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. 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.

Antiandrogens are used to treat an assortment of androgen-dependent conditions. 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. 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). These include AR antagonists, androgen synthesis inhibitors, and antigonadotropins.

Medical uses

Antiandrogens are used in the treatment of an assortment of androgen-dependent conditions in both males and females. 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. In women and girls, antiandrogens are used to treat acne, seborrhea, hidradenitis suppurativa, hirsutism, and hyperandrogenism. Antiandrogens are also used in transgender women as a component of feminizing hormone therapy and as puberty blockers in transgender girls. They act as growth factors in the prostate gland, stimulating cell division and tissue growth. When this occurs, other treatment approaches, such as chemotherapy, may be considered. 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). Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer. 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.

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. 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, but it has largely been replaced by nonsteroidal antiandrogens, which are newer and have greater effectiveness, tolerability, and safety. Bicalutamide, as well as enzalutamide, have largely replaced the earlier nonsteroidal antiandrogens flutamide and nilutamide, which are now little used. 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. 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. 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.

Enlarged prostate

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. They are effective because androgens act as growth factors in the prostate gland.

Scalp hair loss

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. This condition is generally caused by androgens, so antiandrogens can slow or halt its progression. 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.

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. However, they have been studied for acne in males and found to be effective. Clascoterone, a topical antiandrogen, is effective for acne in males, albeit modestly,

Paraphilias

Androgens increase sex drive, and for this reason, antiandrogens are able to reduce sex drive in males. 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). Antiandrogens used for these indications include cyproterone acetate, medroxyprogesterone acetate, and GnRH modulators.

Early puberty

Antiandrogens are used to treat precocious puberty in males. 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. Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed estrogens, while the others can be used alone.

Women and girls

Skin and hair conditions

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. Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with hepatotoxicity. 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. In addition to AR antagonists, oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.

High androgen levels

Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high. Besides estrogens, the main antiandrogens that have been used for this purpose are cyproterone acetate, spironolactone, and GnRH modulators.

Available forms

There are several different types of antiandrogens, including the following: These drugs include the steroidal antiandrogens cyproterone acetate, megestrol acetate, chlormadinone acetate, spironolactone, oxendolone, and osaterone acetate (veterinary) and the nonsteroidal antiandrogens flutamide, bicalutamide, nilutamide, topilutamide, enzalutamide, apalutamide, and darolutamide.

  • Androgen synthesis inhibitors: Drugs that directly inhibit the enzymatic biosynthesis of androgens like testosterone and/or DHT. Examples include the CYP17A1 inhibitors ketoconazole, abiraterone acetate, and seviteronel, A number of other antiandrogens, including cyproterone acetate, spironolactone, medrogestone, flutamide, nilutamide, and bifluranol, are also known to weakly inhibit androgen synthesis.
  • Antigonadotropins: Drugs that suppress the gonadotropin-releasing hormone (GnRH)-induced release of gonadotropins and consequent activation of gonadal androgen production. Examples include GnRH modulators like leuprorelin (a GnRH agonist) and cetrorelix (a GnRH antagonist), and estrogens like estradiol, estradiol esters, ethinylestradiol, conjugated estrogens, and diethylstilbestrol. 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.

{| class="wikitable sortable mw-collapsible <!--mw-collapsed-->" style="margin-left: auto; margin-right: auto; border: none;"

|+ class="nowrap" | Antiandrogens marketed for clinical or veterinary use

! Generic name !! Class !! Type !! Brand name(s) !! Route(s) !! Launch !! Status !! <sup>a</sup>

|-

| || Steroidal || Androgen synthesis inhibitor || Zytiga || Oral || 2011 || Available || 523,000

|-

| || Steroidal || Progestin || Gestanin, Perselin || Oral || 1961 || Available<sup>b</sup> || 61,800

|-

| || Nonsteroidal || Androgen synthesis inhibitor || Cytadren, Orimeten || Oral || 1960 || Available<sup>b</sup> || 222,000

|-

| || Nonsteroidal || AR antagonist || Erleada || Oral || 2018 || Available || 50,400

|-

| || Nonsteroidal || AR antagonist || Casodex || Oral || 1995 || Available || 754,000

|-

| || Steroidal || Progestin; AR antagonist || Belara, Prostal || Oral || 1965 || Available || 220,000

|-

| || Steroidal || Progestin; AR antagonist || Androcur, Diane || Oral, || 1973 || Available || 461,000

|-

| || Nonsteroidal || AR antagonist || Nubeqa || Oral || 2019 || Available || ?

