|Trade names||Androcur, Androcur Depot, Cyprostat, Siterone, others|
|Synonyms||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|
|By mouth, intramuscular injection|
|Drug class||Steroidal antiandrogen; Progestin; Progestogen; Progestogen ester; Antigonadotropin|
• 15β-OH-CPA (major)|
• Cyproterone (minor)
• Acetic acid (minor)
Oral: 1.6–4.3 days|
IM: 3–4.3 days
|Chemical and physical data|
|Molar mass||416.942 g/mol|
|3D model (JSmol)|
|Melting point||200 to 201 °C (392 to 394 °F)|
Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol (EE) under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication which is used in the treatment of androgen-dependent conditions like acne, excessive hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender women, and in birth control pills. It is formulated and used both alone and in combination with an estrogen and is available for use both by mouth and by injection into muscle. CPA is taken by mouth one to three times per day and is given by injection once or twice per week.
Common side effects of high-dose CPA in men include gynecomastia (breast development) and feminization. In both men and women, side effects of CPA include low sex hormone levels, reversible infertility, sexual dysfunction, mental symptoms like depression, fatigue, and irritability, vitamin B12 deficiency, and elevated liver enzymes. At very high doses, cardiovascular complications can occur. Rare but serious adverse reactions of CPA include blood clots, liver damage, and certain types of benign 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 like 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 and hence their concentrations in the body. In addition, it has progesterone-like effects by activating the progesterone receptor (PR). It also has weak cortisol-like effects at high doses.
CPA was discovered in 1961. It was originally developed as a progestin. In 1965, the antiandrogenic effects of CPA were discovered. CPA was first marketed, as an antiandrogen, in 1973, and was the first antiandrogen to be introduced for medical use. A few years later, in 1978, CPA was introduced as a progestin in a birth control pill. It has been described as a "first-generation" progestin. CPA is available widely throughout the world. An exception is the United States, where it is not approved for use. The medication has been described as the prototypical antiandrogen.
CPA is used as a progestin and antiandrogen in hormonal birth control and in the treatment of androgen-dependent conditions. 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. It is used both at low doses and at high doses.
In the United States, where CPA is not available, other medications with antiandrogenic effects are used to treat androgen-dependent conditions instead. 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 inhibitor finasteride. The steroidal antiandrogen and progestin chlormadinone acetate is used as an alternative to CPA in Japan, South Korea, and a few other countries.
CPA is used together with EE as a combined birth control pill to prevent pregnancy in women. This birth control combination has been available since 1978. The formulation is taken once daily for 21 days, followed by a 7-day free interval. CPA has also been available in combination with estradiol valerate (brand name Femilar) as a combined birth control pill in Finland since 1993.
Skin and hair conditions
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. 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 high doses. A birth control pill containing low-dose CPA in combination with EE to treat acne has been found to result in overall improvement in 75 to 90% of women, with responses approaching 100% improvement.
High androgen levels
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.
Transgender hormone therapy
CPA is widely used as an antiandrogen and progestogen in feminizing hormone therapy for transgender women. It has also been used as a puberty blocker and hence as an antiandrogen and antiestrogen to suppress puberty in transgender youth.
CPA is used as an antiandrogen monotherapy and means of androgen deprivation therapy in the palliative treatment of prostate cancer in men. It can significantly extend life in men with the disease. However, CPA is not commonly used for this indication nowadays, having been largely superseded by newer medications such as GnRH modulators and nonsteroidal antiandrogens like bicalutamide and enzalutamide. CPA is used at high doses by mouth or by intramuscular injection to treat prostate cancer.
CPA is used as an antiandrogen and form of chemical castration in the treatment of forms of sexual deviance such as paraphilias and hypersexuality in men. It is used to treat sex offenders. The medication is approved in more than 20 countries for this indication and is predominantly employed in Canada, Europe, and the Middle East. 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. The medication is also useful for treating self-harmful sexual behavior, such as masochism. 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.
High-dose CPA significantly decreases sexual fantasies and sexual activity in 80 to 90% of men with sexual deviance. 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. 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. When only a partial reduction in sexuality is desired, 50 mg/day CPA can be useful. 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.
