Antiandrogen

Source: Wikipedia, the free encyclopedia.
Antiandrogen
Chemical class
Steroidal; Nonsteroidal; Peptide
External links
MeSHD000726
Legal status
In Wikidata

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of

biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production.[1][2] 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.[3]

Antiandrogens are used to treat an assortment of

transgender women and as puberty blockers in transgender girls.[4]

premenopausal
women.

There are a few different major types of antiandrogens.

5α-reductase inhibitors; and antigonadotropins can be further divided into gonadotropin-releasing hormone modulators (GnRH modulators), progestogens, and estrogens.[6][7][8]

Medical uses

Antiandrogens are used in the treatment of an assortment of

transgender women as a component of feminizing hormone therapy and as puberty blockers in transgender girls.[14][15]

Men and boys

Prostate cancer

See also: Management of prostate cancer § Hormonal therapy, and Androgen deprivation therapy

Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer.

prostate gland, stimulating cell division and tissue growth.[16] 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.[16] 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.[17] When this occurs, other treatment approaches, such as chemotherapy, may be considered.[17]

The most common methods of androgen deprivation therapy currently employed to treat prostate cancer are

combined androgen blockade (also known as complete or maximal androgen blockade).[16][19] Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer.[16][20] 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.[16][21][22]

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.[23] 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,[24] but it has largely been replaced by nonsteroidal antiandrogens, which are newer and have greater effectiveness, tolerability, and safety.[25][26] Bicalutamide, as well as enzalutamide, have largely replaced the earlier nonsteroidal antiandrogens flutamide and nilutamide, which are now little used.[19][27][28][29][30] 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.[31]

In addition to active treatment of prostate cancer, antiandrogens are effective as

prophylaxis (preventatives) in reducing the risk of ever developing prostate cancer.[32] 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.[32][33] 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.[34][35][36]

Enlarged prostate

See also: Benign prostatic hyperplasia § 5α-Reductase inhibitors

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.[37] They are effective because androgens act as growth factors in the prostate gland.[37] 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.[38][39]

Scalp hair loss

See also: Management of hair loss § Antiandrogens

5α-Reductase inhibitors like finasteride, dutasteride, and

topical nonsteroidal AR antagonist topilutamide (fluridil) are approved for the treatment of pattern hair loss, also known as scalp hair loss or baldness.[40] This condition is generally caused by androgens, so antiandrogens can slow or halt its progression.[41] 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.[42][43][44][45][46][47][48] However, they have been assessed and reported to be effective for this indication.[42][43][49]

Acne

Systemic antiandrogens are generally not used to treat acne in males due to their high risk of feminization (e.g., gynecomastia) and sexual dysfunction.[50][51] However, they have been studied for acne in males and found to be effective.[52][44][45][53] Clascoterone, a topical antiandrogen, is effective for acne in males and has been approved by the FDA in August 2020.[54][55][56][57]

Paraphilia

See also: Paraphilia § Antiandrogens, and Chemical castration § Treatment for sex offenders

Androgens increase

sex drive,[58] and for this reason, antiandrogens are able to reduce sex drive in men.[59][60] 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).[59][60] They have been used to decrease sex drive in sex offenders so as to reduce the likelihood of recidivism (repeat offenses).[61] Antiandrogens used for these indications include cyproterone acetate, medroxyprogesterone acetate, and GnRH modulators.[62][63]

Early puberty

Antiandrogens are used to treat

sex drive and function until a more appropriate age.[64][65] Antiandrogens that have been used for this purpose include cyproterone acetate, medroxyprogesterone acetate, GnRH modulators, spironolactone, bicalutamide, and ketoconazole.[64][67][68][69][70][71] Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed estrogens, while the others can be used alone.[64][70][71]

Long-lasting erections

Antiandrogens are effective in the treatment of recurrent

penile erections that last more than four hours).[72][73][74][75][76]

Women and girls

Skin and hair conditions

See also:
Acne vulgaris § Hormonal agents, Seborrhoeic dermatitis § Antiandrogens, and Hirsutism § Medications

Antiandrogens are used in the treatment of androgen-dependent

oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.[81][82]

High androgen levels

See also: Hyperandrogenism § Treatment

Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high.

menstrual disturbances, like amenorrhea, are commonly seen.[13] Although antiandrogens do not treat the underlying cause of hyperandrogenism (e.g., PCOS), they are able to prevent and reverse its manifestation and effects.[13] 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.[13] Other antiandrogens, like bicalutamide, may be used alternatively.[13]

