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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 |
| Drug class | Steroidal antiandrogen;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-CPATooltip 15β-Hydroxycyproterone acetate (major)[1][9] •Cyproterone (minor)[10] •Acetic acid (minor)[10] |
| Eliminationhalf-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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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.006.409 |
| Chemical and physical data | |
| Formula | C24H29ClO4 |
| Molar mass | 416.94 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 200 to 201 °C (392 to 394 °F) |
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Cyproterone acetate (CPA), sold alone under the brand nameAndrocur orwith ethinylestradiol under the brand namesDiane orDiane-35 among others, is anantiandrogen andprogestin medication used in the treatment ofandrogen-dependent conditions such asacne,excessive body hair growth,early puberty, andprostate cancer, as a component offeminizing hormone therapy fortransgender individuals, and inbirth control pills.[1][11][13][14][15] It is formulated and used both alone and in combination with anestrogen. CPA is takenby mouth one to three times per day.
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Commonside effects of high-dose CPA in men includegynecomastia (breast development) andfeminization. In both men and women, possible side effects of CPA includelow sex hormone levels, reversibleinfertility,sexual dysfunction,fatigue,depression,weight gain, andelevated liver enzymes. With prolonged use,brain tumors promptingsurgery are common, from 5% at high doses[16] to 2% at low doses. At very high doses in older individuals, significantcardiovascular complications can occur[vague]. Rare but serious adverse reactions of CPA includeblood clots, andliver damage. CPA can also causeadrenal insufficiency as awithdrawal effect if it is discontinued abruptly from a high dosage. CPA blocks the effects ofandrogens such astestosterone in the body, which it does by preventing them from interacting with theirbiological target, theandrogen receptor (AR), and by reducing theirproduction by thegonads, hence their concentrations in the body.[1][13][17] In addition, it hasprogesterone-like effects by activating theprogesterone receptor (PR).[1][13] It can also produce weakcortisol-like effects at very high doses.[1]
CPA was discovered in 1961.[18] It was originally developed as a progestin.[18] In 1965, the antiandrogenic effects of CPA were discovered.[19] CPA was first marketed, as an antiandrogen, in 1973, and was the first antiandrogen to be introduced for medical use.[20] A few years later, in 1978, CPA was introduced as a progestin in a birth control pill.[21] It has been described as a "first-generation" progestin[22] and as the prototypical antiandrogen.[23] CPA is available widely throughout the world.[24][25] An exception is theUnited States, where it is not approved for use.[26][27]
CPA is used as aprogestin andantiandrogen inhormonal birth control and in the treatment ofandrogen-dependent conditions.[13] Specifically, CPA is used incombined birth control pills, in the treatment of androgen-dependentskin and hair conditions such asacne,seborrhea,excessive hair growth, andscalp hair loss,high androgen levels, intransgender hormone therapy, to treatprostate cancer, to reducesex drive insex offenders or men withparaphilias orhypersexuality, to treatearly puberty, and for other uses.[28] Treatment dosages range from 2mg or less, to 100mg or more daily.[29]
In the United States, where CPA is not available, other medications with antiandrogenic effects are used to treat androgen-dependent conditions instead.[30] Examples of such medications includegonadotropin-releasing hormone modulators (GnRH modulators) likeleuprorelin anddegarelix,nonsteroidal antiandrogens likeflutamide andbicalutamide, thediuretic andsteroidal antiandrogenspironolactone, theprogestinmedroxyprogesterone acetate, and the5α-reductase inhibitorsfinasteride anddutasteride.[30] The steroidal antiandrogen and progestinchlormadinone acetate is used as an alternative to CPA inJapan,South Korea, and a few other countries.[citation needed]