CPA is used as an antiandrogen and antiestrogen to treat precocious puberty in boys and girls. However, it is not fully satisfactory for this indication because it is not able to completely suppress puberty. For this reason, CPA has mostly been superseded by GnRH agonists. However, it is still useful for preventing the testosterone flare at the start of GnRH agonist initiation in boys. CPA is not satisfactory for gonadotropin-independent precocious puberty.
CPA is available in the form of oral tablets alone (10 mg, 50 mg, 100 mg) or in combination with ethinylestradiol (EE) or estradiol valerate (low-dose; 2 mg CPA) and in the form of ampoules for intramuscular injection (100 mg/mL, 300 mg/3 mL; brand name Androcur Depot). The high-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.
Use of CPA during pregnancy is contraindicated.
Common side effects of CPA include hypogonadism and associated symptoms like demasculinization, sexual dysfunction, infertility, and osteoporosis, breast changes like gynecomastia, mental changes like depression, anxiety, fatigue, and suicidal ideation, vitamin B12 deficiency, glucocorticoid side effects like stretch marks, and elevated liver enzymes. At very high dosages, CPA can cause cardiovascular side effects. Rarely, CPA can cause blood clots, liver damage, excessively high prolactin levels, prolactinomas, and meningiomas. Upon discontinuation at high dosages, CPA can have withdrawal effects, namely adrenal insufficiency. Some of the side effects of CPA can be improved if it is combined with an estrogen, which prevents estrogen deficiency.
Low hormone levels
Side effects in men resulting from the antiandrogenic and antigonadotropic properties of CPA include physical demasculinization, sexual dysfunction (including loss of libido and erectile dysfunction), impaired spermatogenesis, absence of ejaculate, and reversible infertility. 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. 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. CPA can also sometimes cause breast changes in men including gynecomastia, breast tenderness, and galactorrhea. Rates of gynecomastia of 7 to 13% have been reported.
CPA has been associated with a potential side effect of depression in both men and women. It has been reported that as many as 20 to 30% of women treated with the drug for hirsutism (dosage range 25–100 mg) may show depressive symptoms. Also, a study found that around 20% of women treated with Dianette (which contains only 2 mg CPA) for contraceptive purposes developed depression. 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)). The depressive effects of CPA may be related to its glucocorticoid, antiandrogen, or antigonadotropic effects, as glucocorticoids, antiandrogens (in men), and GnRH analogues have all been associated with depression. Vitamin B12 deficiency induced by CPA might also or alternatively be a critical factor. Because of the side effect of depression, CPA should be used with caution in individuals with a history of the condition, especially if severe.
Vitamin B12 deficiency
High-dose CPA treatment has been found to produce vitamin B12 deficiency. Low-dose (2 mg/day) CPA in combination with EE has also been associated with vitamin B12 deficiency. It is notable that vitamin B12 deficiency is associated with depression, anxiety, irritability, and fatigue via depletion of central monoamine neurotransmitters, and it has been suggested that this may be involved in the adverse neuropsychiatric consequences commonly observed with CPA therapy. Serum vitamin B12 monitoring and supplementation as necessary has been recommended during CPA treatment.
At the very high dosages (e.g., 300 mg/day) used to treat men with prostate cancer, CPA is associated with cardiovascular side effects including coagulation changes and blood clots (5%), fluid retention (4%), ischemic cardiomyopathy (4–40%), and undesirable effects on serum lipid profiles. Severe cardiovascular complications occur in approximately 10% at such dosages and are sometimes fatal.
The most serious potential side effect of CPA is hepatotoxicity. 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. Clinical features may include jaundice, fatigue, nausea, elevated liver enzymes, hepatic necrosis and inflammation, and features of hepatic decompensation. 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. The hepatotoxicity of CPA is related to its C1α,2α methylene group.
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. A study of 2,506 patients given 18 to 136 mg/day for less than 48 months per patient reported a rate of 9.6%. 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. Yet another study of 105 patients found a hepatotoxicity rate of 9.5%, with serious hepatic injury occurring in 3.8%. 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. 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. 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. As such, the prognosis of CPA-induced liver failure is death.
The risk of hepatotoxicity and death associated with CPA treatment is reportedly the reason that CPA has not been approved by the FDA for use in the United States. Patients being treated with high-dose CPA should be closely monitored with liver function tests. 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. 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.
