Androgen receptor antagonists +<unk> s at steroid hormone receptors Relative binding affinities 8–10 60 a a 182 3.6 Notes: (1): Reference ligands (100%) were testosterone for the , progesterone for the , estradiol for the , dexamethasone for the , and aldosterone for the . (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: AR antagonists act by directly binding to and competitively displacing androgens like testosterone and DHT from the AR, thereby preventing them from activating the receptor and mediating their biological effects. AR antagonists are classified into two types, based on chemical structure: steroidal and nonsteroidal. Steroidal AR antagonists are structurally related to steroid hormones like testosterone and progesterone, whereas nonsteroidal AR antagonists are not steroids and are structurally distinct. Steroidal AR antagonists tend to have off-target hormonal actions due to their structural similarity to other steroid hormones. In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity. For this reason, they are sometimes described as "pure"<unk> s. Although they are described as<unk> s and indeed show only such effects generally, most or all steroidal AR antagonists are actually not silent antagonists of the AR but rather are weak partial agonists and are able to activate the receptor in the absence of more potent AR agonists like testosterone and DHT. This may have clinical implications in the specific context of prostate cancer treatment. As an example, steroidal AR antagonists are able to increase prostate weight and accelerate prostate cancer cell growth in the absence of more potent AR agonists, and spironolactone has been found to accelerate progression of prostate cancer in case reports. In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals, it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor. This may be why they have greater efficacy than steroidal AR antagonists in the treatment of prostate cancer and is an important reason as to why they have largely replaced them for this indication in medicine. Nonsteroidal<unk> s have relatively low affinity for the AR compared to steroidal AR ligands. For example, bicalutamide has around 2% of the affinity of DHT for the AR and around 20% of the affinity of CPA for the AR. Despite their low affinity for the AR however, the lack of weak partial agonist activity of NSAAs appears to improve their potency relative to steroidal<unk> s. For example, although flutamide has about 10-fold lower affinity for the AR than CPA, it shows equal or slightly greater potency to CPA as an<unk>  in bioassays. In addition, circulating therapeutic concentrations of nonsteroidal<unk> s are very high, on the order of thousands of times higher than those of testosterone and DHT, and this allows them to efficaciously compete and block AR signaling. AR antagonists may not bind to or block membrane androgen receptors (mARs), which are distinct from the classical nuclear AR. However, the mARs do not appear to be involved in masculinization. This is evidenced by the perfectly female phenotype of women with complete androgen insensitivity syndrome. These women have a 46,XY karyotype (i.e., are genetically "male") and high levels of androgens but possess a defective AR and for this reason never masculinize. They are described as highly feminine, both physically as well as mentally and behaviorally. N-Terminal domain antagonists N-Terminal domain AR antagonists are a new type of AR antagonist that, unlike all currently marketed AR antagonists, bind to the N-terminal domain (NTD) of the AR rather than the ligand-binding domain (LBD). Whereas conventional AR antagonists bind to the LBD of the AR and competitively displace androgens, thereby preventing them from activating the receptor, AR NTD antagonists bind covalently to the NTD of the AR and prevent protein–protein interactions subsequent to activation that are required for transcriptional activity. As such, they are non-competitive and irreversible antagonists of the AR. Examples of AR NTD antagonists include bisphenol A diglycidyl ether (BADGE) and its derivatives EPI-001, ralaniten (EPI-002), and ralaniten acetate (EPI-506). AR NTD antagonists are under investigation for the potential treatment of prostate cancer, and it is thought that they may have greater efficacy as<unk> s relative to conventional AR antagonists. In accordance with this notion, AR NTD antagonists are active against splice variants of the AR, which conventional AR antagonists are not, and AR NTD antagonists are immune to gain-of-function mutations in the AR LBD that convert AR antagonists into AR agonists and commonly occur in prostate cancer. Androgen receptor degraders Selective androgen receptor degraders (SARDs) are another new type of<unk>  that has recently been developed. They work by enhancing the degradation of the AR, and are analogous to selective estrogen receptor degraders (SERDs) like fulvestrant (a drug used to treat estrogen receptor-positive breast cancer). Similarly to AR NTD antagonists, it is thought that SARDs may have greater efficacy than conventional AR antagonists, and for this reason, they are under investigation for the treatment of prostate cancer. An example of a SARD is dimethylcurcumin (ASC-J9), which is under development as a topical medication for the potential treatment of acne. SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR. Androgen synthesis inhibitors Androgen synthesis inhibitors are enzyme inhibitors that prevent the biosynthesis of androgens. This process occurs mainly in the gonads and adrenal glands, but also occurs in other tissues like the prostate gland, skin, and hair follicles. These drugs include aminoglutethimide, ketoconazole, and abiraterone acetate. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of cholesterol into pregnenolone and by extension the production of all steroid hormones, including the androgens. Ketoconazole and abiraterone acetate are inhibitors of the enzyme CYP17A1, also known as 17α-hydroxylase/17,20-lyase, which is responsible for the conversion of pregnane steroids into androgens, as well as the conversion of mineralocorticoids into glucocorticoids. Because these drugs all prevent the formation of glucocorticoids in addition to androgens, they must be combined with a glucocorticoid like prednisone to avoid adrenal insufficiency. A newer drug currently under development for treatment of prostate cancer, seviteronel, is selective for inhibition of the 17,20-lyase functionality of CYP17A1, and for this reason, unlike earlier drugs, does not require concomitant treatment with a glucocorticoid. 5α-Reductase inhibitors 5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of 5α-reductase, an enzyme that is responsible for the formation of DHT from testosterone. DHT is between 2.5- and 10-fold more potent than testosterone as an androgen and is produced in a tissue-selective manner based on expression of 5α-reductase. Tissues in which DHT forms at a high rate include the prostate gland, skin, and hair follicles. In accordance, DHT is involved in the pathophysiology of benign prostatic hyperplasia, pattern hair loss, and hirsutism, and 5α-reductase inhibitors are used to treat these conditions. Antigonadotropins Estradiol and testosterone levels following a single intramuscular injection of 320 mg polyestradiol phosphate, a polymeric estradiol ester and prodrug, in men with prostate cancer. Testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men. Antigonadotropins are drugs that suppress the GnRH-mediated secretion of gonadotropins from the pituitary gland. Gonadotropins include luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and are peptide hormones that signal the gonads to produce sex hormones. By suppressing gonadotropin secretion, antigonadotropins suppress gonadal sex hormone production and by extension circulating androgen levels. GnRH modulators, including both GnRH agonists and GnRH antagonists, are powerful antigonadotropins that are able to suppress androgen levels by 95% in men. In addition, estrogens and progestogens are antigonadotropins via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis). High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators, while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men. Examples of GnRH agonists include leuprorelin (leuprolide) and goserelin, while an example of a GnRH antagonist is cetrorelix. Estrogens that are or that have been used as antigonadotropins include estradiol, estradiol esters like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol (no longer widely used), and bifluranol. Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone. Miscellaneous Sex hormone-binding globulin modulators In addition to their antigonadotropic effects, estrogens are also functional<unk> s by decreasing free concentrations of androgens via increasing the hepatic production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels. Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold
Antiandrogen
Antiestrogen
Antiglucocorticoid
Thyroid blocker
Aromatase inhibitor
Nonsteroidal antiandrogen
Antiprogestogen
Phytoestrogen