Transgender hormone therapy

See also: Feminizing hormone therapy § Antiandrogens

Antiandrogens are used to prevent or reverse

sex reassignment surgery or orchiectomy.[14] Besides estrogens, the main antiandrogens that have been used for this purpose are cyproterone acetate, spironolactone, and GnRH modulators.[14] Nonsteroidal antiandrogens like bicalutamide are also used for this indication.[83][14] In addition to use in transgender women, antiandrogens, mainly GnRH modulators, are used as puberty blockers to prevent puberty in transgender girls until they are older and ready to begin hormone therapy.[15] There is insufficient evidence to determine the efficacy or safety of hormonal treatment approaches for transgender women in transition, although existing reviews point to an improvement in quality of life, depression and anxiety. No studies showed that hormone therapy harms mental health or quality of life among transgender people. [84][85]

Available forms

See also: Steroidal antiandrogen and Nonsteroidal antiandrogen

There are several different types of antiandrogens, including the following:[6]

Certain antiandrogens combine multiple of the above mechanisms.[6][97] 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.[6][97][98][99]

Antiandrogens marketed for clinical or veterinary use
Generic name Class Type Brand name(s) Route(s) Launch Status Hitsa
Abiraterone acetate Steroidal Androgen synthesis inhibitor Zytiga Oral 2011 Available 523,000
Allylestrenol Steroidal Progestin Gestanin, Perselin Oral 1961 Availableb 61,800
Aminoglutethimide Nonsteroidal Androgen synthesis inhibitor Cytadren, Orimeten Oral 1960 Availableb 222,000
Apalutamide Nonsteroidal AR antagonist Erleada Oral 2018 Available 50,400
Bicalutamide Nonsteroidal AR antagonist Casodex Oral 1995 Available 754,000
Chlormadinone acetate Steroidal Progestin; AR antagonist Belara, Prostal Oral 1965 Available 220,000
Cyproterone acetate Steroidal Progestin; AR antagonist Androcur, Diane Oral, IM 1973 Available 461,000
Delmadinone acetate Steroidal Progestin; AR antagonist Tardak Veterinary 1972 Veterinary 42,600
Enzalutamide Nonsteroidal AR antagonist Xtandi Oral 2012 Available 328,000
Flutamide Nonsteroidal AR antagonist Eulexin Oral 1983 Available 712,000
Gestonorone caproate Steroidal Progestin Depostat, Primostat IM 1973 Availableb 119,000
Hydroxyprogesterone caproate Steroidal Progestin Delalutin, Proluton IM 1954 Available 108,000
Ketoconazole Nonsteroidal Androgen synthesis inhibitor Nizoral, others Oral, topical 1981 Available 3,650,000
Medroxyprogesterone acetate Steroidal Progestin Provera, Depo-Provera Oral, IM, SC 1958 Available 1,250,000
Megestrol acetate Steroidal Progestin; AR antagonist Megace Oral 1963 Available 253,000
Nilutamide Nonsteroidal AR antagonist Anandron, Nilandron Oral 1987 Available 132,000
Osaterone acetate Steroidal Progestin; AR antagonist Ypozane Veterinary 2007 Veterinary 87,600
Oxendolone Steroidal Progestin; AR antagonist Prostetin, Roxenone IM 1981 Availableb 36,100
Spironolactone Steroidal AR antagonist Aldactone Oral, topical 1959 Available 3,010,000
Topilutamide 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 = Steroidal antiandrogen. Nonsteroidal = Nonsteroidal antiandrogen. Sources: See individual articles.

Side effects

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

antimineralocorticoid, and/or glucocorticoid activity in addition to their antiandrogen activity, and these off-target activities can result in additional side effects.[100]

In males, the major

fatigue, anemia, and decreased semen/ejaculate volume in males.[failed verification][103] Conversely, the side effects of selective AR antagonists in women are minimal.[80][105] However, antigonadotropic antiandrogens like cyproterone acetate can produce hypoestrogenism, amenorrhea, and osteoporosis in premenopausal women, among other side effects.[81][106][107] In addition, androgen receptor antagonists can produce unfavorable effects on cholesterol levels, which long-term may increase the risk of cardiovascular disease.[108][109][110][111][112][113][114]

A number of antiandrogens have been associated with hepatotoxicity.[115] These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole.[115] In contrast, spironolactone, enzalutamide,[116] 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.[citation needed]

In women who are

contraception.[82]

Overdose

Antiandrogens are relatively safe in acute

overdose.[citation needed
]

Interactions

Inhibitors and inducers of cytochrome P450 enzymes may interact with various antiandrogens.[citation needed]