Used alone, CPA does not appear to have a significant effect on blood clotting factors, but in combination with EE, as in combined oral contraceptives, presents an increased risk of deep vein thrombosis. 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. At least four cases of fatal venous thromboembolism have been attributed to low-dose CPA in combination with EE. The glucocorticoid and progestogenic activities of CPA are thought to be involved in the increased risk of thrombosis with CPA in combination with estrogens.
Benign brain tumors
When used in combination with an estrogen, high-dose CPA has been associated, albeit very rarely, with two different types of benign brain tumors: prolactinomas and meningiomas. The combination has been associated with a 400-fold increased incidence of hyperprolactinemia (high prolactin levels) in transgender women. Hyperprolactinemia caused by the combination is related to prolactinomas, benign tumors of the pituitary gland that secrete prolactin. Estrogen alone has been associated only with single case reports of prolactinoma in this population. The combination has also been associated with the incidence and aggravation of meningiomas, usually-benign tumors of the meninges. For this reason, high-dose CPA is contraindicated in people with meningioma or a history of meningoma. Benign brain tumors caused by high-dose CPA in combination with an estrogen can cause visual disturbances or in severe cases complete blindness due to compression of the optic nerve and/or chiasm.
Abrupt withdrawal of CPA can be harmful, and the package insert from Schering AG recommends the daily dose be reduced by no more than 50 mg at intervals of several weeks. The 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. Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production.
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 relatively safe in acute overdose. It is used at very high doses of up to 300 mg/day by mouth and 700 mg per week by intramuscular injection. For comparison, the dose of CPA used in birth control pills is 2 mg/day. There have been no deaths associated with CPA overdose. There are no specific antidotes for CPA overdose, and treatment should be symptom-based. Gastric lavage can be used in the event of oral overdose within the last 2 to 3 hours.
Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may interact with CPA. 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. Certain anticonvulsant medications can substantially reduce levels of CPA, by as much as 8-fold.
CPA is known to possess the following pharmacological activity:
- Androgen receptor (AR) antagonist/very weak partial agonist (IC50 = 57 nM)
- Progesterone receptor (PR) agonist (Kd = 15 nM; IC50 = 79 nM)
- Glucocorticoid receptor (GR) antagonist (Kd = 45 nM; IC50 = 360 nM)
- Pregnane X receptor (PXR) agonist (EC50 = 1.6 μM) (and thus CYP3A4 and P-glycoprotein inducer)
- Weak inhibitor of 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase/17,20-lyase, and 21-hydroxylase
|PR (promegestone = 100%), AR (metribolone = 100%), ER (E2 = 100%), GR (DEXA = 100%), MR (aldosterone = 100%). Source:|
CPA is a potent competitive antagonist of the androgen receptor (AR), the biological target of androgens such as testosterone and dihydrotestosterone (DHT). It is reportedly the most potent AR antagonist of the steroidal antiandrogens, out of hundreds of other compounds. In accordance, CPA has the highest antiandrogenic activity of any other clinically used progestin. CPA directly blocks endogenous androgens like testosterone and DHT from binding to and activating the AR, and thus prevents them from exerting their androgenic effects, such as masculinization and prostate gland growth, in the body.
The antiandrogenic activity of CPA is dose-dependent. Although CPA is a very potent antiandrogen, high doses of CPA are nonetheless required for clinically important AR antagonism. The clinical antiandrogenic efficacy of birth control pills containing CPA, which have only low doses of CPA in them, often can't be distinguished from that of birth control pills containing other progestins. It is likely that the antiandrogenic effects of CPA-containing birth control pills are due mostly to the EE component, rather than the small doses of CPA present in them. A dosage of 100 mg/day CPA can achieve a 65 to 70% reduction in sebum excretion rate in men within 4 weeks of treatment, but dosages of 10 mg/day CPA or less are said to have a negligible effect. It has been stated that oral doses of CPA of at least 300 mg/day may achieve a combined androgen blockade action in the treatment of prostate cancer. Although higher doses of CPA are necessary for adequate systemic AR antagonistic activity, it is notable that even low doses of oral CPA would appear to be able to significantly antagonize AR signaling in the liver in women. This is probably related to the hepatic first-pass effect of oral administration, and is evidenced by the fact that whereas combined birth control pills containing CPA increase SHBG levels by 300 to 400%, combined birth control pills containing various other progestins, with either androgenic or antiandrogenic activity, increase SHBG levels by only 50 to 300%. (Estrogens stimulate hepatic SHBG production while androgens inhibit hepatic SHBG production, and vice-versa for their antagonists.) The antiandrogenic activity of CPA may also be responsible for the relatively greater risk of venous thromboembolism with CPA-containing birth control pills compared to those containing other progestins.
