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Trade names | Androcur, Androcur Depot, Cyprostat, Siterone, others |
Other names | SH-80714; SH-714; NSC-81430; 1α,2α-Methylene-6-chloro-17α-hydroxy-δ6-progesterone acetate; 1α,2α-Methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione acetate |
AHFS/Drugs.com | Micromedex Detailed Consumer Information |
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Routes of administration | By mouth, intramuscular injection |
Drug class | Steroidal antiandrogen; Progestogen; Progestin; Progestogen ester; Antigonadotropin |
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Pharmacokinetic data | |
Bioavailability | Oral: 68–100% [1] [2] |
Protein binding | Albumin: 93% Free: 7% [3] [4] [5] [6] |
Metabolism | Hepatic (CYP3A4) [7] [8] |
Metabolites | • 15β-OH-CPA (major) [1] [9] • Cyproterone (minor) [10] • Acetic acid (minor) [10] |
Elimination half-life | Oral: 1.6–4.3 days [10] [11] [12] IM: 3–4.3 days [2] [10] [12] |
Excretion | Feces: 70% [10] Urine: 30% [10] |
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ECHA InfoCard | 100.006.409 |
Chemical and physical data | |
Formula | C24H29ClO4 |
Molar mass | 416.94 g·mol−1 |
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Melting point | 200 to 201 °C (392 to 394 °F) |
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Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. [1] [11] [13] [14] [15] It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.
Common side effects of high-dose CPA in men include gynecomastia (breast development) and feminization. In both men and women, possible side effects of CPA include low sex hormone levels, reversible infertility, sexual dysfunction, fatigue, depression, weight gain, and elevated liver enzymes. At very high doses in older individuals, significant cardiovascular complications can occur. Rare but serious adverse reactions of CPA include blood clots, liver damage and brain tumors. CPA can also cause adrenal insufficiency as a withdrawal effect if it is discontinued abruptly from a high dosage. CPA blocks the effects of androgens such as testosterone in the body, which it does by preventing them from interacting with their biological target, the androgen receptor (AR), and by reducing their production by the gonads, hence their concentrations in the body. [1] [13] [16] In addition, it has progesterone-like effects by activating the progesterone receptor (PR). [1] [13] It can also produce weak cortisol-like effects at very high doses. [1]
CPA was discovered in 1961. [17] It was originally developed as a progestin. [17] In 1965, the antiandrogenic effects of CPA were discovered. [18] CPA was first marketed, as an antiandrogen, in 1973, and was the first antiandrogen to be introduced for medical use. [19] A few years later, in 1978, CPA was introduced as a progestin in a birth control pill. [20] It has been described as a "first-generation" progestin [21] and as the prototypical antiandrogen. [22] CPA is available widely throughout the world. [23] [24] An exception is the United States, where it is not approved for use. [25] [26]
CPA is used as a progestin and antiandrogen in hormonal birth control and in the treatment of androgen-dependent conditions. [13] Specifically, CPA is used in combined birth control pills, in the treatment of androgen-dependent skin and hair conditions such as acne, seborrhea, excessive hair growth, and scalp hair loss, high androgen levels, in transgender hormone therapy, to treat prostate cancer, to reduce sex drive in sex offenders or men with paraphilias or hypersexuality, to treat early puberty, and for other uses. [27] It is used both at low doses and at higher doses.[ citation needed ]
In the United States, where CPA is not available, other medications with antiandrogenic effects are used to treat androgen-dependent conditions instead. [28] Examples of such medications include gonadotropin-releasing hormone modulators (GnRH modulators) like leuprorelin and degarelix, nonsteroidal antiandrogens like flutamide and bicalutamide, the diuretic and steroidal antiandrogen spironolactone, the progestin medroxyprogesterone acetate, and the 5α-reductase inhibitors finasteride and dutasteride. [28] The steroidal antiandrogen and progestin chlormadinone acetate is used as an alternative to CPA in Japan, South Korea, and a few other countries.[ citation needed ]