Mechanism of action

Androgen receptor antagonists

Antiandrogens at steroid hormone receptors
Antiandrogen Relative binding affinities
ARTooltip Androgen receptor PRTooltip Progesterone receptor ERTooltip Estrogen receptor GRTooltip Glucocorticoid receptor MRTooltip Mineralocorticoid receptor
Cyproterone acetate 8–10 60 <0.1 5 1
Chlormadinone acetate 5 175 <0.1 38 1
Megestrol acetate 5 152 <0.1 50 3
Spironolactone 7 0.4a <0.1 2a 182
Trimethyltrienolone 3.6 <1 <1 <1 <1
Inocoterone 0.8 <0.1 <0.1 <0.1 <0.1
Inocoterone acetate <0.1 <0.1 <0.1 <0.1 <0.1
Flutamide <0.1 <0.1 <0.1 <0.1 <0.1
Hydroxyflutamide 0.5–0.8 <0.1 <0.1 <0.1 <0.1
Nilutamide 0.5–0.8 <0.1 <0.1 <0.1 <0.1
Bicalutamide 1.8 <0.1 <0.1 <0.1 <0.1
Notes: (1): Reference ligands (100%) were testosterone for the ARTooltip androgen receptor, progesterone for the PRTooltip progesterone receptor, estradiol for the ERTooltip estrogen receptor, dexamethasone for the GRTooltip glucocorticoid receptor, and aldosterone for the MRTooltip mineralocorticoid receptor. (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: [119][120][121][122][123][124][125][126][127][128]
Relative potencies of selected antiandrogens
Antiandrogen Relative potency
Bicalutamide 4.3
Hydroxyflutamide 3.5
Flutamide 3.3
Cyproterone acetate 1.0
Zanoterone 0.4
Description: Relative potencies of
ventral prostate weight increase in castrated immature
male rats. Higher values mean greater potency. Sources: See template.

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.[86][87] AR antagonists are classified into two types, based on chemical structure: steroidal and nonsteroidal.[7][8][86][87][94] 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.[94] In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity.[94] For this reason, they are sometimes described as "pure" antiandrogens.[94]

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.[86][31][129][130] This may have clinical implications in the specific context of prostate cancer treatment.[86][129] 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,[86][129] and spironolactone has been found to accelerate progression of prostate cancer in case reports.[131][132] In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals,[133] it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals.[86] In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor.[134][31][135][129] 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.[134][31][135][129]

Nonsteroidal antiandrogens have relatively low

affinity for the AR compared to steroidal AR ligands.[31][135][136] 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.[136] 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.[136][137] 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.[136][137] 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.[138]

AR antagonists may not bind to or block membrane androgen receptors (mARs), which are distinct from the classical nuclear AR.[139][140][141] 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.[142][143] 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.[142][143] They are described as highly feminine, both physically as well as mentally and behaviorally.[144][145][146]

N-Terminal domain antagonists

gain-of-function mutations in the AR LBD that convert AR antagonists into AR agonists and commonly occur in prostate cancer.[147]

Androgen receptor degraders

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).[150] 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.[151] An example of a SARD is dimethylcurcumin (ASC-J9), which is under development as a topical medication for the potential treatment of acne.[152] SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR.[151]

Androgen synthesis inhibitors

Main article: Androgen synthesis inhibitor

Androgen synthesis inhibitors are

prostate gland, skin, and hair follicles. These drugs include aminoglutethimide, ketoconazole,[153] and abiraterone acetate.[91][31][154] 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.[91] 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.[91][31] 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.[154] 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.[155]

5α-Reductase inhibitors

5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of

prostate gland, skin, and hair follicles.[41][158] 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.[41][158][159]

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.[160]
Testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men.[161]

GnRH antagonists, are powerful antigonadotropins that are able to suppress androgen levels by 95% in men.[162] In addition, estrogens and progestogens are antigonadotropins via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis).[2][95][163] High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators,[164] while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men.[165][166]

Examples of GnRH agonists include

estradiol esters like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol (no longer widely used), and bifluranol.[167][168] Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate,[169] hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.[2][170][171]

Miscellaneous

Sex hormone-binding globulin modulators

In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the

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.[175][176] 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).[172]

Corticosteroid-binding globulin modulators

liver protein synthesis than parenteral estradiol.[183] The decrease in adrenal androgen levels with high-dose estrogen therapy may be beneficial in the treatment of prostate cancer.[179][182]

Anticorticotropins

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.[184][185] 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.[184][185]

Insulin sensitizers

In women with

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.[186][187][188]

Immunogens and vaccines

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.[189][190]

Chemistry

See also: List of antiandrogens and List of steroidal antiandrogens

Antiandrogens can be divided into several different types based on

GnRH analogues like leuprorelin and cetrorelix.[citation needed
]