In 2020, theEuropean Medicine Agency issued a warning that high doses of cyproterone acetate may contribute to risk of meningioma, and recommended physicians use alternative treatment for most indications (or the minimum effective dose where no alternatives were available) with the exception ofprostate carcinoma.[29]
CPA is used withethinylestradiol as acombined birth control pill to preventpregnancy. This birth control combination has been available since 1978.[21] The formulation is taken once daily for 21 days, followed by a 7-day free interval.[31] CPA has also been available in combination withestradiol valerate (brand name Femilar) as a combined birth control pill inFinland since 1993.[32][33] 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.[34]
CPA is used as an antiandrogen to treatandrogen-dependentskin and hair conditions such asacne,seborrhea,hirsutism (excessive hair growth),scalp hair loss, andhidradenitis suppurativa in women.[35][36][37][38][39][40][41] 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.[35][36][37][38][42] A birth control pill containing low-dose CPA in combination withethinylestradiol to treat acne has been found to result in overall improvement in 75 to 90% of women, with responses approaching 100% improvement.[43] High-dose CPA alone likewise has been found to improve symptoms of acne by 75 to 90% in women.[44] Discontinuation of CPA has been found to result in marked recurrence of symptoms in up to 70% of women.[45] CPA is one of the most commonly used medications in the treatment of hirsutism, hyperandrogenism, and polycystic ovary syndrome in women throughout the world.[46][47]
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.[47][48][49] The efficacy of such dosages of CPA in the treatment of hirsutism in women appear to be similar to that ofspironolactone,flutamide, andfinasteride.[48][49][46][47]Randomized controlled trials have found that higher dosages of CPA (e.g., 20 mg/day or 100 mg/day) added cyclically to abirth control pill containingethinylestradiol 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.[47][49][46][50][51][52] 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.[45] CPA has typically been combined with ethinylestradiol, but it can alternatively be used in combination withhormone replacement therapy dosages ofestradiol instead.[47] 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.[49][53]
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 freeandrogen levels as well as additional blockade of theandrogen receptor.[46][47][54]
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.[55][56][57][58] It can also halt further progression of scalp hair loss in men.[59][60][61] Increased head hair and decreased body hair has been observed with CPA in men with scalp hair loss.[62][13] However, its side effects in men, such asdemasculinization,gynecomastia,sexual dysfunction,bone density loss, and reversibleinfertility, make the use of CPA in males impractical in most cases.[59][60][56][57][63][64][65] In addition, lower dosages of CPA, such as 25 mg/day, have been found to be better-tolerated in men.[57] But such doses also show lower effectiveness in the treatment of acne in men.[55]
CPA is used as an antiandrogen to treathigh androgen levels and associatedsymptoms such asmasculinization due to conditions likepolycystic ovary syndrome (PCOS) andcongenital adrenal hyperplasia (CAH) in women.[36][41][66][67][68][69] It is almost always combined with an estrogen, such asethinylestradiol, when it is used in the treatment of PCOS in women.[70]
CPA is used at low doses inmenopausal hormone therapy in combination with an estrogen to provideendometrial protection and treatmenopausal symptoms.[71][1][72][73] It is used in menopausal hormone therapy under the brand name Climen, which is a sequential preparation that contains 2 mgestradiol valerate and 1 mg CPA.[71][72][73] Climen was the first product for use in menopausal hormone therapy containing CPA to be marketed.[72] It is available in more than 40 countries.[71]
CPA is widely used as anantiandrogen andprogestogen infeminizing hormone therapy fortransgender individuals.[74][75][76][77][78][79][80] 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.[81][82] 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.[60]