CPA is used with ethinylestradiol as a combined birth control pill to prevent pregnancy. This birth control combination has been available since 1978. [20] The formulation is taken once daily for 21 days, followed by a 7-day free interval. [29] CPA has also been available in combination with estradiol valerate (brand name Femilar) as a combined birth control pill in Finland since 1993. [30] [31] High-dose CPA tablets have a contraceptive effect and can be used as a form of birth control, although they are not specifically licensed as such. [32]
CPA is used as an antiandrogen to treat androgen-dependent skin and hair conditions such as acne, seborrhea, hirsutism (excessive hair growth), scalp hair loss, and hidradenitis suppurativa in women. [33] [34] [35] [36] [37] [38] [39] These conditions are worsened by the presence of androgens, and by suppressing androgen levels and blocking their actions, CPA improves the symptoms of these conditions. CPA is used to treat such conditions both at low doses as a birth control pill and on its own at higher doses. [33] [34] [35] [36] [40] A birth control pill containing low-dose CPA in combination with ethinylestradiol to treat acne has been found to result in overall improvement in 75 to 90% of women, with responses approaching 100% improvement. [41] High-dose CPA alone likewise has been found to improve symptoms of acne by 75 to 90% in women. [42] Discontinuation of CPA has been found to result in marked recurrence of symptoms in up to 70% of women. [43] CPA is one of the most commonly used medications in the treatment of hirsutism, hyperandrogenism, and polycystic ovary syndrome in women throughout the world. [44] [45]
Higher dosages of CPA are used in combination with an estrogen specifically at doses of 25 to 100 mg/day cyclically in the treatment of hirsutism in women. [45] [46] [47] The efficacy of such dosages of CPA in the treatment of hirsutism in women appear to be similar to that of spironolactone, flutamide, and finasteride. [46] [47] [44] [45] Randomized controlled trials have found that higher dosages of CPA (e.g., 20 mg/day or 100 mg/day) added cyclically to a birth control pill containing ethinylestradiol and 2 mg/day CPA were no more effective or only marginally more effective in the treatment of severe hirsutism in women than the birth control pill alone. [45] [47] [44] [48] [49] [50] Maintenance therapy with lower doses of CPA, such as 25 mg/day, has been found to be effective in preventing relapse of symptoms of hirsutism. [43] CPA has typically been combined with ethinylestradiol, but it can alternatively be used in combination with hormone replacement therapy dosages of estradiol instead. [45] CPA at a dosage of 50 mg/day in combination with 100 μg/day transdermal estradiol patches has been found to be effective in the treatment of hirsutism similarly to the combination of CPA with ethinylestradiol. [47] [51]
The efficacy of the combination of an estrogen and CPA in the treatment of hirsutism in women appears to be due to marked suppression of total and free androgen levels as well as additional blockade of the androgen receptor. [44] [45] [52]
CPA has been found to be effective in the treatment of acne in males, with marked improvement in symptoms observed at dosages of 25, 50, and 100 mg/day in different studies. [53] [54] [55] [56] It can also halt further progression of scalp hair loss in men. [57] [58] [59] Increased head hair and decreased body hair has been observed with CPA in men with scalp hair loss. [60] [13] However, its side effects in men, such as demasculinization, gynecomastia, sexual dysfunction, bone density loss, and reversible infertility, make the use of CPA in males impractical in most cases. [57] [58] [54] [55] [61] [62] [63] In addition, lower dosages of CPA, such as 25 mg/day, have been found to be better-tolerated in men. [55] But such doses also show lower effectiveness in the treatment of acne in men. [53]
CPA is used as an antiandrogen to treat high androgen levels and associated symptoms such as masculinization due to conditions like polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH) in women. [34] [39] [64] [65] [66] [67] It is almost always combined with an estrogen, such as ethinylestradiol, when it is used in the treatment of PCOS in women. [68]
CPA is used at low doses in menopausal hormone therapy in combination with an estrogen to provide endometrial protection and treat menopausal symptoms. [69] [1] [70] [71] It is used in menopausal hormone therapy under the brand name Climen, which is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA. [69] [70] [71] Climen was the first product for use in menopausal hormone therapy containing CPA to be marketed. [70] It is available in more than 40 countries. [69]