In rats, a dosage of CPA of 25 mg/kg/day results in complete regression of prostate gland growth in gonadally intact males. The equivalent dosage in humans, on the basis of body surface (conversion factor from rat to human of 6), is 4 mg/kg/day, or approximately 300 mg/day CPA for a 75 kg (165 lb) man. Other techniques for determining the dosage of CPA have validated this extrapolation, for instance affinity studies and prostatic CPA levels. The affinity of CPA for the AR is around 20-fold lower than that of DHT, and an excess of CPA levels of around 20 to 30 times those of DHT would hence be expected to maximally neutralize androgen signaling. In accordance, it has been experimentally determined that a 3- to 10-fold excess of CPA can inhibit the effects of an "androgen" (probably testosterone or DHT) by 50%. High-dose CPA has been found to achieve prostatic levels that are at least 30-fold those of DHT. One study found that levels of CPA in the prostate gland in men being treated with 200 mg/day oral CPA were about 28 times those of DHT.
In accordance with such findings, high-dose CPA shows equivalent effects on the prostate gland in men as high-dose diethylstilbestrol or buserelin, which both achieve castrate levels of testosterone. However, a lower dosage of 50 mg/day CPA has been found to produce a reduction in prostate volume in men with benign prostatic hyperplasia that is reportedly comparable to that observed with surgical or medical castration. In accordance, the dosage of CPA that achieves complete inhibition of the secretory function of the healthy prostate gland is around 50 to 100 mg/day, which is less than the dosage of 200 to 300 mg/day CPA that is used to treat prostate cancer. It has been said that in combined androgen blockade regimens with castration and CPA as the AR antagonist for prostate cancer, due to the marked reduction in androgen levels, lower dosages of CPA than those used as a monotherapy would seem to be equally effective. Relative to the 200 to 300 mg/day dosage of CPA used as a monotherapy in prostate cancer, the recommended dosage in combined androgen blockade is 100 to 200 mg/day, which it has been said should be more than necessary to inhibit the effects of the adrenal androgens that remain in castrated men.
Significant spermatogenesis occurs with 50 mg/day CPA, but is significantly reduced compared to normal. At a dosage of 200 mg/day, CPA has been found to produce azoospermia (sperm count of less than 1 million/mL) in men within 8 to 10 weeks of treatment. However, fertility is generally lost even at a lower dosage of CPA of 100 mg/day because there is complete inhibition of the accessory sex glands and hence an absence of semen production and ejaculate upon orgasm. Ejaculate volume decreases to almost zero after 6 weeks of high-dose CPA therapy. The effects of CPA on fertility are completely reversible. This has been demonstrated in clinical studies of male adolescents and adults treated with CPA continuously for 6 to 7 years. The antiandrogenic effects of CPA in general appear to be greater than those of surgical or medical castration; high-dose CPA therapy greatly reduces libido and erectile potency and results in an absence of ejaculate, whereas in castrated adult men there is relatively little loss of sex drive and erectile function in most cases and it is still possible to produce ejaculate. This is in spite of a much greater reduction in androgen levels with surgical or medical castration than with CPA, which demonstrates the potent AR antagonistic activity of CPA.
CPA, like spironolactone and other steroidal antiandrogens such as chlormadinone acetate and megestrol acetate, is actually not a pure antagonist of the AR – that is, a silent antagonist – but rather is a very weak partial agonist. Clinically, CPA generally functions purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as testosterone and DHT from interacting with the receptor and thus its net effect is virtually always to lower physiological androgenic activity. But unlike silent antagonists of the AR like nonsteroidal antiandrogens such as flutamide, bicalutamide, and enzalutamide, CPA, by virtue of its slight intrinsic activity at the AR, may be unable to abolish androgenic activity in the body, which may persist to an extent in some tissues such as the prostate gland. 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. As a result, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to nonsteroidal antiandrogens with a silent antagonist profile at the AR. Indeed, CPA has never been found to extend life in prostate cancer patients when added to castration relative to castration alone, unlike nonsteroidal antiandrogens. In any case, the very weak androgenic activity of CPA and its significance in humans has been contested.
