A | B | C | D | E | F | G | H | CH | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z | 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9
| Antiandrogen | |
|---|---|
| Drug class | |
 Bicalutamide, a nonsteroidal antiandrogen and the most widely used androgen receptor antagonist in the treatment of prostate cancer. | |
| Class identifiers | |
| Synonyms | Androgen antagonists; Androgen blockers; Testosterone blockers |
| Use | • Men and boys: Prostate cancer; Benign prostatic hyperplasia; Scalp hair loss; Paraphilias; Hypersexuality; Sex offenders; Precocious puberty; Priapism • Women and girls: Acne; Seborrhea; Hidradenitis suppurativa; Hirsutism; Scalp hair loss; Hyperandrogenism; Transgender hormone therapy |
| ATC code | L02BB |
| Biological target | Androgen receptor; Progesterone receptor; Estrogen receptor; GnRH receptor; 5α-Reductase; CYP17A1 (17α-hydroxylase/ |
| Chemical class | Steroidal; Nonsteroidal; Peptide |
| External links | |
| MeSH | D000726 |
| Legal status | |
| In Wikidata | |
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.[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 androgen-dependent conditions.[4] 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.[4][5] 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).[4] Antiandrogens are also used as a component of feminizing hormone therapy for transgender women and as puberty blockers in transgender girls.[4]
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.[6] These include AR antagonists, androgen synthesis inhibitors, and antigonadotropins.[6] AR antagonists work by directly blocking the effects of androgens, while androgen synthesis inhibitors and antigonadotropins work by lowering androgen levels.[6] 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.[6][7][8]
Medical uses
Antiandrogens are used in the treatment of an assortment of androgen-dependent conditions in both males and females.[4][9] 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.[9][10][11] In women and girls, antiandrogens are used to treat acne, seborrhea, hidradenitis suppurativa, hirsutism, and hyperandrogenism.[9][12][13] Antiandrogens are also used in transgender women as a component of feminizing hormone therapy and as puberty blockers in transgender girls.[14][15]
Men and boys
Prostate cancer
Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer.[16] They act as growth factors in the 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 castration (with a GnRH modulator or orchiectomy), nonsteroidal antiandrogens, and the androgen synthesis inhibitor abiraterone acetate.[16] Castration may be used alone or in combination with one of the other two treatments.[16][18] 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).[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
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
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.[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
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 precocious puberty in boys.[64][65][66][67] 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.[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 priapism (potentially painful penile erections that last more than four hours).[72][73][74][75][76]
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.[12] All of these conditions are dependent on androgens, and for this reason, antiandrogens are effective in treating them.[12] The most commonly used antiandrogens for these indications are cyproterone acetate and spironolactone.[77] Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with hepatotoxicity.[78] 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.[79][80] In addition to AR antagonists, oral contraceptives containing ethinylestradiol are effective in treating these conditions, and may be combined with AR antagonists.[81][82]
High androgen levels
Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high.[13] It is commonly seen in women with PCOS, and also occurs in women with intersex conditions like congenital adrenal hyperplasia.[13] 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.[13] 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.[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
Antiandrogens are used to prevent or reverse masculinization and to facilitate feminization in transgender women who are undergoing hormone therapy and who have not undergone 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 the onset of puberty in transgender girls until they are older and ready to begin hormone therapy.[15]
Available forms
There are several different types of antiandrogens, including the following:[6]
- Androgen receptor antagonists: Drugs that bind directly to and block the AR.[84][85] 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, and apalutamide.[84][85][7][8] Aside from cyproterone acetate and chlormadinone acetate, a few other progestins used in oral contraceptives and/or in menopausal HRT including dienogest, drospirenone, medrogestone, nomegestrol acetate, promegestone, and trimegestone also have varying degrees of AR antagonistic activity.[86][87][88]
- Androgen synthesis inhibitors: Drugs that directly inhibit the enzymatic biosynthesis of androgens like testosterone and/or DHT.[89][31] Examples include the CYP17A1 inhibitors ketoconazole, abiraterone acetate, and seviteronel,[89] the CYP11A1 (P450scc) inhibitor aminoglutethimide,[89] and the 5α-reductase inhibitors finasteride, dutasteride, epristeride, alfatradiol, and saw palmetto extract (Serenoa repens).[90] 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.[2][91] Examples include GnRH modulators like leuprorelin (a GnRH agonist) and cetrorelix (a GnRH antagonist),[92] progestogens like allylestrenol, chlormadinone acetate, cyproterone acetate, gestonorone caproate, hydroxyprogesterone caproate, medroxyprogesterone acetate, megestrol acetate, osaterone acetate (veterinary), and oxendolone,[93][94] and estrogens like estradiol, estradiol esters, ethinylestradiol, conjugated estrogens, and diethylstilbestrol.[2][93]
- Miscellaneous: Drugs that oppose the effects of androgens by means other than the above. Examples include estrogens, especially oral and synthetic (e.g., ethinylestradiol, diethylstilbestrol), which stimulate sex hormone-binding globulin (SHBG) production in the liver and thereby decrease free and hence bioactive levels of testosterone and DHT; anticorticotropins such as glucocorticoids, which suppress the adrenocorticotropic hormone (ACTH)-induced production of adrenal androgens; and immunogens and vaccines against androstenedione like ovandrotone albumin and androstenedione albumin, which decrease levels of androgens via the generation of antibodies against the androgen and androgen precursor androstenedione (used only in veterinary medicine).
Certain antiandrogens combine multiple of the above mechanisms.[6][95] 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][95][96][97]
| 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 off-target activity in the antiandrogen in question.[21][98] 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.[21][99][100] 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).[21] 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.[98]
In males, the major side effects of antiandrogens are demasculinization and feminization.[101] 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.[101] The rates of gynecomastia in men with selective AR antagonist monotherapy have been found to range from 30 to 85%.[102] 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.[failed verification][101] Conversely, the side effects of selective AR antagonists in women are minimal.[80][103] However, antigonadotropic antiandrogens like cyproterone acetate can produce hypoestrogenism, amenorrhea, and osteoporosis in premenopausal women, among other side effects.[81][104][105] In addition, androgen receptor antagonists can produce unfavorable effects on cholesterol levels, which long-term may increase the risk of cardiovascular disease.[106][107][108][109][110][111][112]
A number of antiandrogens have been associated with hepatotoxicity.[113] These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole.[113] In contrast, spironolactone, enzalutamide,[114] 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 pregnant, antiandrogens can interfere with the androgen-mediated sexual differentiation of the genitalia and brain of male fetuses.[115] 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.[115][116] As such, antiandrogens are teratogens, and women who are pregnant should not be treated with an antiandrogen.[82] Moreover, women who can or may become pregnant are strongly recommended to take an antiandrogen only in combination with proper 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]