CPA is widely used as an antiandrogen and progestogen in feminizing hormone therapy for transgender individuals. [72] [73] [74] [75] [76] [77] [78] It has been historically used orally at a dosage of 10 to 100 mg/day and by intramuscular injection at a dosage of 300 mg once every 4 weeks. [79] [80] Many transgender individuals seeking feminizing hormone therapy have breast growth as one of the goals for undergoing feminizing hormone therapy, making this particular side effect of CPA generally viewed as a beneficial outcome rather than an issue. [58]
Studies have found that 10, 25, 50, and 100 mg/day CPA in combination with estrogen all result in equivalent and full testosterone suppression in transgender women. [81] [82] [83] [84] In light of risks of CPA such as fatigue, blood clots, benign brain tumors, and liver damage, the use of lower dosages of CPA may help to minimize such risks. [84] As a result, a CPA dosage of 10 mg/day and no greater is now recommended by the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (SOC8). [85]
CPA has an advantage over spironolactone as an antiandrogen in transgender people, as the combination of estrogen and CPA consistently suppresses testosterone levels into the normal female range whereas estrogen with spironolactone does not. [86] [87] [88] [89] [90] [91] [92] Spironolactone is the most widely used antiandrogen in transgender women in the United States, whereas CPA is widely used in Europe and throughout the rest of the world. [87] [85]
Aside from adult transgender people, CPA has also been used as a puberty blocker and hence as an antiandrogen and antiestrogen to suppress puberty in transgender adolescents, although GnRH modulators are primarily used and more effective for this purpose. [93] [94] [74] [95] [96]
CPA is used as an antiandrogen monotherapy and means of androgen deprivation therapy in the palliative treatment of prostate cancer in men. [11] [97] [98] [99] [100] [101] It is used at very high doses by mouth or by intramuscular injection to treat this disease. Antiandrogens do not cure prostate cancer, but can significantly extend life in men with the disease. [102] [103] [97] CPA has similar effectiveness to GnRH modulators and surgical castration, high-dose estrogen therapy (e.g., with diethylstilbestrol), and high-dose nonsteroidal antiandrogen monotherapy (e.g., with bicalutamide), but has significantly inferior effectiveness to combined androgen blockade with a GnRH modulator and a nonsteroidal antiandrogen (e.g., with bicalutamide or enzalutamide). [97] [103] [104] [105] [106] In addition, the combination of CPA with a GnRH modulator or surgical castration has not been found to improve outcomes relative to a GnRH modulator or surgical castration alone, in contrast to nonsteroidal antiandrogens. [107] Due to its inferior effectiveness, tolerability, and safety, CPA is rarely used in the treatment of prostate cancer today, having largely been superseded by GnRH modulators and nonsteroidal antiandrogens. [108] [109] CPA is the only steroidal antiandrogen that continues to be used in the treatment of prostate cancer. [103]
Dose-ranging studies of CPA for prostate cancer were not performed, and the optimal dosage of CPA for the treatment of the condition has not been established. [110] [111] A dosage range of oral CPA of 100 to 300 mg/day is used in the treatment of prostate cancer, but generally 150 to 200 mg/day oral CPA is used. [112] [113] Schröder (1993, 2002) reviewed the issue of CPA dosage and recommended a dosage of 200 to 300 mg/day for CPA as a monotherapy and a dosage of 100 to 200 mg/day for CPA in combined androgen blockade (that is, CPA in combination with surgical or medical castration). [114] [99] However, the combination of CPA with castration for prostate cancer has been found to significantly decrease overall survival compared to castration alone. [115] Hence, the use of CPA as the antiandrogen component in combined androgen blockade would appear not to be advisable. [115] When used by intramuscular injection to treat prostate cancer, CPA is used at a dosage of 300 mg once a week. [63]
The combination of CPA with an estrogen such as ethinylestradiol sulfonate or low-dose diethylstilbestrol has been used as a form of combined androgen blockade and as an alternative to the combination of CPA with surgical or medical castration. [114] [116] [117] [118] [119]
