Cyproterone acetate

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Cyproterone acetate
Cyproterone acetate.svg
Acetato de ciproterona3D.png
Systematic (IUPAC) name
Clinical data
Trade names Androcur, Cyprostat, Siterone, others
AHFS/ Micromedex Detailed Consumer Information
  • X
Routes of
Oral, intramuscular
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 100%[1]
Protein binding Albumin: 93%
Free: 7%[2][3][4][5]
Metabolism Hepatic (CYP3A4)[6][7]
Metabolites 15β-OH-CPA (major)[1][8]
Cyproterone (minor)[9]
Acetic acid (minor)[9]
Biological half-life Oral: 38 hours[9][10]
Intramusclar: 72 hours[9][10]
Excretion Feces: 70%[9]
Urine: 30%[9]
CAS Number 427-51-0 YesY
ATC code G03HA01 (WHO)
PubChem CID 9880
ChemSpider 9496 YesY
ChEBI CHEBI:50743 YesY
Synonyms NSC-81430; SH-714; SH-80714[11]
Chemical data
Formula C24H29ClO4
Molar mass 416.94 g/mol

Cyproterone acetate (abbreviated as CPA), also sold under brand names such as Androcur among others, is a synthetic steroidal antiandrogen, progestin, and antigonadotropin.[11][12] It is primarily used in the treatment of androgen-related conditions by virtue of its ability to suppress androgenic activity in the body, an effect which it mediates by preventing endogenous androgens from interacting with the androgen receptor (AR) and by suppressing androgen biosynthesis.[13] CPA is also used for its progestogenic effects, for instance, as a component of some combined oral contraceptive pills in combination with ethinyl estradiol (EE), such as in Diane-35 among others.[14]

Medical uses[edit]

CPA has been in use as an antiandrogen since 1973, and was the first antiandrogen introduced for clinical use.[15] It is used widely throughout Europe, and is also used in Canada, Mexico, and other countries. It is not FDA-approved for use in the United States, due to concerns about hepatotoxicity; medroxyprogesterone acetate has been used in the United States instead.[16] CPA has been approved for the treatment of prostate cancer, precocious puberty, androgen-related dermatological conditions such as acne, seborrhea, hirsutism, and androgenic alopecia, and to reduce sex drive in sex offenders.[17] For the treatment of hypersexuality, severe hirsutism, or for the treatment of transgender women, 50–100 mg daily is usually sufficient, although higher doses per day is permitted.[citation needed] As side effects are dose-dependent, treatment with the lowest effective dose is advisable.[citation needed]

The combination of CPA and EE, a formulation sometimes referred to as co-cyprindiol, has been available as contraceptive since at least 1997.[15] This formulation is taken once daily for 21 days, followed by a 7-day free interval.[citation needed] CPA has also been available in combination with estradiol valerate (brand name Femilar) as a contraceptive in Finland since 1993.[18]

Other uses of CPA include the treatment of benign prostatic hyperplasia, priapism, hypersexuality, paraphilias, hot flashes, and hyperandrogenism in women. In addition, with the exception of the United States, where it is not available and spironolactone, a diuretic with antiandrogen properties, is generally employed instead, CPA is widely used as a component of hormone replacement therapy (HRT) for transgender women.[19]

In the treatment of acne in women, a formulation of low-dose CPA in combination with EE has been found to result in overall improvement in 75 to 90% of patients, with responses approaching 100% improvement.[20]


Use during pregnancy is contraindicated, and for women of childbearing age, CPA should be administered with a combined oral contraceptive.[citation needed]

Side effects[edit]

Hypogonadism and feminization[edit]

Side effects in males resulting directly from the antiandrogen and antigonadotropic properties of CPA include physical demasculinization, gynecomastia (breast enlargement) and general physical feminization, breast pain/tenderness, galactorrhea (milk outflow), sexual dysfunction (including loss of libido and erectile dysfunction), impaired spermatogenesis, and reversible infertility.[15] In the treatment of men with prostate cancer, CPA has been described as causing "severe" suppression of libido and erectile potency, comparable to that seen with surgical castration.[21] Due to suppression of the production of estrogens, long-term use of high-dose CPA without concomitant estrogen therapy can result in the development of osteoporosis in both sexes.[22]


