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Antiandrogen

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Template:Short description Template:Infobox drug class

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production.<ref name = Mowszowicz>Template:Cite journal</ref><ref name="Brueggemeier2006">Template:Cite book</ref> They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.<ref name="Nath2006">Template:Cite book</ref>

Antiandrogens are used to treat an assortment of androgen-dependent conditions.<ref name="pmid31712062">Template:Cite journal</ref> In men, antiandrogens are used in the treatment of prostate cancer, enlarged prostate, scalp hair loss, overly high sex drive, unusual and problematic sexual urges, and early puberty.<ref name="pmid31712062" /><ref name="pmid16845534">Template:Cite journal</ref> In women, antiandrogens are used to treat acne, seborrhea, excessive hair growth, scalp hair loss, and high androgen levels, such as those that occur in polycystic ovary syndrome (PCOS).<ref name="pmid31712062" /> Antiandrogens are also used as a component of feminizing hormone therapy for transgender women and as puberty blockers in transgender girls.<ref name="pmid31712062" />

Side effects of antiandrogens depend on the type of antiandrogen and the specific antiandrogen in question. In any case, common side effects of antiandrogens in men include breast tenderness, breast enlargement, feminization, hot flashes, sexual dysfunction, infertility, and osteoporosis. In women, antiandrogens are much better tolerated, and antiandrogens that work only by directly blocking androgens are associated with minimal side effects. However, because estrogens are made from androgens in the body, antiandrogens that suppress androgen production can cause low estrogen levels and associated symptoms like hot flashes, menstrual irregularities, and osteoporosis in premenopausal women.

There are a few different major types of antiandrogens.<ref name="pmid11502457">Template:Cite journal</ref> These include AR antagonists, androgen synthesis inhibitors, and antigonadotropins.<ref name="pmid11502457" /> AR antagonists work by directly blocking the effects of androgens, while androgen synthesis inhibitors and antigonadotropins work by lowering androgen levels.<ref name="pmid11502457" /> AR antagonists can be further divided into steroidal antiandrogens and nonsteroidal antiandrogens; androgen synthesis inhibitors can be further divided mostly into CYP17A1 inhibitors and 5α-reductase inhibitors; and antigonadotropins can be further divided into gonadotropin-releasing hormone modulators (GnRH modulators), progestogens, and estrogens.<ref name="pmid11502457" /><ref name="SchröderRadlmaier2009">Template:Cite book</ref><ref name="KolvenbagFurr2009">Template:Cite book</ref>

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Medical usesEdit

Antiandrogens are used in the treatment of an assortment of androgen-dependent conditions in both males and females.<ref name="pmid31712062" /><ref name="pmid2147859">Template:Cite journal</ref> They are used to treat men with prostate cancer, benign prostatic hyperplasia, pattern hair loss, hypersexuality, paraphilias, and priapism, as well as boys with precocious puberty.<ref name="pmid2147859" /><ref name="pmid20092449">Template:Cite journal</ref><ref name="SteinbergForget2009">Template:Cite book</ref> In women and girls, antiandrogens are used to treat acne, seborrhea, hidradenitis suppurativa, hirsutism, and hyperandrogenism.<ref name="pmid2147859" /><ref name="pmid16828411">Template:Cite journal</ref><ref name="RabeGrunwald2009">Template:Cite journal</ref> Antiandrogens are also used in transgender women as a component of feminizing hormone therapy and as puberty blockers in transgender girls.<ref name="pmid21714669" /><ref name="pmid25404716" />

Men and boysEdit

Prostate cancerEdit

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Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer.<ref name="pmid27019626">Template:Cite journal</ref> They act as growth factors in the prostate gland, stimulating cell division and tissue growth.<ref name="pmid27019626" /> In accordance, therapeutic modalities that reduce androgen signaling in the prostate gland, referred to collectively as androgen deprivation therapy, are able to significantly slow the course of prostate cancer and extend life in men with the disease.<ref name="pmid27019626" /> Although antiandrogens are effective in slowing the progression of prostate cancer, they are not generally curative, and with time, the disease adapts and androgen deprivation therapy eventually becomes ineffective.<ref name="pmid21680543">Template:Cite journal</ref> When this occurs, other treatment approaches, such as chemotherapy, may be considered.<ref name="pmid21680543" />

The most common methods of androgen deprivation therapy currently employed to treat prostate cancer are castration (with a GnRH modulator or orchiectomy), nonsteroidal antiandrogens, and the androgen synthesis inhibitor abiraterone acetate.<ref name="pmid27019626" /> Castration may be used alone or in combination with one of the other two treatments.<ref name="pmid27019626" /><ref name="pmid17604502">Template:Cite journal</ref> When castration is combined with a nonsteroidal antiandrogen like bicalutamide, this strategy is referred to as combined androgen blockade (also known as complete or maximal androgen blockade).<ref name="pmid27019626" /><ref name="pmid21091846">Template:Cite journal</ref> Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer.<ref name="pmid27019626" /><ref name="pmid24390422">Template:Cite journal</ref> Monotherapy with the nonsteroidal antiandrogen bicalutamide is also used in the treatment of prostate cancer as an alternative to castration with comparable effectiveness but with a different and potentially advantageous side effect profile.<ref name="pmid27019626" /><ref name="pmid11121992" /><ref name="pmid11502439">Template:Cite journal</ref>

High-dose estrogen was the first functional antiandrogen used to treat prostate cancer. It was widely used, but has largely been abandoned for this indication in favor of newer agents with improved safety profiles and fewer feminizing side effects.<ref name="pmid12667881">Template:Cite journal</ref> Cyproterone acetate was developed subsequently to high-dose estrogen and is the only steroidal antiandrogen that has been widely used in the treatment of prostate cancer,<ref name="SmithWilliams2005">Template:Cite book</ref> but it has largely been replaced by nonsteroidal antiandrogens, which are newer and have greater effectiveness, tolerability, and safety.<ref name="ChabnerLongo2010">Template:Cite book</ref><ref name="KaliksDel Giglio2008">Template:Cite journal</ref> Bicalutamide, as well as enzalutamide, have largely replaced the earlier nonsteroidal antiandrogens flutamide and nilutamide, which are now little used.<ref name="pmid21091846" /><ref name="HHS2010">Template:Citation</ref><ref name="Gulley2011">Template:Cite book</ref><ref name="Moser2008">Template:Cite book</ref><ref name="Demnos2011">Template:Cite book</ref> The earlier androgen synthesis inhibitors aminoglutethimide and ketoconazole have only limitedly been used in the treatment of prostate cancer due to toxicity concerns and have been replaced by abiraterone acetate.<ref name="FiggChau2010" />