Studies have found that 10, 25, 50, and 100 mg/day CPA in combination with estrogen all result in equivalent and full testosterone suppression intransgender women.[83][84][85][86] In light of risks of CPA such asfatigue,blood clots,benignbrain tumors, andliver damage, the use of lower dosages of CPA may help to minimize such risks.[86] As a result, a CPA dosage of 10 mg/day and no greater is now recommended by theWorld Professional Association for Transgender Health (WPATH)Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (SOC8).[87]
CPA has an advantage overspironolactone as an antiandrogen in transgender people, as the combination of estrogen and CPA consistently suppressestestosterone levels into the normal female range whereas estrogen with spironolactone does not.[88][89][90][91][92][93][94] 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.[89][87]
Aside from adult transgender people, CPA has also been used as apuberty blocker and hence as an antiandrogen andantiestrogen to suppresspuberty intransgender adolescents, althoughGnRH modulators are primarily used and more effective for this purpose.[95][96][76][97][98]
CPA is used as an antiandrogen monotherapy and means ofandrogen deprivation therapy in thepalliative treatment ofprostate cancer in men.[11][99][100][101][102][103] 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.[104][105][99] CPA has similar effectiveness toGnRH modulators andsurgical castration,high-dose estrogen therapy (e.g., withdiethylstilbestrol), and high-dosenonsteroidal antiandrogen monotherapy (e.g., withbicalutamide), but has significantly inferior effectiveness tocombined androgen blockade with a GnRH modulator and a nonsteroidal antiandrogen (e.g., with bicalutamide orenzalutamide).[99][105][106][107][108] 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.[109] Due to its inferior effectiveness,tolerability, andsafety, CPA is rarely used in the treatment of prostate cancer today, having largely been superseded by GnRH modulators and nonsteroidal antiandrogens.[110][111] CPA is the only steroidal antiandrogen that continues to be used in the treatment of prostate cancer.[105]
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.[112][113] 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.[114][115] 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 incombined androgen blockade (that is, CPA in combination withsurgical ormedical castration).[116][101] However, the combination of CPA with castration for prostate cancer has been found to significantly decreaseoverall survival compared to castration alone.[117] Hence, the use of CPA as the antiandrogen component in combined androgen blockade would appear not to be advisable.[117] When used by intramuscular injection to treat prostate cancer, CPA is used at a dosage of 300 mg once a week.[65]
The combination of CPA with an estrogen such asethinylestradiol sulfonate or low-dosediethylstilbestrol has been used as a form of combined androgen blockade and as an alternative to the combination of CPA with surgical or medical castration.[116][118][119][120][121]
CPA is used as an antiandrogen and form ofchemical castration in the treatment ofparaphilias andhypersexuality in men.[122][123][124][62][125][126] It is used to treatsex offenders.[citation needed] The medication is approved in more than 20 countries for this indication and is predominantly employed inCanada,Europe, and theMiddle East.[127] CPA works by decreasingsex drive andsexual arousal and producingsexual dysfunction. CPA can also be used to reduce sex drive in individuals with inappropriate sexual behaviors, such as people withintellectual disability anddementia.[128][129] The medication is also used to reduce sexual behavior diagnosed as self-harmful, such asmasochism.[130] CPA has comparable effectiveness tomedroxyprogesterone acetate in suppressing sexual urges and function but appears to be less effective thanGnRH modulators likeleuprorelin and has moreside effects.[123]
High-dose CPA significantly decreasessexual fantasies andsexual activity in 80 to 90% of men with paraphilias.[127] 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.[127] 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.[131] When only a partial reduction in sexuality is desired, 50 mg/day CPA can be useful.[131] 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.[131][65] The dosage range is 50 to 300 mg/day.[65][131]