CPA has been associated with an increased rate of depression in both men and women.[23] It has been reported that as many as 20–30% of women treated with the drug for hirsutism (dosage range 25–100 mg) may show depressive symptoms.[24][25] Also, a study found that around 20% of women treated with Dianette (which contains only 2 mg CPA) for contraceptive purposes developed depression.[26] As the antiandrogen component of transgender HRT, treatment with CPA (as well as with spironolactone to a lesser extent) has also been associated with a significantly higher rate of depressive symptomatology in transgender women relative to treatment with GnRH analogues (which are more selective in their action and are considered not to have a significant risk of depression in this patient population (with concomitant supplementation of estrogen)).[27] The depressive effects of CPA may be related to its glucocorticoid, antiandrogen, and/or antigonadotropic effects, as glucocorticoids, antiandrogens (in men), and GnRH analogues have all been associated with depression.[28][29][30][31] Vitamin B12 deficiency induced by CPA might also or alternatively be a critical factor.[26] Because of the side effect of depression, CPA should be used with caution in individuals with a history of the condition, especially if severe.[32]

Vitamin B12 deficiency[edit]

High-dose CPA treatment has been found to produce vitamin B12 deficiency.[33][34] Low-dose (2 mg/day) CPA in combination with EE has also been associated with vitamin B12 deficiency.[35] It is notable that vitamin B12 deficiency is associated with depression, anxiety, irritability, and fatigue via depletion of central monoamine neurotransmitters,[36][37] and it has been suggested that this may be involved in the adverse neuropsychiatric consequences commonly observed with CPA therapy.[26] Serum vitamin B12 monitoring and supplementation as necessary is recommended during CPA treatment.[33][34][35]

Other side effects[edit]

CPA has been associated with the formation of stretch marks, due potentially to glucocorticoid activity and/or causing dry skin.[38]

Rare reactions[edit]

Blood clots[edit]

Used alone, CPA does not appear to have a significant effect on blood clotting factors, but in combination with EE, as in combined oral contraceptive pills, presents an increased risk of deep vein thrombosis.[39] Women who take contraceptive pills containing CPA have a 6- to 7-fold increased risk of developing thromboembolism compared to women not taking a contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.[40] At least four cases of fatal venous thromboembolism have been attributed to low-dose CPA in combination with EE.[41]


The most serious potential side effect of CPA is hepatotoxicity.[42] A variety of manifestations of liver disease in association with CPA treatment have been documented, including immunoallergic cytotoxic reactions, cholestasis, autoimmune hepatitis, acute hepatitis, fulminant liver failure, and cirrhosis, as well as an increased risk of hepatocellular carcinoma.[43][44] Clinical features may include jaundice, fatigue, nausea, elevated liver enzymes, hepatic necrosis and inflammation, and features of hepatic decompensation.[44] Hepatotoxicity due to CPA therapy is most common in elderly patients who are treated with high dosages of the drug for prolonged periods of time, but has also occurred in younger patients.[43]

In a study of 1,685 patients treated with CPA, elevated liver enzymes were seen in 10% of patients at a dosage of 50 mg/day and in 20% of patients at a dosage of greater than 100 mg/day.[42] A study of 2,506 patients given 18–136 mg/day for less than 47.5 months per patient reported a rate of 9.6%.[43][44] In a trial of 89 prostate cancer patients who received high-dose CPA for 4 years, there were elevated liver enzymes in 28.2% of the patients.[44] Yet another study of 105 patients found a hepatotoxicity rate of 9.5%, with serious hepatic injury occurring in 3.8%.[44] In 2002, it was reported that there were 18 case reports of CPA-associated hepatitis in the medical literature, with 6 of the cases resulting in death.[42] In addition, a review article cited a report of 96 instances of hepatotoxicity that were attributed to CPA, and 33 of these instances resulted in death.[42] Moreover, a 2014 review found that 15 cases specifically of CPA-induced fulminant (sudden-onset and severe) liver failure had been reported to date, with only one of these cases not resulting in death.[44] As such, the prognosis of CPA-induced liver failure is fatal.[44]

The risk of hepatotoxicity and death associated with CPA treatment is the reason that CPA has not been approved by the FDA for use in the United States.[45] Patients being treated with high-dose CPA should be closely monitored with liver function tests.[46] The risk is dose-dependent, and the low doses of CPA used in birth control pills (2 mg) have been said to represent a non-significant risk.[47] However, a German woman who had been taking Diane-35 (containing 2 mg/day CPA) for contraception for 14 years died of liver cancer, and this led to a safety review by drug regulators and the eventual restriction of CPA throughout Europe for the indication of acne treatment in women.[41]