In addition to active treatment of prostate cancer, antiandrogens are effective as prophylaxis (preventatives) in reducing the risk of ever developing prostate cancer.<ref name="pmid21604953">Template:Cite journal</ref> Antiandrogens have only limitedly been assessed for this purpose, but the 5α-reductase inhibitors finasteride and dutasteride and the steroidal AR antagonist spironolactone have been associated with significantly reduced risk of prostate cancer.<ref name="pmid21604953" /><ref name="pmid27735065">Template:Cite journal</ref> In addition, it is notable that prostate cancer is extremely rare in transgender women who have been on feminizing hormone therapy for an extended period of time.<ref name="pmid19509099">Template:Cite journal</ref><ref name="pmid24329588">Template:Cite journal</ref><ref name="pmid24032068">Template:Cite journal</ref>

Enlarged prostateEdit

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The 5α-reductase inhibitors finasteride and dutasteride are used to treat benign prostatic hyperplasia, a condition in which the prostate becomes enlarged and this results in urinary obstruction and discomfort.<ref name="pmid19030020">Template:Cite journal</ref> They are effective because androgens act as growth factors in the prostate gland.<ref name="pmid19030020" /> The antiandrogens chlormadinone acetate and oxendolone and the functional antiandrogens allylestrenol and gestonorone caproate are also approved in some countries for the treatment of benign prostatic hyperplasia.<ref name="pmid12534901">Template:Cite journal</ref><ref name="RaspéBrosig2013">Template:Cite book</ref>

Scalp hair lossEdit

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5α-Reductase inhibitors like finasteride, dutasteride, and alfatradiol and the topical nonsteroidal AR antagonist topilutamide (fluridil) are approved for the treatment of pattern hair loss, also known as scalp hair loss or baldness.<ref name="TrüebLee2014">Template:Cite book</ref> This condition is generally caused by androgens, so antiandrogens can slow or halt its progression.<ref name="BologniaJorizzo">Template:Cite book</ref> Systemic antiandrogens besides 5α-reductase inhibitors are not generally used to treat scalp hair loss in males due to risks like feminization (e.g., gynecomastia) and sexual dysfunction.<ref name="Simpson1989">Template:Cite book</ref><ref name="Unger1995">Template:Cite book</ref><ref name="Rasmusson1986" /><ref name="Cormanevan der Meeren1981" /><ref name="pmid19297634">Template:Cite journal</ref><ref name="LamHempstead2012">Template:Cite book</ref><ref name="Neumann1996" /> However, they have been assessed and reported to be effective for this indication.<ref name="Simpson1989"/><ref name="Unger1995"/><ref name="Coskey1984">Template:Cite journal</ref>

AcneEdit

Systemic antiandrogens are generally not used to treat acne in males due to their high risk of feminization (e.g., gynecomastia) and sexual dysfunction.<ref name="PlewigKligman2012">Template:Cite book</ref><ref name="AlldredgeCorelli2012">Template:Cite book</ref> However, they have been studied for acne in males and found to be effective.<ref name="WardBrogden1984">Template:Cite journal</ref><ref name="Rasmusson1986">Template:Cite book</ref><ref name="Cormanevan der Meeren1981">Template:Cite journal</ref><ref name="pmid2945742">Template:Cite journal</ref> Clascoterone, a topical antiandrogen, is effective for acne in males, albeit modestly,<ref name="BasendwhAlharbiBukhamsin2024" /> and has been approved by the FDA in August 2020.<ref name="pmid31487336">Template:Cite journal</ref><ref name="pmid27416311">Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ParaphiliasEdit

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Androgens increase sex drive,<ref name="JonesLopez2013">Template:Cite book</ref> and for this reason, antiandrogens are able to reduce sex drive in men.<ref name="pmid11221487">Template:Cite journal</ref><ref name="pmid19243704">Template:Cite journal</ref> In accordance, antiandrogens are used in the treatment of conditions such as hypersexuality (excessively high sex drive) and paraphilias (atypical and sometimes societally unacceptable sexual interests) like pedophilia (sexual attraction to children).<ref name="pmid11221487" /><ref name="pmid19243704" /> They have been used to decrease sex drive in sex offenders so as to reduce the likelihood of recidivism (repeat offenses).<ref name="MarshallLaws2013">Template:Cite book</ref> Antiandrogens used for these indications include cyproterone acetate, medroxyprogesterone acetate, and GnRH modulators.<ref name="StunkardBaum1989">Template:Cite book</ref><ref name="PhenixHoberman2015">Template:Cite book</ref>

Early pubertyEdit

Antiandrogens are used to treat precocious puberty in boys.<ref name="pmid18345393">Template:Cite journal</ref><ref name="pmid6205409">Template:Cite journal</ref><ref name="pmid2462132">Template:Cite journal</ref><ref name="pmid3109366">Template:Cite journal</ref> They work by opposing the effects of androgens and delaying the development of secondary sexual characteristics and onset of changes in sex drive and function until a more appropriate age.<ref name="pmid18345393" /><ref name="pmid6205409" /> Antiandrogens that have been used for this purpose include cyproterone acetate, medroxyprogesterone acetate, GnRH modulators, spironolactone, bicalutamide, and ketoconazole.<ref name="pmid18345393" /><ref name="pmid3109366" /><ref name="pmid10969925">Template:Cite journal</ref><ref name="pmid1838080">Template:Cite journal</ref><ref name="pmid1903104">Template:Cite journal</ref><ref name="pmid16361981">Template:Cite journal</ref> Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed estrogens, while the others can be used alone.<ref name="pmid18345393" /><ref name="pmid1903104" /><ref name="pmid16361981" />

Long-lasting erectionsEdit

Antiandrogens are effective in the treatment of recurrent priapism (potentially painful penile erections that last more than four hours).<ref name="LeveyKutlu2011">Template:Cite journal</ref><ref name="BroderickKadioglu2010">Template:Cite journal</ref><ref name="ChowPayne2008">Template:Cite journal</ref><ref name="DahmRao2002">Template:Cite journal</ref><ref name="YuanDeSouza2008">Template:Cite journal</ref>