History

See also: Discovery and development of antiandrogens

Antigonadotropins like estrogens and progestogens were both first introduced in the 1930s.[191] The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941.[31]: 56 [192] AR antagonists were first discovered in the early 1960s.[98] 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.[193][62] However, spironolactone was introduced in 1959,[194][195] although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug.[196] 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.[197][198][199] 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).[200][201]

The nonsteroidal antiandrogen flutamide was first reported in 1967.[24] It was introduced in 1983 and was the first nonsteroidal antiandrogen marketed.[202][203] Another early nonsteroidal antiandrogen,[204] DIMP (Ro 7–8117), which is structurally related to thalidomide[205] and is a relatively weak antiandrogen,[206][207] was first described in 1973 and was never marketed.[208] Flutamide was followed by nilutamide in 1989 and bicalutamide in 1995.[209] 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.[210][211][212] They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison.[211]

The androgen synthesis inhibitors aminoglutethimide and ketoconazole were first marketed in 1960 and 1977, respectively,[213][214] and the newer drug abiraterone acetate was introduced in 2011.[215] GnRH modulators were first introduced in the 1980s.[216] The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992 and 2002, respectively.[217][218] Elagolix, the first orally active GnRH modulator to be marketed, was introduced in 2018.[219]

Timeline

The following is a timeline of events in the history of antiandrogens:[220]

  • 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[221]
  • 1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid[221]
  • 1961: The steroidal antiandrogen cyproterone acetate is first synthesized[222]
  • 1962: Spironolactone is first reported to produce gynecomastia in men[221][223]
  • 1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women[224][225]
  • 1963: The antiandrogenic activity of cyproterone acetate is discovered[48][226]
  • 1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males[224]
  • 1967: The first-generation nonsteroidal antiandrogen flutamide is first synthesized
  • 1967: Cyproterone acetate was first studied clinically, to treat sexual deviance in men[227]
  • 1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women[228]
  • 1969: The antiandrogenic activity of spironolactone is discovered[229]
  • 1972: The antiandrogenic activity of flutamide is first reported[230][231]
  • 1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance[232]
  • 1977: The first-generation antiandrogen nilutamide is first described[233]
  • 1978: Spironolactone is first studied in the treatment of hirsutism in women[65][234]
  • 1979: Combined androgen blockade is first studied[235][236]
  • 1980: Medical castration via a GnRH analogue is first achieved[citation needed]
  • 1982: The first-generation antiandrogen bicalutamide is first described[237]
  • 1982: Combined androgen blockade for prostate cancer is developed
  • 1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer[238][239]
  • 1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer[209]
  • 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[240]
  • 1989: Flutamide is first studied in the treatment of hirsutism in women[9]
  • 1992: The androgen synthesis inhibitor abiraterone acetate is first described[241]
  • 1995: Bicalutamide is first introduced for medical use, to treat prostate cancer[209]
  • 1996: Nilutamide is first introduced for medical use in the United States, to treat prostate cancer[242]
  • 2006: The second-generation nonsteroidal antiandrogen enzalutamide is first described[243]
  • 2007: The second-generation nonsteroidal antiandrogen apalutamide is first described[244]
  • 2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer[245]
  • 2012: Enzalutamide is first introduced for medical use, to treat prostate cancer[246]
  • 2018: Apalutamide is first introduced for medical use, to treat prostate cancer[247]
  • 2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use[219]
  • 2019: Relugolix is the second orally active GnRH antagonist to be introduced for medical use[248]

Society and culture

Etymology

The term antiandrogen is generally used to refer specifically to AR antagonists, as described by Dorfman (1970):[249][250]

Antiandrogens are substances which prevent androgens from expressing their activity at target sites. The inhibitory effect of these substances, therefore, should be differentiated from compounds which decrease the synthesis and/or release of hypothalamic (releasing) factors, from anterior pituitary hormones (gonadotropins, particularly luteinizing hormone) and from material which acts directly on the gonads to inhibit biosynthesis and/or secretion of androgens.[249][250]

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.[2][6][251] 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.[252][251]

Research

See also: List of investigational sex-hormonal agents § Androgenics

Topical administration

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.

affinity steroidal AR antagonists like cyproterone acetate and spironolactone have been employed.[253] 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.[253]

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 clascoterone, 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.[40] 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.[40] 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.[254]

Male contraception

Antiandrogens, such as cyproterone acetate, have been studied for potential use as

birth control pill.[265][266]

Breast cancer

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.[267][268][269][270][271]

Miscellaneous

Antiandrogens may be effective in the treatment of obsessive–compulsive disorder.[272]

See also

References

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Further reading

Retrieved from "https://en.wikipedia.org/w/index.php?title=Antiandrogen&oldid=1219046098"