CPA is used as an antiandrogen and form of chemical castration in the treatment of paraphilias and hypersexuality in men. [120] [121] [122] [60] [123] [124] It is used to treat sex offenders.[ citation needed ] The medication is approved in more than 20 countries for this indication and is predominantly employed in Canada, Europe, and the Middle East. [125] CPA works by decreasing sex drive and sexual arousal and producing sexual dysfunction. CPA can also be used to reduce sex drive in individuals with inappropriate sexual behaviors, such as people with intellectual disability and dementia. [126] [127] The medication is also used to reduce sexual behavior diagnosed as self-harmful, such as masochism. [128] CPA has comparable effectiveness to medroxyprogesterone acetate in suppressing sexual urges and function but appears to be less effective than GnRH modulators like leuprorelin and has more side effects. [121]
High-dose CPA significantly decreases sexual fantasies and sexual activity in 80 to 90% of men with paraphilias. [125] In addition, it has been found to decrease the rate of reoffending in sex offenders from 85% to 6%, with most of the reoffenses being committed by individuals who did not follow their CPA treatment prescription. [125] It has been reported that in 80% of cases, 100 mg/day CPA is adequate to achieve the desired reduction of sexuality, whereas in the remaining 20% of cases, 200 mg/day is sufficient. [129] When only a partial reduction in sexuality is desired, 50 mg/day CPA can be useful. [129] Reduced sexual desire and erectile function occurs with CPA by the end of the first week of treatment, and becomes maximal within three to four weeks. [129] [63] The dosage range is 50 to 300 mg/day. [63] [129]
CPA is used as an antiandrogen and antiestrogen to treat precocious puberty in boys and girls. [13] [65] [130] However, it is not fully satisfactory for this indication because it is not able to completely suppress puberty. [131] For this reason, CPA has mostly been superseded by GnRH agonists in the treatment of precocious puberty. [65] CPA is not satisfactory for gonadotropin-independent precocious puberty. [132] CPA has been used at dosages of 50 to 300 mg/m2 to treat precocious puberty. [63] [13]
CPA is useful in the treatment of hot flashes, for instance due to androgen deprivation therapy for prostate cancer. [104] [133] [134] [135]
CPA is useful for suppressing the testosterone flare at the initiation of GnRH agonist therapy. [136] [104] [137] [11] [65] [138] [139] [140] [141] It has been used successfully both alone and in combination with estrogens such as diethylstilbestrol for this purpose. [136] [142]
CPA is available in the form of oral tablets alone (higher-dose; 10 mg, 50 mg, 100 mg) or in combination with ethinylestradiol or estradiol valerate (low-dose; 1 or 2 mg CPA) and in the form of ampoules for intramuscular injection (higher-dose; 100 mg/mL, 300 mg/3 mL; brand name Androcur Depot). [143] [144] [145] [146] [147]
The higher-dose formulations are used to treat prostate cancer and certain other androgen-related indications while the low-dose formulations which also have an estrogen are used as combined birth control pills and are used in menopausal hormone therapy for the treatment of menopausal symptoms. [146] [148]
Contraindications of CPA include: [149] [150] [52]
When CPA is used in combination with an estrogen, contraindications for birth control pills should also be considered. [52]
CPA is generally well-tolerated and has a mild side-effect profile regardless of dosage when it is used in combination with an estrogen in women. [151] [152] Side effects of CPA in general include hypogonadism (low sex-hormone levels) and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis (fragile bones); breast changes such as breast tenderness, breast enlargement, and gynecomastia (breasts in men); emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. [52] Weight gain can occur with CPA when it is used at high doses. [153] [49] Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. [68] [41] Few quantitative data are available on many of the potential side effects of CPA. [154] Pooled tolerability data for CPA is not available in the literature. [155] Cyproterone is also known to suppress adrenocortical function. [156]
At very high doses in aged men with prostate cancer, CPA can cause cardiovascular side effects. Rarely, CPA can produce blood clots, liver toxicity (including hepatitis, liver failure, and liver cancer), excessively high prolactin levels, and certain benign brain tumors including meningiomas (tumors of the meninges) and prolactinomas (prolactin-secreting tumors of the pituitary gland). Upon discontinuation from high doses, CPA can produce adrenal insufficiency as a withdrawal effect.