Women and girlsEdit

Skin and hair conditionsEdit

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Antiandrogens are used in the treatment of androgen-dependent skin and hair conditions including acne, seborrhea, hidradenitis suppurativa, hirsutism, and pattern hair loss in women.<ref name="pmid16828411" /> All of these conditions are dependent on androgens, and for this reason, antiandrogens are effective in treating them.<ref name="pmid16828411" /> The most commonly used antiandrogens for these indications are cyproterone acetate and spironolactone.<ref name="BaranMaibach1998">Template:Cite book</ref> Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with hepatotoxicity.<ref name="MaibachGorouhi2011">Template:Cite book</ref> Bicalutamide, which has a relatively minimal risk of hepatotoxicity, has been evaluated for the treatment of hirsutism and found effective similarly to flutamide and may be used instead of it.<ref name="WilliamsBigby2009">Template:Cite book</ref><ref name="pmid24455796">Template:Cite journal</ref> In addition to AR antagonists, oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.<ref name="Becker2001">Template:Cite book</ref><ref name="CamachoGharib2012">Template:Cite book</ref>

High androgen levelsEdit

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Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high.<ref name="RabeGrunwald2009" /> It is commonly seen in women with PCOS, and also occurs in women with intersex conditions like congenital adrenal hyperplasia.<ref name="RabeGrunwald2009" /> Hyperandrogenism is associated with virilization – that is, the development of masculine secondary sexual characteristics like male-pattern facial and body hair growth (or hirsutism), voice deepening, increased muscle mass and strength, and broadening of the shoulders, among others.<ref name="RabeGrunwald2009" /> Androgen-dependent skin and hair conditions like acne and pattern hair loss may also occur in hyperandrogenism, and menstrual disturbances, like amenorrhea, are commonly seen.<ref name="RabeGrunwald2009" /> Although antiandrogens do not treat the underlying cause of hyperandrogenism (e.g., PCOS), they are able to prevent and reverse its manifestation and effects.<ref name="RabeGrunwald2009" /> As with androgen-dependent skin and hair conditions, the most commonly used antiandrogens in the treatment of hyperandrogenism in women are cyproterone acetate and spironolactone.<ref name="RabeGrunwald2009" /> Other antiandrogens, like bicalutamide, may be used alternatively.<ref name="RabeGrunwald2009" />

Transgender hormone therapyEdit

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Antiandrogens are used to prevent or reverse masculinization and to facilitate feminization in transgender women and some non-binary transfeminine individuals who are undergoing hormone therapy and who have not undergone sex reassignment surgery or orchiectomy.<ref name="pmid21714669">Template:Cite journal</ref> Besides estrogens, the main antiandrogens that have been used for this purpose are cyproterone acetate, spironolactone, and GnRH modulators.<ref name="pmid21714669" /> Nonsteroidal antiandrogens like bicalutamide are also used for this indication.<ref name="pmid30256230">Template:Cite journal</ref><ref name="pmid21714669" /> In addition to use in transgender women, antiandrogens, mainly GnRH modulators, are used as puberty blockers to prevent the onset of puberty in transgender girls until they are older and ready to begin hormone therapy.<ref name="pmid25404716">Template:Cite journal</ref>

Available formsEdit

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There are several different types of antiandrogens, including the following:<ref name="pmid11502457" />

Certain antiandrogens combine multiple of the above mechanisms.<ref name="pmid11502457" /><ref name="HannaCrosby2015">Template:Cite book</ref> An example is the steroidal antiandrogen cyproterone acetate, which is a potent AR antagonist, a potent progestogen and hence antigonadotropin, a weak glucocorticoid and hence anticorticotropin, and a weak androgen synthesis inhibitor.<ref name="pmid11502457" /><ref name="HannaCrosby2015" /><ref name="Weber2015">Template:Cite book</ref><ref name="pmid9592622">Template:Cite journal</ref>

Antiandrogens marketed for clinical or veterinary use
Generic name Class Type Brand name(s) Route(s) Launch Status Template:Abbra
Template:No selflink Steroidal Androgen synthesis inhibitor Zytiga Oral 2011 Available 523,000
Template:No selflink Steroidal Progestin Gestanin, Perselin Oral 1961 Availableb 61,800
Template:No selflink Nonsteroidal Androgen synthesis inhibitor Cytadren, Orimeten Oral 1960 Availableb 222,000
Template:No selflink Nonsteroidal AR antagonist Erleada Oral 2018 Available 50,400
Template:No selflink Nonsteroidal AR antagonist Casodex Oral 1995 Available 754,000
Template:No selflink Steroidal Progestin; AR antagonist Belara, Prostal Oral 1965 Available 220,000
Template:No selflink Steroidal Progestin; AR antagonist Androcur, Diane Oral, Template:Abbr 1973 Available 461,000
Template:No selflink Nonsteroidal AR antagonist Nubeqa Oral 2019 Available ?
Template:No selflink Steroidal Progestin; AR antagonist Tardak Veterinary 1972 Veterinary 42,600
Template:No selflink Nonsteroidal AR antagonist Xtandi Oral 2012 Available 328,000
Template:No selflink Nonsteroidal AR antagonist Eulexin Oral 1983 Available 712,000
Template:No selflink Steroidal Progestin Depostat, Primostat Template:Abbr 1973 Availableb 119,000
Template:No selflink Steroidal Progestin Delalutin, Proluton Template:Abbr 1954 Available 108,000
Template:No selflink Nonsteroidal Androgen synthesis inhibitor Nizoral, others Oral, topical 1981 Available 3,650,000
Template:No selflink Steroidal Progestin Provera, Depo-Provera Oral, Template:Abbr, Template:Abbr 1958 Available 1,250,000
Template:No selflink Steroidal Progestin; AR antagonist Megace Oral 1963 Available 253,000
Template:No selflink Nonsteroidal AR antagonist Anandron, Nilandron Oral 1987 Available 132,000
Template:No selflink Steroidal Progestin; AR antagonist Ypozane Veterinary 2007 Veterinary 87,600
Template:No selflink Steroidal Progestin; AR antagonist Prostetin, Roxenone Template:Abbr 1981 Availableb 36,100
Template:No selflink Steroidal AR antagonist Aldactone Oral, topical 1959 Available 3,010,000
Template:No selflink Nonsteroidal AR antagonist Eucapil Topical 2003 Availableb 36,300
Footnotes: a = Hits = Google Search hits (as of February 2018). b = Availability limited / mostly discontinued. Class: Steroidal = Template:No selflink. Nonsteroidal = Template:No selflink. Note: For other antiandrogens not included in the table like 5α-reductase inhibitors, GnRH modulators, and estrogens, see elsewhere. Sources: See individual articles.