CPA is used as an antiandrogen and antiestrogen to treatprecocious puberty in boys and girls.[13][67][132] However, it is not fully satisfactory for this indication because it is not able to completely suppress puberty. It does not suppress skeletal maturation enough to avoid a reduction in height at adulthood.[133] For this reason, CPA has mostly been superseded byGnRH agonists in the treatment of precocious puberty.[67] CPA is not satisfactory forgonadotropin-independent precocious puberty.[134] CPA has been used at dosages of 50 to 300 mg/m2 to treat precocious puberty.[65][13]
CPA is useful in the treatment ofhot flashes, for instance due toandrogen deprivation therapy for prostate cancer.[106][135][136][137]
CPA is useful for suppressing the testosterone flare at the initiation of GnRH agonist therapy.[138][106][139][11][67][140][141][142][143] It has been used successfully both alone and in combination withestrogens such asdiethylstilbestrol for this purpose.[138][144]
CPA is available in the form oforaltablets alone (higher-dose; 10 mg, 50 mg, 100 mg) or in combination withethinylestradiol orestradiol valerate (low-dose; 1 or 2 mg CPA) and in the form ofampoules forintramuscular injection (higher-dose; 100 mg/mL, 300 mg/3 mL; brand name Androcur Depot).[145][146][147][148][149]
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 ascombinedbirth control pills and are used inmenopausal hormone therapy for the treatment ofmenopausalsymptoms.[148][150]
Contraindications of CPA include:[151][152][54]
When CPA is used in combination with an estrogen, contraindications forbirth control pills should also be considered.[54]
CPA is generally well-tolerated and has a mildside-effect profile regardless of dosage when it is used in combination with an estrogen in women.[153][154] Side effects of CPA in general includehypogonadism (low sex-hormone levels) and associatedsymptoms such asdemasculinization,sexual dysfunction,infertility, andosteoporosis (fragile bones);breast changes such asbreast tenderness,breast enlargement, andgynecomastia (breasts in men);emotional changes such asfatigue anddepression; and other side effects such asvitamin B12 deficiency[failed verification], weakglucocorticoid effects, andelevated liver enzymes.[54]Weight gain can occur with CPA when it is used at high doses.[155][51] Some of the side effects of CPA can be improved or fully prevented if it is combined with an estrogen to preventestrogen deficiency.[70][43] Fewquantitative data are available on many of the potential side effects of CPA.[156] Pooled tolerability data for CPA is not available in the literature.[157] Cyproterone is also known to suppress adrenocortical function.[158]
At very high doses in aged men with prostate cancer, CPA can causecardiovascular side effects. Rarely, CPA can produceblood clots,liver toxicity (includinghepatitis,liver failure, andliver cancer),excessively high prolactin levels, and certainbenignbrain tumors includingmeningiomas (tumors of themeninges) andprolactinomas (prolactin-secreting tumors of thepituitary gland). Upondiscontinuation from high doses, CPA can produceadrenal insufficiency as awithdrawal effect.
CPA is relatively safe in acuteoverdose.[152] It is used at very high doses of up to 300 mg/day by mouth and 700 mg per week by intramuscular injection.[152][159] For comparison, the dose of CPA used in birth control pills is 2 mg/day.[160] There have been no deaths associated with CPA overdose.[152] There are no specificantidotes for CPA overdose, and treatment should besymptom-based.[152]Gastric lavage can be used in the event of oral overdose within the last 2 to 3 hours.[152]
Inhibitors andinducers of thecytochrome P450enzymeCYP3A4 mayinteract with CPA.[152] Examples of strong CYP3A4 inhibitors includeketoconazole,itraconazole,clotrimazole, andritonavir, while examples of strong CYP3A4 inducers includerifampicin,rifampin,phenytoin,carbamazepine,phenobarbital, andSt. John's wort.[152] Certainanticonvulsant medications can substantially reduce levels of CPA, by as much as 8-fold.[38]
CPA hasantiandrogenic activity,[1][161]progestogenic activity,[1][161] weakpartialglucocorticoid activity,[162] weaksteroidogenesis inhibitor activity,[163] andagonist activity at thepregnane X receptor.[164][165][166] It has noestrogenic orantimineralocorticoid activity.[1] In terms ofpotency, CPA is described as a highly potent progestogen, a moderately potent antiandrogen, and a weak glucocorticoid.[54][155][43] Due to its progestogenic activity, CPA hasantigonadotropic effects, and is able to suppressfertility andsex-hormone levels in both males and females.[1][13][54]