CPA is relatively safe in acute overdose. [150] It is used at very high doses of up to 300 mg/day by mouth and 700 mg per week by intramuscular injection. [150] [157] For comparison, the dose of CPA used in birth control pills is 2 mg/day. [158] There have been no deaths associated with CPA overdose. [150] There are no specific antidotes for CPA overdose, and treatment should be symptom-based. [150] Gastric lavage can be used in the event of oral overdose within the last 2 to 3 hours. [150]
Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may interact with CPA. [150] Examples of strong CYP3A4 inhibitors include ketoconazole, itraconazole, clotrimazole, and ritonavir, while examples of strong CYP3A4 inducers include rifampicin, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John's wort. [150] Certain anticonvulsant medications can substantially reduce levels of CPA, by as much as 8-fold. [36]
CPA has antiandrogenic activity, [1] [159] progestogenic activity, [1] [159] weak partial glucocorticoid activity, [160] weak steroidogenesis inhibitor activity, [161] and agonist activity at the pregnane X receptor. [162] [163] [164] It has no estrogenic or antimineralocorticoid activity. [1] In terms of potency, CPA is described as a highly potent progestogen, a moderately potent antiandrogen, and a weak glucocorticoid. [52] [153] [41] Due to its progestogenic activity, CPA has antigonadotropic effects, and is able to suppress fertility and sex-hormone levels in both males and females. [1] [13] [52]
CPA can be taken by mouth or by injection into muscle. [13] It has near-complete oral bioavailability, is highly and exclusively bound to albumin in terms of plasma protein binding, is metabolized in the liver by hydroxylation and conjugation, has 15β-hydroxycyproterone acetate (15β-OH-CPA) as a single major active metabolite, has a long elimination half-life of about 2 to 4 days regardless of route of administration, and is excreted in feces primarily and to a lesser extent in urine. [1] [4] [12]
CPA, also known as 1α,2α-methylene-6-chloro-17α-acetoxy-δ6-progesterone or as 1α,2α-methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione acetate, is a synthetic pregnane steroid and an acetylated derivative of 17α-hydroxyprogesterone. [165] [166] It is structurally related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate. [166]
Chemical syntheses of CPA have been published. [144] [167] [168] The following is one such synthesis: [169] [170]
The dehydrogenation of 17α-hydroxyprogesterone acetate [302-23-8] (1) with chloranil (tetrachloro-p-benzoquinone) gives a compound that has been called melengestrol acetate [425-51-4] (2). Dehydrogenation with selenium dioxide gives 17-acetoxy-1,4,6-pregnatriene-3,20-dione [2668-75-9] (3). Reacting this with diazomethane results in a 1,3-dipolar addition reaction at C1–C2 of the double bond of the steroid system, which forms a derivative of dihydropyrazole, CID:134990386 (4). This compound cleaves when reacted with perchloric acid, [171] releasing nitrogen molecules and forming a cyclopropane derivative, 6-deschloro cyproterone acetate [2701-50-0] (5). Selective oxidation of the C6=C7 olefin with benzoyl peroxide gives the epoxide, i.e. 6-deschloro-6,7-epoxy cyproterone [15423-97-9] (6). The penultimate step involves a reaction with hydrochloric acid in acetic acid, resulting in the formation of chlorine and its subsequent dehydration, and a simultaneous opening of the cyclopropane ring giving 1α-(chloromethyl) chlormadinone acetate [17183-98-1] (7). The heating of this in collidine reforms the cyclopropane ring, completing the synthesis of CPA (8).