Side effectsEdit

The side effects of antiandrogens vary depending on the type of antiandrogen – namely whether it is a selective AR antagonist or lowers androgen levels – as well as the presence of off-target activity in the antiandrogen in question.<ref name="pmid11121992">Template:Cite journal</ref><ref name="Thomas1997">Template:Cite book</ref> For instance, whereas antigonadotropic antiandrogens like GnRH modulators and cyproterone acetate are associated with pronounced sexual dysfunction and osteoporosis in men, selective AR antagonists like bicalutamide are not associated with osteoporosis and have been associated with only minimal sexual dysfunction.<ref name="pmid11121992" /><ref name="pmid12603397">Template:Cite journal</ref><ref name="Priestman2012">Template:Cite book</ref> These differences are thought related to the fact that antigonadotropins suppress androgen levels and by extension levels of bioactive metabolites of androgens like estrogens and neurosteroids whereas selective AR antagonists similarly neutralize the effects of androgens but leave levels of androgens and hence their metabolites intact (and in fact can even increase them as a result of their progonadotropic effects).<ref name="pmid11121992" /> As another example, the steroidal antiandrogens cyproterone acetate and spironolactone possess off-target actions including progestogenic, antimineralocorticoid, and/or glucocorticoid activity in addition to their antiandrogen activity, and these off-target activities can result in additional side effects.<ref name="Thomas1997" />

In males, the major side effects of antiandrogens are demasculinization and feminization.<ref name="pmid12667885">Template:Cite journal</ref> These side effects include breast pain/tenderness and gynecomastia (breast development/enlargement), reduced body hair growth/density, decreased muscle mass and strength, feminine changes in fat mass and distribution, and reduced penile length and testicular size.<ref name="pmid12667885" /> The rates of gynecomastia in men with selective AR antagonist monotherapy have been found to range from 30 to 85%.<ref name="pmid16321765">Template:Cite journal</ref> In addition, antiandrogens can cause infertility, osteoporosis, hot flashes, sexual dysfunction (including loss of libido and erectile dysfunction), depression, fatigue, anemia, and decreased semen/ejaculate volume in males.Template:Failed verification<ref name="pmid12667885" /> Conversely, the side effects of selective AR antagonists in women are minimal.<ref name="pmid24455796" /><ref name="Shapiro2012">Template:Cite book</ref> However, antigonadotropic antiandrogens like cyproterone acetate can produce hypoestrogenism, amenorrhea, and osteoporosis in premenopausal women, among other side effects.<ref name="Becker2001" /><ref name="Futterweit2012">Template:Cite book</ref><ref name="pmid20082945">Template:Cite journal</ref> In addition, androgen receptor antagonists can produce unfavorable effects on cholesterol levels, which long-term may increase the risk of cardiovascular disease.<ref name="pmid28944709">Template:Cite journal</ref><ref name="pmid19843067">Template:Cite journal</ref><ref name="pmid33334002">Template:Cite journal</ref><ref name="pmid29211888">Template:Cite journal</ref><ref name="WPATH-SOC8">Template:Cite journal</ref><ref name="pmid3318361">Template:Cite journal</ref><ref name="pmid30586774">Template:Cite journal</ref>

A number of antiandrogens have been associated with hepatotoxicity.<ref name="pmid15604569">Template:Cite journal</ref> These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole.<ref name="pmid15604569" /> In contrast, spironolactone, enzalutamide,<ref name="pmid25711765">Template:Cite journal</ref> and other antiandrogens are not associated with significant rates of hepatotoxicity. However, although they do not pose a risk of hepatotoxicity, spironolactone has a risk of hyperkalemia and enzalutamide has a risk of seizures.Template:Citation needed

In women who are pregnant, antiandrogens can interfere with the androgen-mediated sexual differentiation of the genitalia and brain of male fetuses.<ref name="LeppertPeipert2004">Template:Cite book</ref> This manifests primarily as ambiguous genitalia – that is, undervirilized or feminized genitalia, which, anatomically, are a cross between a penis and a vagina – and theoretically also as femininity.<ref name="LeppertPeipert2004" /><ref name="RathusNevid2005">Template:Cite book</ref> As such, antiandrogens are teratogens, and women who are pregnant should not be treated with an antiandrogen.<ref name="CamachoGharib2012" /> Moreover, women who can or may become pregnant are strongly recommended to take an antiandrogen only in combination with proper contraception.<ref name="CamachoGharib2012" />

OverdoseEdit

Antiandrogens are relatively safe in acute overdose.Template:Citation needed

InteractionsEdit

Inhibitors and inducers of cytochrome P450 enzymes may interact with various antiandrogens.Template:Citation needed

Mechanism of actionEdit

Androgen receptor antagonistsEdit

Antiandrogens at steroid hormone receptors
Template:No selflink Relative binding affinities
Template:Abbrlink Template:Abbrlink Template:Abbrlink Template:Abbrlink Template:Abbrlink
Template:No selflink 8–10 60 <0.1 5 1
Template:No selflink 5 175 <0.1 38 1
Template:No selflink 5 152 <0.1 50 3
Template:No selflink 7 0.4a <0.1 2a 182
Template:No selflink 3.6 <1 <1 <1 <1
Template:No selflink 0.8 <0.1 <0.1 <0.1 <0.1
Template:No selflink <0.1 <0.1 <0.1 <0.1 <0.1
Template:No selflink <0.1 <0.1 <0.1 <0.1 <0.1
Template:No selflink 0.5–0.8 <0.1 <0.1 <0.1 <0.1
Template:No selflink 0.5–0.8 <0.1 <0.1 <0.1 <0.1
Template:No selflink 1.8 <0.1 <0.1 <0.1 <0.1
Notes: (1): Reference ligands (100%) were testosterone for the Template:Abbrlink, progesterone for the Template:Abbrlink, estradiol for the Template:Abbrlink, dexamethasone for the Template:Abbrlink, and aldosterone for the Template:Abbrlink. (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:<ref name="pmid3059062">Template:Cite journal</ref><ref name="pmid1992602">Template:Cite journal</ref><ref name="pmid3009970">Template:Cite journal</ref><ref name="pmid8136296">Template:Cite journal</ref><ref name="RaynaudFortin1986">Template:Cite book</ref><ref name="RaynaudOjasoo1981">Template:Cite book</ref><ref name="pmid7421203">Template:Cite journal</ref><ref name="pmid359134">Template:Cite journal</ref><ref name="pmid171505">Template:Cite journal</ref><ref name="pmid14600402">Template:Cite journal</ref>