High-dose CPA in combination with estrogen has been associated with a dramatically (400-fold) increased incidence of hyperprolactinemia in transgender women.[48] Estrogen alone has been associated only with single case reports of prolactinoma in this population.[48]


Very rarely, high-dose (but not low-dose (i.e., contraceptive-dose)) CPA treatment has been associated with the incidence and aggravation of meningiomas (a type of usually-benign brain tumor).[49][50] For this reason, high-dose CPA is contraindicated in people with meningioma or a history of meningoma.[6][32]


Adrenal insufficiency[edit]

Abrupt withdrawal of CPA can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg at intervals of several weeks. The primary concern is the manner in which CPA affects the adrenal glands. Due to its glucocorticoid activity, high levels of CPA may reduce ACTH, resulting in adrenal insufficiency if discontinued abruptly. In addition, although CPA reduces androgen production in the gonads, it can increase the production of adrenal androgens, in some cases resulting in an overall rise in testosterone levels.[51] Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects.[citation needed] This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production.[52]

Suppression of adrenal function and reduced response to adrenocorticotropic hormone (ACTH) have been reported with CPA treatment. As a result, adrenal insufficiency and hence low cortisol and aldosterone levels and ACTH responsiveness can occur upon discontinuation of CPA. Low aldosterone levels may lead to hyponatremia (sodium loss) and hyperkalemia (excess potassium). Patients taking CPA should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, should reduce the consumption of foods with high potassium content or discontinue the medication.


CPA is known to possess the following pharmacological activity:

CPA does not have significant affinity for the estrogen receptor (ER) or for the mineralocorticoid receptor (MR).[citation needed]

CPA is equally potent as a progestogen and antiandrogen.[60] It is the most potent progestin of the 17α-hydroxyprogesterone group, being 1200-fold more potent than hydroxyprogesterone acetate, 12-fold more potent than medroxyprogesterone acetate, and 3-fold more potent than chlormadinone acetate.[60] The progestins of the 17α-hydroxyprogesterone group are extremely potent; in fact, CPA is the strongest progestogen known, with about 1000-fold the potency of progesterone in an animal assay.[61] CPA is also the most potent of the steroidal antiandrogens,[62] out of hundreds of other steroids.[63]

CPA may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting.[64][65][66] In any case, the combination of CPA and finasteride, a well-established, selective 5α-reductase inhibitor, has been found to result in significantly improved effectiveness in the treatment of hirsutism relative to CPA alone, suggesting that if CPA does have any direct inhibitory effects on 5α-reductase, they must be far from maximal.[67][68]

CPA has been found to bind non-selectively to the opioid receptors, including the μ-, δ-, and κ-opioid receptor subtypes, albeit very weakly relative to its other actions (IC50 for inhibition of [3H]diprenorphine binding = 1.62 ± 0.33 µM).[69] It has been suggested that activation of opioid receptors could have the potential to explain the side effect of sedation sometimes seen at high doses with CPA treatment and/or its effectiveness in the treatment of cluster headaches.[69]


CPA is a potent androgen receptor (AR) competitive antagonist.[53] It directly blocks endogenous androgens such as testosterone (T) and dihydrotestosterone (DHT) from binding to and activating the AR, and thus prevents them from exerting their androgenic effects in the body. However, CPA, like spironolactone and other steroidal antiandrogens such as chlormadinone acetate and medroxyprogesterone acetate, is not actually a pure antagonist of the AR – that is, a silent antagonist – but rather is a very weak partial agonist.[53][70][71][72] Clinically, CPA generally behaves purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as T and DHT from interacting with the receptor and thus its net effect is usually to lower physiological androgenic activity. But unlike silent antagonists of the AR such as flutamide, CPA, by virtue of its slight intrinsic activity at the receptor, is inherently incapable of fully abolishing androgenic activity in the body and will always maintain at least some degree of it.