|-

| || Steroidal || Progestin; AR antagonist || Tardak || Veterinary || 1972 || Veterinary || 42,600

|-

| || Nonsteroidal || AR antagonist || Xtandi || Oral || 2012 || Available || 328,000

|-

| || Nonsteroidal || AR antagonist || Eulexin || Oral || 1983 || Available || 712,000

|-

| || Steroidal || Progestin || Depostat, Primostat || || 1973 || Available<sup>b</sup> || 119,000

|-

| || Steroidal || Progestin || Delalutin, Proluton || || 1954 || Available || 108,000

|-

| || Nonsteroidal || Androgen synthesis inhibitor || Nizoral, others || Oral, topical || 1981 || Available || 3,650,000

|-

| || Steroidal || Progestin || Provera, Depo-Provera || Oral, , || 1958 || Available || 1,250,000

|-

| || Steroidal || Progestin; AR antagonist || Megace || Oral || 1963 || Available || 253,000

|-

| || Nonsteroidal || AR antagonist || Anandron, Nilandron || Oral || 1987 || Available || 132,000

|-

| || Steroidal || Progestin; AR antagonist || Ypozane || Veterinary || 2007 || Veterinary || 87,600

|-

| || Steroidal || Progestin; AR antagonist || Prostetin, Roxenone || || 1981 || Available<sup>b</sup> || 36,100

|-

| || Steroidal || AR antagonist || Aldactone || Oral, topical || 1959 || Available || 3,010,000

|-

| || Nonsteroidal || AR antagonist || Eucapil || Topical || 2003 || Available<sup>b</sup> || 36,300

|- class="sortbottom"

| colspan="8" style="width: 1px; background-color:var(--background-color-notice-subtle,#eaecf0); color:inherit; text-align: center;" | Footnotes: <sup>a</sup> = Hits = Google Search hits (as of February 2018). <sup>b</sup> = Availability limited / mostly discontinued. Class: Steroidal = . Nonsteroidal = . Note: For other antiandrogens not included in the table like 5α-reductase inhibitors, GnRH modulators, and estrogens, see elsewhere. 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 off-target activity in the antiandrogen in question. 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. 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). 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. 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. However, antigonadotropic antiandrogens like cyproterone acetate can produce hypoestrogenism, amenorrhea, and osteoporosis in premenopausal women, among other side effects. In addition, androgen receptor antagonists can produce unfavorable effects on cholesterol levels, which long-term may increase the risk of cardiovascular disease.

A number of antiandrogens have been associated with hepatotoxicity. These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole. 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.

In women who are pregnant, antiandrogens can interfere with the androgen-mediated sexual differentiation of the genitalia and brain of male fetuses. 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. As such, antiandrogens are teratogens, and women who are pregnant should not be treated with an antiandrogen.</small>

|}

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. 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. This may have clinical implications in the specific context of prostate cancer treatment. In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals, it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. 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. 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.

AR antagonists may not bind to or block membrane androgen receptors (mARs), which are distinct from the classical nuclear AR. However, the mARs do not appear to be involved in masculinization. This is evidenced by the perfectly female phenotype of women with complete androgen insensitivity syndrome. These women have a 46,XY karyotype (i.e., are genetically "male") and high levels of androgens but possess a defective AR and for this reason never masculinize.

N-Terminal domain antagonists

N-Terminal domain AR antagonists are a new type of AR antagonist that, unlike all currently marketed AR antagonists, bind to the N-terminal domain (NTD) of the AR rather than the ligand-binding domain (LBD). Whereas conventional AR antagonists bind to the LBD of the AR and competitively displace androgens, thereby preventing them from activating the receptor, AR NTD antagonists bind covalently to the NTD of the AR and prevent protein–protein interactions subsequent to activation that are required for transcriptional activity. Examples of AR NTD antagonists include bisphenol A diglycidyl ether (BADGE) and its derivatives EPI-001, ralaniten (EPI-002), and ralaniten acetate (EPI-506). AR NTD antagonists are under investigation for the potential treatment of prostate cancer, and it is thought that they may have greater efficacy as antiandrogens relative to conventional AR antagonists. 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). An example of a SARD is dimethylcurcumin (ASC-J9), which is under development as a topical medication for the potential treatment of acne. SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR. and abiraterone acetate. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of cholesterol into pregnenolone and by extension the production of all steroid hormones, including the androgens.