CPA was first synthesized in 1961 by Rudolf Wiechert, a Schering employee, and together with Friedmund Neumann in Berlin, they filed for a patent for CPA as "progestational agent" in 1962. [17] [172] The antiandrogenic activity of CPA was discovered serendipitously by Hamada, Neumann, and Karl Junkmann in 1963. [173] [63] Along with the steroidal antiandrogens benorterone (17α-methyl-B-nortestosterone; SKF-7690), cyproterone, BOMT (Ro 7–2340), and trimethyltrienolone (R-2956) and the nonsteroidal antiandrogens flutamide and DIMP (Ro 7–8117), CPA was one of the first antiandrogens to be discovered and researched. [41] [174] [175] [176]
CPA was initially developed as a progestogen for the prevention of threatened abortion. [63] As part of its development, it was assessed for androgenic activity to ensure that it would not produce teratogenic effects in female fetuses. [63] The drug was administered to pregnant rats and its effects on the rat fetuses were studied. [63] To the surprise of the researchers, all of the rat pups born appeared to be female. [63] After 20 female rat pups in a row had been counted, it was clear that this could not be a chance occurrence. [63] The rat pups were further evaluated and it was found that, in terms of karyotype, about 50% were actually males. [63] The male rat pups had been feminized, and this resultant finding constituted the discovery of the powerful antiandrogenic activity of CPA. [63] A year after patent approval in 1965, Neumann published additional evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain". [18] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation. [177]
The first clinical use of CPA in the treatment of sexual deviance and prostate cancer occurred in 1966. [14] [178] [179] It was first studied in the treatment of androgen-dependent skin and hair symptoms, specifically acne, hirsutism, seborrhea, and scalp hair loss, in 1969. [180] CPA was first approved for medical use in 1973 in Europe under the brand name Androcur. [167] [181] In 1977, a formulation of CPA was introduced for use by intramuscular injection. [182] CPA was first marketed as a birth control pill in 1978 in combination with ethinylestradiol under the brand name Diane. [20] Following phase III clinical trials, CPA was approved for the treatment of prostate cancer in Germany in 1980. [182] [183] CPA became available in Canada as Androcur in 1987, as Androcur Depot in 1990, and as Diane-35 in 1998. [184] [185] [186] Conversely, CPA was never introduced in any form in the United States. [25] [28] This was reportedly due to concerns about breast tumors observed with high-dose pregnane progestogens in beagle dogs as well as concerns about potential teratogenicity in pregnant women. [187] Use of CPA in transgender women, an off-label indication, was reported as early as 1977. [188] [189] The use of CPA in transgender women was well-established by the early 1990s. [190]
The history of CPA, including its discovery, development, and marketing, has been reviewed. [191] [13]
The English and generic name of CPA is cyproterone acetate and this is its USAN , BAN , and JAN . [23] [24] [192] [193] The English and generic name of unacetylated cyproterone is cyproterone and this is its INN and BAN , [192] [193] [194] while cyprotérone is the DCF and French name and ciproterone is the DCIT and Italian name. [23] [24] The name of unesterified cyproterone in Latin is cyproteronum, in German is cyproteron, and in Spanish is ciproterona. [23] [24] These names of cyproterone correspond for CPA to acétate de cyprotérone in French, acetato de ciproterona in Spanish, ciproterone acetato in Italian, cyproteronacetat in German, siproteron asetat in Turkish, and cyproteronacetaat in Dutch. CPA is also known by the developmental code names SH-80714 and SH-714, while unacetylated cyproterone is known by the developmental code names SH-80881 and SH-881. [23] [24] [192] [193]