Template:Relative potencies of selected antiandrogens in rats

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.<ref name="pmid10637363" /><ref name="ShenTaplin2010" /> AR antagonists are classified into two types, based on chemical structure: steroidal and nonsteroidal.<ref name="SchröderRadlmaier2009" /><ref name="KolvenbagFurr2009" /><ref name="pmid10637363" /><ref name="ShenTaplin2010" /><ref name="LemkeWilliams2012">Template:Cite book</ref> 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.<ref name="LemkeWilliams2012" /> In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity.<ref name="LemkeWilliams2012" /> For this reason, they are sometimes described as "pure" antiandrogens.<ref name="LemkeWilliams2012" />

Although they are described as antiandrogens 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.<ref name="pmid10637363" /><ref name="FiggChau2010" /><ref name="PoyetLabrie1985">Template:Cite journal</ref><ref name="pmid2462135">Template:Cite journal</ref> This may have clinical implications in the specific context of prostate cancer treatment.<ref name="pmid10637363" /><ref name="PoyetLabrie1985" /> 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,<ref name="pmid10637363" /><ref name="PoyetLabrie1985" /> and spironolactone has been found to accelerate progression of prostate cancer in case reports.<ref name="pmid22665559">Template:Cite journal</ref><ref name="pmid27641657">Template:Cite journal</ref> In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals,<ref name="JamesPasqualini2013">Template:Cite book</ref> it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.<ref name="pmid10637363" /> In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor.<ref name="pmid9000189">Template:Cite journal</ref><ref name="FiggChau2010"/><ref name=SinghGauthier2000>Template:Cite journal</ref><ref name="PoyetLabrie1985" /> 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.<ref name="pmid9000189" /><ref name="FiggChau2010" /><ref name=SinghGauthier2000 /><ref name="PoyetLabrie1985" />

Nonsteroidal antiandrogens have relatively low affinity for the AR compared to steroidal AR ligands.<ref name="FiggChau2010" /><ref name="SinghGauthier2000" /><ref name="pmid2788775v">Template:Cite journal</ref> 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.<ref name="pmid2788775v" /> 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 antiandrogens.<ref name="pmid2788775v" /><ref name="pmid14751673">Template:Cite journal</ref> 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 antiandrogen in bioassays.<ref name="pmid2788775v" /><ref name="pmid14751673" /> In addition, circulating therapeutic concentrations of nonsteroidal antiandrogens 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.<ref name="Pratt1994">Template:Cite book</ref>

AR antagonists may not bind to or block membrane androgen receptors (mARs), which are distinct from the classical nuclear AR.<ref name="pmid19931639">Template:Cite journal</ref><ref name="pmid25257522">Template:Cite journal</ref><ref name="pmid23746222">Template:Cite journal</ref> 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.<ref name="PescovitzEugster2004">Template:Cite book</ref><ref name="BuonocoreBracci2012">Template:Cite book</ref> 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.<ref name="PescovitzEugster2004" /><ref name="BuonocoreBracci2012" /> They are described as highly feminine, both physically as well as mentally and behaviorally.<ref name="Jordan-Young2011">Template:Cite book</ref><ref name="BlakemoreBerenbaum2013">Template:Cite book</ref><ref name="Maggi2012">Template:Cite book</ref>

N-Terminal domain antagonistsEdit

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).<ref name="ImamuraSadar2016">Template:Cite journal</ref> 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.<ref name="ImamuraSadar2016" /> As such, they are non-competitive and irreversible antagonists of the AR.<ref name="De MolFenwick2016">Template:Cite journal</ref> Examples of AR NTD antagonists include bisphenol A diglycidyl ether (BADGE) and its derivatives EPI-001, ralaniten (EPI-002), and ralaniten acetate (EPI-506).<ref name="ImamuraSadar2016" /><ref name="pmid26389532">Template:Cite journal</ref> AR NTD antagonists are under investigation for the potential treatment of prostate cancer, and it is thought that they may have greater efficacy as antiandrogens relative to conventional AR antagonists.<ref name="ImamuraSadar2016" /> 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.<ref name="ImamuraSadar2016" />

Androgen receptor degradersEdit

Selective androgen receptor degraders (SARDs) are another new type of antiandrogen that has recently been developed.<ref name="pmid27885283">Template:Cite journal</ref> 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).<ref name="pmid27885283" /> 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.<ref name="pmid23219429">Template:Cite journal</ref> An example of a SARD is dimethylcurcumin (ASC-J9), which is under development as a topical medication for the potential treatment of acne.<ref name="AdisInsight-ASC-J9">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR.<ref name="pmid23219429" />

Androgen synthesis inhibitorsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Androgen synthesis inhibitors are enzyme inhibitors that prevent the biosynthesis of androgens.<ref name="FiggChau2010" /> 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,<ref name = "pmid2652864">Template:Cite journal</ref> and abiraterone acetate.<ref name="IIIBarbieri2013" /><ref name="FiggChau2010" /><ref name="Held-Warmkessel2006">Template:Cite book</ref> 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.<ref name="IIIBarbieri2013" /> 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.<ref name="IIIBarbieri2013" /><ref name="FiggChau2010" /> 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.<ref name="Held-Warmkessel2006" /> 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.<ref name="pmid27154414">Template:Cite journal</ref>

5α-Reductase inhibitorsEdit

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.<ref name = Flores>Template:Cite journal</ref> DHT is between 2.5- and 10-fold more potent than testosterone as an androgen<ref name="MozayaniRaymon2011">Template:Cite book</ref> and is produced in a tissue-selective manner based on expression of 5α-reductase.<ref name="Bhagavan2002">Template:Cite book</ref> Tissues in which DHT forms at a high rate include the prostate gland, skin, and hair follicles.<ref name="BologniaJorizzo" /><ref name="Bhagavan2002" /> 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.<ref name="BologniaJorizzo" /><ref name="Bhagavan2002" /><ref name="pmid27672412">Template:Cite journal</ref>

AntigonadotropinsEdit

File:Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men.png
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.<ref name="pmid8610057">Template:Cite journal</ref>
File:Testosterone and luteinizing hormone levels with 100 mg per day oral cyproterone acetate in men.png
Testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men.<ref name="FourcadeMcLeod2015">Template:Cite journal</ref>

Antigonadotropins are drugs that suppress the GnRH-mediated secretion of gonadotropins from the pituitary gland.<ref name="FarmerWalker2012" /> 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.<ref name="FarmerWalker2012" /> GnRH modulators, including both GnRH agonists and GnRH antagonists, are powerful antigonadotropins that are able to suppress androgen levels by 95% in men.<ref name="Urotext2001">Template:Cite book</ref> In addition, estrogens and progestogens are antigonadotropins via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis).<ref name="Brueggemeier2006" /><ref name="pmid10997774">Template:Cite journal</ref><ref name="pmid368741">Template:Cite journal</ref> High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators,<ref name="pmid7000222">Template:Cite journal</ref> while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men.<ref name="WeinKavoussi2011">Template:Cite book</ref><ref name="pmid519881">Template:Cite journal</ref>