In accordance with its, albeit weak, capacity for activation of the AR, CPA has been found to stimulate androgen-sensitive carcinoma growth in the absence of other androgens, an effect which could be blocked by co-treatment with flutamide.[70][71] As a result, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to non-steroidal antiandrogens with a silent antagonist profile at the AR such as flutamide, bicalutamide, and enzalutamide.[53][73] Indeed, CPA has never been found to extend life in prostate cancer patients when added to castration relative to castration alone, unlike non-steroidal antiandrogens.[74]

A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their ARs. These altered ARs can be activated, rather than inhibited, by CPA. In such cases, withdrawal of CPA may result in a reduction in cancer growth, rather than the reverse.[75] This is known as antiandrogen withdrawal syndrome.


CPA is a highly potent progestogen.[76] The dosage needed to inhibit ovulation in women (i.e., to act as a contraceptive) is less than 1 mg per day,[77] and the drug is marketed as a contraceptive (combined with low-dose EE) at a dosage of 2 mg/day.[76][78]

Through its action as a progestogen, CPA has been found to significantly increase prolactin secretion and to induce extensive lobuloalveolar development of the mammary glands of female rhesus macaques.[79] In accordance, a study found that CPA, in all cases, induced full lobuloalveolar development of the breasts in transgender women treated with the drug in combination with estrogen for a prolonged period of time.[80][81][82] Pregnancy-like breast hyperplasia was observed in two of the subjects.[82] In contrast, the same study found that men with prostate cancer treated with a non-progestogenic antiandrogen like flutamide or bicalutamide and no estrogen produced only moderate and incomplete lobuloalveolar development of the breasts.[80] Based on the above research, it was concluded by the study authors that combined estrogenic and progestogenic action is required in transgender women for fully mature female-like histologic breast development (i.e., that includes complete lobuloalveolar maturation).[80][81] Also, it was observed that lobuloalveolar maturation reverses upon discontinuation of CPA after surgical castration, similarly to the case of mammary gland involution in postpartum women, indicating that continued progestogen treatment is necessary to maintain the histology.[80] It should be noted however that although these findings may have important implications in the context of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue),[83][84][85][86] and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a type of epithelial tissue) contributes to breast size and/or shape.[87]

The action of CPA as a progestogen is responsible for its antigonadotropic effects.[53][76]


CPA has powerful antigonadotropic effects via activation of the PR.[53][21][53][76] In humans, it blunts the gonadotropin releasing hormone (GnRH)-induced secretion of gonadotropins,[88] and accordingly, markedly suppresses circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at high dosages.[citation needed] Consequently, progesterone (P4), androstenedione, T, DHT, and estradiol (E2) are also markedly lowered at high dosages, while an elevation in sex hormone-binding globulin (SHBG) and prolactin levels is observed.[89][90][91][92][93] CPA is able to lower circulating T concentrations by 70 to 80% in men at high dosages.[94] However, in spite of strong suppression of testosterone levels, CPA, at least by itself (e.g., without estrogen), is not able to reduce testosterone levels into the castrate range (<50 ng/dL), and testosterone levels may remain just above it at circulating levels of roughly 50 to 100 ng/dL.[95]

Although the reduction of sex steroid levels with CPA is predominantly mediated by its progestogenic and antigonadotropic activities, inhibition of steroidogenic enzymes by the drug may also contribute to this to some extent.[96]


Due to negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, administration of exogenous glucocorticoids such as prednisone and dexamethasone suppress the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland and the production of cortisol from the adrenal glands, resulting in adrenal suppression and atrophy and, upon discontinuation of the glucocorticoid, temporary adrenal insufficiency. Similarly, albeit relatively weakly, CPA has the ability to reduce ACTH and cortisol levels and produce adrenal gland shrinkage, as well as, upon discontinuation, adrenal insufficiency, in both animals and humans, indicating that it possesses weak glucocorticoid properties.[97][98][99][100][101][102][103] Paradoxically however, in vitro, CPA is an antagonist of the glucocorticoid receptor (GR)[55][104][105] and a suppressor of adrenal cortisol and corticosterone production by inhibiting the enzymes 3β-hydroxysteroid dehydrogenase and 21-hydroxylase,[99][106][107][108] which are antiglucocorticoid actions. This paradox may be explained by the fact that certain active metabolites of CPA, such as its major metabolite 15β-hydroxycyproterone acetate (which is present at serum levels approximately twice those of CPA in humans[8]),[109] are, contrarily, agonists of the GR,[110] and it can be assumed that their glucocorticoid actions overall significantly outweigh the simultaneous antiglucocorticoid actions of CPA. Both cyproterone and CPA, via their metabolites, have been found to possess glucocorticoid effects, and based on studies in mice, it has been suggested that CPA has approximately 1/5th the potency of prednisone as a glucocorticoid.[111]