CPA is marketed under brand names including Androcur, Androcur Depot, Androcur-100, Androstat, Asoteron, Cyprone, Cyproplex, Cyprostat, Cysaxal, Imvel, and Siterone. [23] [24] When CPA is formulated in combination with ethinylestradiol, it is also known as co-cyprindiol, and brand names for this formulation include Andro-Diane, Bella HEXAL 35, Chloe, Cypretil, Cypretyl, Cyproderm, Diane, Diane Mite, Diane-35, Dianette, Dixi 35, Drina, Elleacnelle, Estelle, Estelle-35, Ginette, Linface, Minerva, Vreya, and Zyrona. [23] [24] CPA is also marketed in combination with estradiol valerate as Climen, Climene, Elamax, and Femilar. [23]
CPA is widely available throughout the world, and is marketed in almost every developed country, [195] with the notable major exceptions of the United States and Japan. [23] [24] [25] [196] [197] In almost all countries in which CPA is marketed, it is available both alone and in combination with an estrogen in birth control pills. [23] [196] [197] CPA is marketed widely in combination with both ethinylestradiol and estradiol valerate. [23] [24] [196] [197] CPA-containing birth control pills are available in South Korea, but CPA as a standalone medication is not marketed in this country. [23] [24] [196] [197] In Japan and South Korea, the closely related antiandrogen and progestin chlormadinone acetate, as well as other medications, are used instead of CPA. [198] Specific places in which CPA is marketed include the United Kingdom, elsewhere throughout Europe, Canada, Australia, New Zealand, South Africa, Latin America, and Asia. [23] [24] [196] [197] CPA is not marketed in most of Africa and the Middle East. [23] [24] [196] [197]
It has been said that the lack of availability of CPA in the United States explains why there are relatively few studies of it in the treatment of androgen-dependent conditions such as hyperandrogenism and hirsutism in women. [151]
Progestins in birth control pills are sometimes grouped by generation. [199] [200] While the 19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes". [199] [200] In any case, CPA has been described as a "first-generation" progestin similarly to closely related progestins like chlormadinone acetate, medroxyprogesterone acetate, and megestrol acetate. [21] [201]
CPA has been studied and used in combination with low-dose diethylstilbestrol in the treatment of prostate cancer. [116] [118] [117] The combination results in suppression of testosterone levels into the castrate range, which normally cannot be achieved with CPA alone. [118] CPA has been studied as a form of androgen deprivation therapy for the treatment of benign prostatic hyperplasia (enlarged prostate). [202] [203] [204] The medication has been studied in the treatment of breast cancer as well. [205] [206]
CPA has been studied for use as a potential male hormonal contraceptive both alone and in combination with testosterone in men. [207] [208] CPA was under development by Barr Pharmaceuticals in the 2000s for the treatment of hot flashes in prostate cancer patients in the United States. [209] It reached phase III clinical trials for this indication and had the tentative brand name CyPat but development was ultimately discontinued in 2008. [209] CPA is not satisfactorily effective as topical antiandrogen, for instance in the treatment of acne. [165] CPA has been used to treat estrogen hypersensitivity vulvovaginitis in women. [210]
CPA has been investigated for use in reducing aggression and self-injurious behavior via its antiandrogenic effects in conditions like autism spectrum disorders, dementias like Alzheimer's disease, and psychosis. [211] [212] [213] [214] CPA may be effective in the treatment of obsessive–compulsive disorder (OCD). [215] [216] [217] [218] CPA has been studied in the treatment of cluster headaches in men. [219]
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.
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.
Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.
Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.