Examples of GnRH agonists include leuprorelin (leuprolide) and goserelin, while an example of a GnRH antagonist is cetrorelix.<ref name="LemkeWilliams2012" /> 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.<ref name="pmid18268497">Template:Cite journal</ref><ref name="pmid6258683">Template:Cite journal</ref> Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate,<ref name="pmid694436">Template:Cite journal</ref> hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.<ref name="Brueggemeier2006" /><ref name="PrentkyBurgess2000">Template:Cite book</ref><ref name="pmid294107">Template:Cite journal</ref>

MiscellaneousEdit

Sex hormone-binding globulin modulatorsEdit

In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the hepatic production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels.<ref name="NieschlagBehre2012">Template:Cite book</ref><ref name="HumansOrganization2007">Template:Cite book</ref><ref name="pmid22294742">Template:Cite journal</ref> Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%.<ref name="HumansOrganization2007" /> However, combined oral contraceptives that contain the particularly androgenic progestin levonorgestrel have been found to increase SHBG levels by only 50 to 100%,<ref name="HumansOrganization2007" /> which is likely because activation of the AR in the liver has the opposite effect of estrogen and suppresses production of SHBG.<ref name="KrishnaR.2000">Template:Cite book</ref> Levonorgestrel and certain other 19-nortestosterone progestins used in combined oral contraceptives like norethisterone also directly bind to and displace androgens from SHBG, which may additionally antagonize the functional antiandrogenic effects of ethinylestradiol.<ref name="KrishnaR.2000"/><ref name="FilshieGuillebaud2013">Template:Cite book</ref> In men, a study found that treatment with a relatively low dosage of 20 μg/day ethinylestradiol for 5 weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease free testosterone levels, increased total circulating levels of testosterone by 50% (via reduced negative feedback by androgens on the HPG axis).<ref name="NieschlagBehre2012" />

Corticosteroid-binding globulin modulatorsEdit

Estrogens at high doses can partially suppress adrenal androgen production.<ref name="Oettel1999">Template:Cite book</ref><ref name="MargiorisChrousos2001">Template:Cite book</ref><ref name="pmid7586614">Template:Cite journal</ref><ref name="pmid2958420">Template:Cite journal</ref><ref name="pmid2734983">Template:Cite journal</ref><ref name="pmid7500443">Template:Cite journal</ref> A study found that treatment with a high-dose ethinylestradiol (100 μg/day) reduced levels of major circulating adrenal androgens by 27 to 48% in transgender women.<ref name="Oettel1999" /><ref name="MargiorisChrousos2001" /><ref name="pmid7586614" /> Decreased adrenal androgens with estrogens is apparent with oral and synthetic estrogens like ethinylestradiol and estramustine phosphate but is minimal with parenteral bioidentical estradiol forms like polyestradiol phosphate.<ref name="pmid2734983" /> It is thought to be mediated via a hepatic mechanism, probably increased corticosteroid-binding globulin (CBG) production and levels and compensatory changes in adrenal steroid production (e.g., shunting of adrenal androgen synthesis to cortisol production).<ref name="pmid2734983" /><ref name="pmid7500443" /> It is notable in this regard that oral and synthetic estrogens, due to the oral first pass and resistance to hepatic metabolism, have much stronger influences on liver protein synthesis than parenteral estradiol.<ref name="pmid2664738">Template:Cite journal</ref> The decrease in adrenal androgen levels with high-dose estrogen therapy may be beneficial in the treatment of prostate cancer.<ref name="pmid7586614" /><ref name="pmid7500443" />

AnticorticotropinsEdit

Anticorticotropins such as glucocorticoids and mineralocorticoids work by exerting negative feedback on the hypothalamic–pituitary–adrenal axis (HPA axis), thereby inhibiting the secretion of corticotropin-releasing hormone (CRH) and hence adrenocorticotropic hormone (ACTH; corticotropin) and consequently suppressing the production of androgen prohormones like dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione in the adrenal gland.<ref name="MelmedPolonsky2011">Template:Cite book</ref><ref name="KumarAbbas2009">Template:Cite book</ref> They are rarely used clinically as functional antiandrogens, but are used as such in the case of congenital adrenal hyperplasia in girls and women, in which there are excessive production and levels of adrenal androgens due to glucocorticoid deficiency and hence HPA axis overactivity.<ref name="MelmedPolonsky2011" /><ref name="KumarAbbas2009" />

Insulin sensitizersEdit

In women with insulin resistance, such as those with polycystic ovary syndrome, androgen levels are often elevated.<ref name="NikolakisKyrgidis2019">Template:Cite journal</ref> Metformin, an insulin-sensitizing medication, has indirect antiandrogenic effects in such women, decreasing testosterone levels by as much as 50% secondary to its beneficial effects on insulin sensitivity.<ref name="NikolakisKyrgidis2019" /><ref name="pmid28058854">Template:Cite journal</ref><ref name="pmid33014044">Template:Cite journal</ref>

Immunogens and vaccinesEdit

Ovandrotone albumin (Fecundin, Ovastim) and Androvax (androstenedione albumin) are immunogens and vaccines against androstenedione that are used in veterinary medicine to improve fecundity (reproductive rate) in ewes (adult female sheep).<ref name="SreenanDiskin2012">Template:Cite book</ref><ref name="JindalSharma2010">Template:Cite book</ref> The generation of antibodies against androstenedione by these agents is thought to decrease circulating levels of androstenedione and its metabolites (e.g., testosterone and estrogens), which in turn increases the activity of the HPG axis via reduced negative feedback and increases the rate of ovulation, resulting in greater fertility and fecundity.<ref name="SreenanDiskin2012" /><ref name="JindalSharma2010" />

ChemistryEdit

Template:See also

Antiandrogens can be divided into several different types based on chemical structure, including steroidal antiandrogens, nonsteroidal antiandrogens, and peptides. Steroidal antiandrogens include compounds like cyproterone acetate, spironolactone, estradiol, abiraterone acetate, and finasteride; nonsteroidal antiandrogens include compounds like bicalutamide, elagolix, diethylstilbestrol, aminoglutethimide, and ketoconazole; and peptides include GnRH analogues like leuprorelin and cetrorelix.Template:Citation needed