CPA can be takenby mouth or byinjection into muscle.[13] It has near-complete oralbioavailability, is highly and exclusively bound toalbumin in terms ofplasma protein binding, ismetabolized in theliver byhydroxylation andconjugation, has15β-hydroxycyproterone acetate (15β-OH-CPA) as a single majoractive metabolite, has a longelimination half-life of about 2 to 4 days regardless of route of administration, and isexcreted infeces primarily and to a lesser extent inurine.[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 asyntheticpregnanesteroid and anacetylatedderivative of17α-hydroxyprogesterone.[167][168] It is structurally related to other 17α-hydroxyprogesterone derivatives such aschlormadinone acetate,hydroxyprogesterone caproate,medroxyprogesterone acetate, andmegestrol acetate.[168]
Chemical syntheses of CPA have been published.[146][169][170] The following is one such synthesis:[171][172]
The dehydrogenation of17α-hydroxyprogesterone acetate [302-23-8] (1) withchloranil (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 withperchloric acid,[173] 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 firstsynthesized in 1961 byRudolf Wiechert, aSchering employee, and together withFriedmund Neumann inBerlin, they filed for a patent for CPA as "progestational agent" in 1962.[18][174] The antiandrogenic activity of CPA was discovered serendipitously by Hamada, Neumann, and Karl Junkmann in 1963.[175][65] Along with the steroidal antiandrogensbenorterone (17α-methyl-B-nortestosterone; SKF-7690),cyproterone,BOMT (Ro 7–2340), andtrimethyltrienolone (R-2956) and thenonsteroidal antiandrogensflutamide andDIMP (Ro 7–8117), CPA was one of the first antiandrogens to be discovered and researched.[43][176][177][178]
CPA was initially developed as a progestogen for the prevention ofthreatened abortion.[65] As part of its development, it was assessed for androgenic activity to ensure that it would not produceteratogenic effects in femalefetuses.[65] The drug was administered topregnant rats and its effects on the rat fetuses were studied.[65] To the surprise of the researchers, all of the rat pups born appeared to be female.[65] After 20 female rat pups in a row had been counted, it was clear that this could not be a chance occurrence.[65] The rat pups were further evaluated and it was found that, in terms ofkaryotype, about 50% were actually males.[65] The male rat pups had been feminized, and this resultant finding constituted the discovery of the powerful antiandrogenic activity of CPA.[65] 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".[19] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetalsexual differentiation.[179]
The first clinical use of CPA in the treatment ofsexual deviance andprostate cancer occurred in 1966.[14][180][181] It was first studied in the treatment of androgen-dependent skin and hair symptoms, specifically acne, hirsutism, seborrhea, and scalp hair loss, in 1969.[182] CPA was first approved for medical use in 1973 inEurope under the brand name Androcur.[169][183] In 1977, a formulation of CPA was introduced for use by intramuscular injection.[184] CPA was first marketed as a birth control pill in 1978 in combination with ethinylestradiol under the brand name Diane.[21] Followingphase IIIclinical trials, CPA was approved for the treatment of prostate cancer in Germany in 1980.[184][185] CPA became available inCanada as Androcur in 1987, as Androcur Depot in 1990, and as Diane-35 in 1998.[186][187][188] Conversely, CPA was never introduced in any form in theUnited States.[26][30] This was reportedly due to concerns aboutbreast tumors observed with high-dosepregnane progestogens in beagle dogs as well as concerns about potentialteratogenicity in pregnant women.[189] Use of CPA intransgender women, anoff-label indication, was reported as early as 1977.[190][191] The use of CPA in transgender women was well-established by the early 1990s.[192]
The history of CPA, including its discovery, development, and marketing, has been reviewed.[193][13]