5α-Reductase inhibitors

5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of 5α-reductase, an enzyme that is responsible for the formation of DHT from testosterone. DHT is between 2.5- and 10-fold more potent than testosterone as an androgen and is produced in a tissue-selective manner based on expression of 5α-reductase. Tissues in which DHT forms at a high rate include the prostate gland, skin, and hair follicles.

Antigonadotropins

thumb|right|300px|class=skin-invert-image|Estradiol and testosterone levels following a single intramuscular injection of 320&nbsp;mg [[polyestradiol phosphate, a polymeric estradiol ester and prodrug, in men with prostate cancer.]]

thumb|right|300px|class=skin-invert-image|Testosterone and luteinizing hormone levels with 100&nbsp;mg/day oral [[cyproterone acetate in men.]]

Antigonadotropins are drugs that suppress the GnRH-mediated secretion of gonadotropins from the pituitary gland. In addition, estrogens and progestogens are antigonadotropins via exertion of negative feedback on the hypothalamic–pituitary–gonadal axis (HPG axis). High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators, while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men.

Examples of GnRH agonists include leuprorelin (leuprolide) and goserelin, while an example of a GnRH antagonist is cetrorelix. Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, and oxendolone.

Miscellaneous

Sex hormone-binding globulin modulators

In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the hepatic production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels. Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. 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. In men, a study found that treatment with a relatively low dosage of 20&nbsp;μg/day ethinylestradiol for 5&nbsp;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). A study found that treatment with a high-dose ethinylestradiol (100&nbsp;μg/day) reduced levels of major circulating adrenal androgens by 27 to 48% in transgender women. The decrease in adrenal androgen levels with high-dose estrogen therapy may be beneficial in the treatment of prostate cancer. 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. 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.

Immunogens and vaccines

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). 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. The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941. AR antagonists were first discovered in the early 1960s. although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug. 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. 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).

The nonsteroidal antiandrogen flutamide was first reported in 1967. Another early nonsteroidal antiandrogen, DIMP (Ro 7–8117), which is structurally related to thalidomide and is a relatively weak antiandrogen, was first described in 1973 and was never marketed. Flutamide was followed by nilutamide in 1989, and bicalutamide in 1995. 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. They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison. and the newer drug abiraterone acetate was introduced in 2011. GnRH modulators were first introduced in the 1980s. The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992. and 2002. respectively. Elagolix, the first orally active GnRH modulator to be marketed, was introduced in 2018.

Timeline

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

  • 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
  • 1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid
  • 1962: Spironolactone is first reported to produce gynecomastia in men
  • 1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women
  • 1963: The antiandrogenic activity of cyproterone acetate is discovered
  • 1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males
  • 1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women
  • 1969: The antiandrogenic activity of spironolactone is discovered
  • 1972: The antiandrogenic activity of flutamide is first reported
  • 1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance
  • 1977: The first-generation antiandrogen nilutamide is first described
  • 1978: Spironolactone is first studied in the treatment of hirsutism in women
  • 1979: Combined androgen blockade is first studied
  • 1980: Medical castration via a GnRH analogue is first achieved
  • 1982: The first-generation antiandrogen bicalutamide is first described
  • 1982: Combined androgen blockade for prostate cancer is developed
  • 1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer
  • 1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer
  • 1989: Flutamide is first studied in the treatment of hirsutism in women
  • 1995: Bicalutamide is first introduced for medical use, to treat prostate cancer
  • 2006: The second-generation nonsteroidal antiandrogen enzalutamide is first described
  • 2007: The second-generation nonsteroidal antiandrogen apalutamide is first described
  • 2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer
  • 2012: Enzalutamide is first introduced for medical use, to treat prostate cancer
  • 2018: Apalutamide is first introduced for medical use, to treat prostate cancer
  • 2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use
  • 2019: Darolutamide is first introduced for medical use, to treat prostate cancer

Society and culture

Etymology

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