HistoryEdit

Template:See also

Antigonadotropins like estrogens and progestogens were both first introduced in the 1930s.<ref name="FritzSperoff2012">Template:Cite book</ref> The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941.<ref name="FiggChau2010"/>Template:Rp<ref name="KavoussiCostabile2012">Template:Cite book</ref> AR antagonists were first discovered in the early 1960s.<ref name="Weber2015" /> The steroidal antiandrogen cyproterone acetate was discovered in 1961 and introduced in 1973, and is often described as the first antiandrogen to have been marketed.<ref name="AcademicPress1997">Template:Cite book</ref><ref name="StunkardBaum1989" /> However, spironolactone was introduced in 1959,<ref name="Jugdutt2014">Template:Cite book</ref><ref name="Wermuth2011">Template:Cite book</ref> although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug.<ref name="Azziz2007">Template:Cite book</ref> In addition to spironolactone, chlormadinone acetate and megestrol acetate are steroidal antiandrogens that are weaker than cyproterone acetate but were also introduced earlier, in the 1960s.<ref name="RunnebaumRabe2012">Template:Cite book</ref><ref name="OrfanosMontagna2012">Template:Cite book</ref><ref name="Marks2010">Template:Cite book</ref> Other early steroidal antiandrogens that were developed around this time but were never marketed include benorterone (SKF-7690; 17α-methyl-B-nortestosterone), BOMT (Ro 7–2340), cyproterone (SH-80881), and trimethyltrienolone (R-2956).<ref name="HorskyPresl2012">Template:Cite book</ref><ref name="AcademicPress1976">Template:Cite book</ref>

The nonsteroidal antiandrogen flutamide was first reported in 1967.<ref name="SmithWilliams2005" /> It was introduced in 1983 and was the first nonsteroidal antiandrogen marketed.<ref name="Neal2012">Template:Cite book</ref><ref name="OttowWeinmann2008">Template:Cite book</ref> Another early nonsteroidal antiandrogen,<ref name="SinghalThomas1976">Template:Cite book</ref> DIMP (Ro 7–8117), which is structurally related to thalidomide<ref name="LiuSu2010">Template:Cite journal</ref> and is a relatively weak antiandrogen,<ref name="HeynsG.1976">Template:Cite journal</ref><ref>Template:Cite book</ref> was first described in 1973 and was never marketed.<ref name="BorisScott1973">Template:Cite journal</ref> Flutamide was followed by nilutamide in 1989, and bicalutamide in 1995.<ref name="BéguéBonnet-Delpon2008">Template:Cite book</ref> In addition to these three drugs, which have been regarded as first-generation nonsteroidal antiandrogens, the second-generation nonsteroidal antiandrogens enzalutamide and apalutamide were introduced in 2012 and 2018, respectively.<ref name="pmid23341368">Template:Cite journal</ref><ref name="pmid19359544">Template:Cite journal</ref><ref name="FDA2018">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison.<ref name="pmid19359544" />

The androgen synthesis inhibitors aminoglutethimide and ketoconazole were first marketed in 1960 and 1977, respectively,<ref name="Sneader2005">Template:Cite book</ref><ref name="Golan2008">Template:Cite book</ref> and the newer drug abiraterone acetate was introduced in 2011.<ref name="Demos2011">Template:Cite book</ref> GnRH modulators were first introduced in the 1980s.<ref name="BowsherCarter2008">Template:Cite book</ref> The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992. and 2002. respectively.<ref name="AllahbadiaAgrawal2007">Template:Cite book</ref><ref name="Bentham2010">Template:Cite book</ref> Elagolix, the first orally active GnRH modulator to be marketed, was introduced in 2018.<ref name="AdisInsight-Elagolix">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

TimelineEdit

The following is a timeline of events in the history of antiandrogens:<ref name="pmid29730201">Template:Cite journal</ref>

  • 1941: Hudgins and Hodges show that androgen deprivation via high-dose estrogen therapy or surgical castration treats prostate cancer
  • 1957: The steroidal antiandrogen spironolactone is first synthesized<ref name="pmid28634268">Template:Cite journal</ref>
  • 1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid<ref name="pmid28634268" />
  • 1961: The steroidal antiandrogen cyproterone acetate is first synthesized<ref name="pmid9476091">Template:Cite journal</ref>
  • 1962: Spironolactone is first reported to produce gynecomastia in men<ref name="pmid28634268" /><ref name="Smith1962">Template:Cite journal</ref>
  • 1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women<ref name="pmid148431">Template:Cite journal</ref><ref name="pmid4225258">Template:Cite journal</ref>
  • 1963: The antiandrogenic activity of cyproterone acetate is discovered<ref name="Neumann1996">Template:Cite book</ref><ref name="pmid14071315">Template:Cite journal</ref>
  • 1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males<ref name="pmid148431" />
  • 1967: The first-generation nonsteroidal antiandrogen flutamide is first synthesized
  • 1967: Cyproterone acetate was first studied clinically, to treat sexual deviance in men<ref name="pmid20459370">Template:Cite journal</ref>
  • 1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women<ref name="pmid4304873">Template:Cite journal</ref>
  • 1969: The antiandrogenic activity of spironolactone is discovered<ref name="pmid5344274">Template:Cite journal</ref>
  • 1972: The antiandrogenic activity of flutamide is first reported<ref name="pmid4264731">Template:Cite journal</ref><ref name="pmid4116667">Template:Cite journal</ref>
  • 1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance<ref name="pmid8005205">Template:Cite journal</ref>
  • 1977: The first-generation antiandrogen nilutamide is first described<ref name="pmid385986">Template:Cite journal</ref>
  • 1978: Spironolactone is first studied in the treatment of hirsutism in women<ref name="pmid6205409"/><ref name="pmid717935">Template:Cite journal</ref>
  • 1979: Combined androgen blockade is first studied<ref name="pmid16631454">Template:Cite journal</ref><ref name="pmid6819101">Template:Cite journal</ref>
  • 1980: Medical castration via a GnRH analogue is first achievedTemplate:Citation needed
  • 1982: The first-generation antiandrogen bicalutamide is first described<ref name="EngelKleemann2014">Template:Cite book</ref>
  • 1982: Combined androgen blockade for prostate cancer is developed
  • 1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer<ref name="Publishing2013">Template:Cite book</ref><ref name="Ireland2013">Template:Cite book</ref>
  • 1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer<ref name="BéguéBonnet-Delpon2008"/>
  • 1989: Combined androgen blockade via flutamide and a GnRH analogue is found to be superior to a GnRH analogue alone for prostate cancer
  • 1989: Flutamide is first introduced for medical use in the United States, to treat prostate cancer<ref name="Regitz-Zagrosek2012">Template:Cite book</ref>
  • 1989: Flutamide is first studied in the treatment of hirsutism in women<ref name="pmid2147859"/>
  • 1992: The androgen synthesis inhibitor abiraterone acetate is first described<ref name="ICR2014">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 1995: Bicalutamide is first introduced for medical use, to treat prostate cancer<ref name="BéguéBonnet-Delpon2008" />
  • 1996: Nilutamide is first introduced for medical use in the United States, to treat prostate cancer<ref name="AdisInsight-Nilutamide">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2006: The second-generation nonsteroidal antiandrogen enzalutamide is first described<ref name="US20070004753">Sawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://patents.google.com/patent/US20070004753 [1]</ref>
  • 2007: The second-generation nonsteroidal antiandrogen apalutamide is first described<ref name="WO2007126765">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Abiraterone-Acetate">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2012: Enzalutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Enzalutamide">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2018: Apalutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Apalutamide">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use<ref name="AdisInsight-Elagolix" />
  • 2019: Relugolix is the second orally active GnRH antagonist to be introduced for medical use<ref name="AdisInsight-Relugolix">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • 2019: Darolutamide is first introduced for medical use, to treat prostate cancer<ref name="AdisInsight-Darolutamide">{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