The first antiandrogen was discovered in the 1960s. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological effects of testosterone and dihydrotestosterone (DHT). Antiandrogens are important for men with hormonally responsive diseases like prostate cancer, benign prostatic hyperplasia (BHP), acne, seborrhea, hirsutism and androgen alopecia. Antiandrogens are mainly used for the treatment of prostate diseases. Research from 2010 suggests that ARs could be linked to the disease progression of triple-negative breast cancer and salivary duct carcinoma and that antiandrogens can potentially be used to treat it.
Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued .The medication has been given by injection into muscle usually once a month.
Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. It is a precursor of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. Cyproterone and CPA were among the first antiandrogens to be developed.
Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. It was the first known antiandrogen to be studied in humans. It is taken by mouth or by application to skin.
A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like testosterone and dihydrotestosterone (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of steroidal antiandrogens (SAAs), which are antiandrogens that are steroids and are structurally related to testosterone.
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.
The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility.
The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.
The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.
The side effects of cyproterone acetate (CPA), a steroidal antiandrogen and progestin, including its frequent and rare side effects, have been studied and characterized. It is generally well-tolerated and has a mild side-effect profile, regardless of dosage, when it used as a progestin or antiandrogen in combination with an estrogen such as ethinylestradiol or estradiol valerate in women. Side effects of CPA include hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis; breast changes such as breast tenderness, enlargement, and gynecomastia; emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes. Weight gain can occur with CPA when it is used at high doses. Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to prevent estrogen deficiency. Few quantitative data are available on many of the potential side effects of CPA. Pooled tolerability data for CPA is not available in the literature.
Estradiol valerate/cyproterone acetate (EV/CPA), sold under the brand names Climen and Femilar among others, is a combination product of estradiol valerate (EV), an estrogen, and cyproterone acetate (CPA), a progestogen, which is used in menopausal hormone therapy and as a birth control pill to prevent pregnancy. It is taken by mouth. Climen, which is used in menopausal hormone therapy, is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA. It was the first product for use in menopausal hormone therapy containing CPA to be marketed and is available in more than 40 countries. Femilar, which is an estradiol-containing birth control pill, contains 1 to 2 mg estradiol valerate and 1 to 2 mg CPA, and has been approved for use in Finland since 1993.
Ethinylestradiol/cyproterone acetate (EE/CPA), also known as co-cyprindiol and sold under the brand names Diane and Diane-35 among others, is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also used to treat androgen-dependent conditions in women such as acne, seborrhea, excessive facial/body hair growth, scalp hair loss, and high androgen levels associated with ovaries with cysts. The medication is taken by mouth once daily for 21 days, followed by a 7-day free interval.
Since there is no binding of CPA to SHBG and CBG in the serum, 93% of the compound is bound to serum albumin.
It is almost exclusively bound to plasma albumin.
The terminal half-life is about 38 h. A portion of the drug is metabolized by hydrolysis to cyproterone and acetic acid. However, in contrast to many other steroid esters hydrolysis is not extensive, and much of the pharmacological activity is exerted by the acetate form. Excretion is about 70% in the feces, mainly in the form of glucuronidated metabolites, and about 30% in the urine, predominantly as non-conjugated metabolites.
CPA is 100% bioavailable when taken orally with a half life of 38 hours. The injectable form reaches maximum plasma levels in 82 hours and has a half life of about 72 hours.
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ignored (help)When compared to flutamide, [cyproterone acetate] has significant intrinsic androgenic and estrogenic activities. [...] The effects of flutamide and the steroidal derivatives, cyproterone acetate, chlormadinone acetate, megestrol acetate and medroxyprogesterone acetate were compared in vivo in female nude mice bearing androgen-sensitive Shionogi tumors. All steroidal compounds stimulated tumor growth while flutamide had no stimulatory effect [51]. Thus, CPA due to its intrinsic properties stimulates androgen-sensitive parameters and cancer growth. Cyproterone acetate added to castration has never been shown in any controlled study to prolong disease-free survival or overall survival in prostate cancer when compared with castration alone [152-155].
From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
No quantitative data on these adverse events are available, even in the product prescribing information and data sheets.
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