While various studies have clearly shown reduced cortisol and ACTH levels and ACTH responsiveness in humans with CPA treatment, some studies contradict these findings and report no such effects even with high dosages.[110][112][113][114][115]

Megestrol acetate, medroxyprogesterone acetate, and chlormadinone acetate, steroidal progestins and close analogues of CPA, all similarly possess glucocorticoid properties and the potential for producing adrenal insufficiency upon their discontinuation.[116][117]


Because CPA does not bind to the ER, and because it suppresses estrogen production via its action as an antigonadotropin, the drug produces no general estrogenic effects (direct or indirect) and is potently antiestrogenic at sufficient dosages. However, androgens strongly antagonize the action of estrogen in the breasts, so CPA can produce a sole indirect estrogenic effect of slight gynecomastia in males via its action as an antiandrogen. In any case, the incidence and severity of this side effect is less than that observed with non-steroidal antiandrogens such as flutamide and bicalutamide, which, in contrast, do not lower estrogen levels (and actually can increase them).[118][119]


The pharmacokinetics of CPA are complicated due to its lipophilic nature. Although the mean elimination half-life is usually estimated to be around 40 hours, this primarily reflects its accumulation in adipose cells. Elimination from the bloodstream is considerably quicker, and the amount stored in fat may be affected by food intake. Therefore, it is recommended that CPA be given in divided doses 2–3 times per day, or in the form of a long-acting injection.

A portion of ingested CPA is metabolized by hydrolysis into cyproterone and acetic acid.[120] However, unlike many other steroid esters, CPA is not extensively hydrolyzed, and much of its pharmacological activity is attributable to its unchanged form.[46] CPA has approximately three times the potency as an antiandrogen of cyproterone;[121] in addition, cyproterone is completely devoid of progestogenic activity.[61]

CPA is metabolized by CYP3A4, forming the major active metabolite 15β-hydroxycyproterone acetate.[1][8] This metabolite circulates at concentrations approximately twice those of CPA, and has similar antiandrogen activity to that of CPA, but only 10% of the activity of CPA as a progestogen.[1][8][122][123] As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.[2]

CPA does not bind to sex hormone-binding globulin or transcortin,[124] and is instead bound by albumin (93%).[1]


CPA is also known chemically as 1,2α-methylene-6-chloro-δ6-17α-acetoxyprogesterone.[citation needed] It is acetylated derivative of 17α-hydroxyprogesterone and is structurally related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate.[citation needed]


CPA was discovered in the early 1960s, and Rudolf Wiechert, a Schering employee, together with F. Neumann in Berlin filed for a patent as "progestational agent" in 1962.U.S. Patent 3,234,093 Only one year after patent approval in 1965, Neumann published evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain".[125] During the same year, in 1966, prenatal administration of CPA in male rats was shown to cause urogenital malformations by a group in Lund, Sweden.[126] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation.

In 1970, the first human experiments with CPA began by measuring serum levels after oral administration,[127] rates of spermatogenesis, and hair growth in women. Starting in 1972, psychiatrists trialed "sexually deviant" persons with CPA.[128] In 1973, CPA was first approved in Europe, under the brand name Androcur.[129][130] In the mid-1970s, non- or weakly-progestogenic antiandrogens like spironolactone became available. Until the development of leuprolide, CPA was one of the few drugs used to treat precocious puberty.

Along with benorterone, cyproterone, and BOMT, CPA was one of the first antiandrogens to be discovered and studied clinically.[citation needed]

Society and culture[edit]

Brand names[edit]

CPA is marketed under brand names including Androcur, Cyprostat, and Siterone, among many others.[citation needed]

When CPA is used in combination with EE, it is also known as co-cyprindiol, and brand names for this formulation include Diane-35 throughout most of the world, Dianette in the United Kingdom, Bella Hexal in Germany, Diane in Sweden, and Dixi-35 in Chile.[14]


CPA is available in Europe and Canada, as well as many other places throughout the world, but is notably not available in the United States.[131]


Obsessive-compulsive disorder[edit]

CPA may be effective in the treatment of obsessive-compulsive disorder (OCD).[132] In very limited clinical research, it has been reported to be "considerably" effective in the treatment of OCD in women.[133][134]


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Further reading[edit]