Society and cultureEdit

EtymologyEdit

The term antiandrogen is generally used to refer specifically to AR antagonists, as described by Dorfman (1970):<ref name="pmid66176">Template:Cite journal</ref><ref name="Dorfman1970">Template:Cite journal</ref>

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However, in spite of the above, the term may also be used to describe functional antiandrogens like androgen synthesis inhibitors and antigonadotropins, including even estrogens and progestogens.<ref name="Brueggemeier2006" /><ref name="pmid11502457" /><ref name="GräfBrotherton1974">Template:Cite book</ref> For example, the progestogen and hence antigonadotropin medroxyprogesterone acetate is sometimes described as a steroidal antiandrogen, even though it is not an antagonist of the AR.<ref name="Vogelzang2006">Template:Cite book</ref><ref name="GräfBrotherton1974" />

ResearchEdit

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Topical administrationEdit

There has been much interest and effort in the development of topical AR antagonists to treat androgen-dependent conditions like acne and pattern hair loss in males.<ref name="HelmsQuan2006">Template:Cite book</ref> Unfortunately, whereas systemic administration of antiandrogens is very effective in treating these conditions, topical administration has disappointingly been found generally to possess limited and only modest effectiveness, even when high-affinity steroidal AR antagonists like cyproterone acetate and spironolactone have been employed.<ref name="HelmsQuan2006" /> Moreover, in the specific case of acne treatment, topical AR antagonists have been found much less effective compared to established treatments like benzoyl peroxide and antibiotics.<ref name="HelmsQuan2006" />

A variety of AR antagonists have been developed for topical use but have not completed development and hence have never been marketed. These include the steroidal AR antagonists cyproterone, rosterolone, and topterone and the nonsteroidal AR antagonists cioteronel, inocoterone acetate, RU-22930, RU-58642, and RU-58841. However, one topical AR antagonist, topilutamide (fluridil), has been introduced in a few European countries for the treatment of pattern hair loss in men.<ref name="TrüebLee2014" /> In addition, a topical 5α-reductase inhibitor and weak estrogen, alfatradiol, has also been introduced in some European countries for the same indication, although its effectiveness is controversial.<ref name="TrüebLee2014" /> Spironolactone has been marketed in Italy in the form of a topical cream under the brand name Spiroderm for the treatment of acne and hirsutism, but this formulation was discontinued and hence is no longer available.<ref name="FARIDDiamanti-Kandarakis2009">Template:Cite book</ref>

Topical clascoterone, brand name Winlevi, was approved to treat acne in males and females in the United States in 2020.<ref name="AdisInsight">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Dhillon2020">Template:Cite journal</ref> However, although significantly more effective than placebo, topical clascoterone, like previous topical antiandrogens that have been developed, showed modest effectiveness in treating acne in clinical trials, and it appeared to be far less effective than systemic spironolactone.<ref name="BasendwhAlharbiBukhamsin2024">Template:Cite journal</ref>

Male contraceptionEdit

Antiandrogens, such as cyproterone acetate, have been studied for potential use as male hormonal contraceptives.<ref name="pmid793446">Template:Cite journal</ref><ref name="pmid797248">Template:Cite journal</ref><ref name="pmid206192">Template:Cite journal</ref><ref name="pmid6354690">Template:Cite journal</ref><ref name="pmid6205409"/><ref name="pmid2687939">Template:Cite book</ref><ref name="pmid3075164">Template:Cite journal</ref><ref name="pmid14667989">Template:Cite journal</ref> While effective in suppressing male fertility, their use as monotherapies is precluded by side effects, such as androgen deficiency (e.g., demasculinization, sexual dysfunction, hot flashes, osteoporosis) and feminization (e.g., gynecomastia).<ref name="pmid6205409" /><ref name="pmid2687939" /><ref name="pmid3075164" /><ref name="pmid20933120">Template:Cite journal</ref> The combination of a primary antigonadotropin such as cyproterone acetate to prevent fertility and an androgen like testosterone to prevent systemic androgen deficiency, resulting in a selective antiandrogenic action locally in the testes, has been extensively studied and has shown promising results, but has not been approved for clinical use at this time.<ref name="pmid3075164" /><ref name="pmid14667989" /><ref name="pmid16313066">Template:Cite journal</ref><ref name="pmid27016468">Template:Cite journal</ref><ref name="pmid20933120" /> Dimethandrolone undecanoate (developmental code name CDB-4521), an orally active dual AAS and progestogen, is under investigation as a potential male contraceptive and as the first male birth control pill.<ref name="pmid16497801">Template:Cite journal</ref><ref name="pmid27907978">Template:Cite journal</ref>

Breast cancerEdit

Antiandrogens such as bicalutamide, enzalutamide, and abiraterone acetate are under investigation for the potential treatment of breast cancer, including AR-expressing triple-negative breast cancer and other types of AR-expressing breast cancer.<ref name="pmid24740738">Template:Cite journal</ref><ref name="pmid27816190">Template:Cite journal</ref><ref name="pmid24888812">Template:Cite journal</ref><ref name="pmid28216075">Template:Cite journal</ref><ref name="pmid29940524">Template:Cite journal</ref>

MiscellaneousEdit

Antiandrogens might be effective and useful in the treatment of obsessive–compulsive disorder (OCD).<ref name="pmid31814547">Template:Cite journal</ref>

See alsoEdit

ReferencesEdit

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Further readingEdit

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