TheEnglish andgeneric name of CPA iscyproterone acetate and this is itsUSANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[24][25][194][195] The English and generic name of unacetylatedcyproterone iscyproterone and this is itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name,[194][195][196] whilecyprotérone is theDCFTooltip Dénomination Commune Française andFrench name andciproterone is theDCITTooltip Denominazione Comune Italiana andItalian name.[24][25] The name of unesterified cyproterone inLatin iscyproteronum, inGerman iscyproteron, and inSpanish isciproterona.[24][25] These names of cyproterone correspond for CPA toacétate de cyprotérone in French,acetato de ciproterona in Spanish,ciproterone acetato in Italian,cyproteronacetat in German,siproteron asetat in Turkish, andcyproteronacetaat inDutch. CPA is also known by the developmental code namesSH-80714 andSH-714, while unacetylated cyproterone is known by the developmental code namesSH-80881 andSH-881.[24][25][194][195]
CPA is marketed under brand names including Androcur, Androcur Depot, Androcur-100, Androstat, Asoteron, Cyprone, Cyproplex, Cyprostat, Cysaxal, Imvel, and Siterone.[24][25] When CPA is formulated in combination with ethinylestradiol, it is also known asco-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.[24][25] CPA is also marketed in combination withestradiol valerate as Climen, Climene, Elamax, and Femilar.[24]
CPA is widely available throughout the world, and is marketed in almost every developed country,[197] with the notable major exceptions of theUnited States andJapan.[24][25][26][198][199] In almost all countries in which CPA is marketed, it is available both alone and in combination with an estrogen in birth control pills.[24][198][199] CPA is marketed widely in combination with bothethinylestradiol andestradiol valerate.[24][25][198][199] CPA-containing birth control pills are available inSouth Korea, but CPA as a standalone medication is not marketed in this country.[24][25][198][199] In Japan and South Korea, the closely related antiandrogen and progestinchlormadinone acetate, as well as other medications, are used instead of CPA.[200] Specific places in which CPA is marketed include theUnited Kingdom, elsewhere throughoutEurope,Canada,Australia,New Zealand,South Africa,Latin America, andAsia.[24][25][198][199] CPA is not marketed in most ofAfrica and theMiddle East.[24][25][198][199]
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.[153]
Progestins in birth control pills are sometimes grouped by generation.[201][202] While the19-nortestosterone progestins are consistently grouped into generations, thepregnane 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".[201][202] In any case, CPA has been described as a "first-generation" progestin similarly to closely related progestins likechlormadinone acetate,medroxyprogesterone acetate, andmegestrol acetate.[22][203]
CPA has been studied and used in combination with low-dosediethylstilbestrol in the treatment ofprostate cancer.[118][120][119] The combination results in suppression of testosterone levels into thecastrate range, which normally cannot be achieved with CPA alone.[120] CPA has been studied as a form ofandrogen deprivation therapy for the treatment ofbenign prostatic hyperplasia (enlarged prostate).[204][205][206] The medication has been studied in the treatment ofbreast cancer as well.[207][208]
CPA has been studied for use as a potentialmale hormonal contraceptive both alone and in combination withtestosterone in men.[209][210] CPA was under development by Barr Pharmaceuticals in the 2000s for the treatment ofhot flashes in prostate cancer patients in theUnited States.[211] It reachedphase IIIclinical trials for this indication and had the tentative brand name CyPat but development was ultimately discontinued in 2008.[211] CPA is not satisfactorily effective astopical antiandrogen, for instance in the treatment ofacne.[167] CPA has been used to treatestrogen hypersensitivity vulvovaginitis in women.[212]
CPA has been investigated for use in reducingaggression andself-injurious behavior via its antiandrogenic effects in conditions likeautism spectrum disorders,dementias likeAlzheimer's disease, andpsychosis.[213][214][215][216] CPA may be effective in the treatment ofobsessive–compulsive disorder (OCD).[217][218][219][220] CPA has been studied in the treatment ofcluster headaches in men.[221]
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.
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.
