidal" />.
+R-<scene name='85/857155/Bicatulamide_in_ar/1'>bicatulamide</scene>, marketed as Casodex <ref name="ARA prostate" /><ref name="nonsteroidal" />, is one of the most stable and tolerated androgen receptor antagonists used in the treatment of prostate cancer <ref name="ARA prostate" /><ref name="bicalutamide" /><ref name="AAWS">PMID: 28971898</ref>, belonging to the first generation of antiandrogens developed <ref name="ARA prostate" /><ref name="MoA">PMID: 35245614</ref>. It is a competitive antagonist <ref name="Bicalutamide functions" /><ref name="MoA" /><ref name="AAWS" /> which binds to the LBD producing a transcriptionally inactive androgen receptor <ref name="Bicalutamide functions" />. However, it seems that the long-term use of these drugs and other first generation antiandrogens leads to withdrawal syndrome in prostate cancer resistant to castration patients <ref name="ARA prostate" /><ref name="nonsteroidal" />. In many cases associated androgen receptor mutations like W741L that can switch the mechanism of action of the drug from antagonist to agonist or partial agonist <ref name="ARA prostate" /><ref name="bicalutamide" /><ref name="MoA" /><ref name="Unexpected" /><ref name="nonsteroidal" />.
 Although bicalutamide has been patented since 1982 and approved to be clinical used by the FDA since 1995 <ref name="bicalutamide" />, its mechanism of action it's still a debate, because the X-ray structure of the wild-type androgen receptor binded to an antagonist is not yet solved <ref name="MoA" />.
 Changes in the conformation of the androgen receptor due to association with antagonists have been hypothesized to be similar to those produced in the steroid receptor family <ref name="ARA prostate" /><ref name="MoA" />.