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. This is known as antiandrogen withdrawal syndrome.
CPA may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting. 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.
In addition to its AR antagonistic activity and suppression of gonadal sex-hormone production, high-dose CPA has been found to suppress the levels of adrenal androgens such as dehydroepiandrosterone sulfate (DHEA-S), which is due to exertion of negative feedback by CPA on adrenocorticotropic hormone (ACTH) secretion via the glucocorticoid activity of CPA.
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 nonsteroidal antiandrogens such as flutamide and bicalutamide, which, in contrast, do not lower estrogen levels (and actually can increase them).
CPA is a highly potent progestogen. It is described as the most potent progestin of the 17α-hydroxyprogesterone group, being about 1,200-fold more potent than hydroxyprogesterone acetate, 12-fold more potent than medroxyprogesterone acetate, and 3-fold more potent than chlormadinone acetate in animal bioassays. Based on results in the animal bioassays, CPA has also been said to be the most potent progestin known, with 1,000 times the potency of progesterone. With oral administration in humans however, CPA is distinctly less potent as a progestogen than various other progestins such as the 19-nortestosterone derivatives. The effective dosage needed to inhibit ovulation in women (i.e., to act as a contraceptive) is 1 mg/day, and the medication is marketed as a contraceptive (combined with low-dose EE) at a dosage of 2 mg/day. For comparison, the ovulation-inhibiting dosage of levonorgestrel is 50 µg/day. CPA is said to be equipotent as a progestogen and antiandrogen.
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. 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. Pregnancy-like breast hyperplasia was observed in two of the subjects. 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 moderate but incomplete lobuloalveolar development of the breasts. 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). 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. 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), and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a type of epithelial tissue) contributes to breast size or shape.
CPA has potent antigonadotropic effects via activation of the PR. It blunts the gonadotropin releasing hormone (GnRH)-induced secretion of gonadotropins, and accordingly, markedly suppresses circulating levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) at sufficiently high dosages. Consequently, levels of progesterone, androstenedione, testosterone, DHT, and estradiol are also markedly lowered at sufficiently high dosages, while an elevation in sex hormone-binding globulin (SHBG) and prolactin levels is observed. CPA is able to lower circulating testosterone concentrations by 70 to 80% in men at sufficiently high dosages. However, in spite of strong suppression of testosterone levels, CPA, at least by itself (e.g., without estrogen), is not usually able to reduce testosterone levels into the castrate/female range (<50 ng/dL) at any dosage, and testosterone levels generally remain just above it at circulating levels of roughly 50 to 100 ng/dL. CPA has been found to maximally suppress testosterone and estradiol levels in young men within 7 days of continuous administration. Following discontinuation of CPA, the recovery of testosterone levels is variable and may require 14 days to 6 months for completion.
Oral CPA has been studied at low dosages of 5 to 20 mg/day as a potential male hormonal contraceptive. A dosage of as low as 10 mg/day oral CPA was found to suppress circulating testosterone levels in men by 50 to 70%. For comparison, the suppression of circulating testosterone levels in men with a high dosage of 100 mg/day oral CPA was 77% and with a very high dosage of 300 mg/week intramuscular CPA was 76%. Another study found no difference in suppression of circulating testosterone levels in transgender women by the combination of estrogen and 25 mg/day oral CPA (95% suppression) and the combination of estrogen and 50 mg/day oral CPA (94% suppression). The estrogen used was moderate-dose oral or transdermal estradiol (mean 3.3 mg/day oral, 3.4 g/day gel, 95.6 µg/day patches).
A high dosage of CPA given for 7 days prior to initiation of GnRH agonist therapy was found to prevent the GnRH agonist-induced flare in testosterone levels. CPA should be given continuously for at least a week prior to GnRH agonist initiation for an optimal preventative effect on the testosterone flare.
CPA is much more potent than nonsteroidal antiandrogens like flutamide and bicalutamide in gonadally intact male animals, which is due to its antigonadotropic effects and consequent suppression of testosterone levels. Conversely, nonsteroidal antiandrogens are relatively more efficacious than CPA in castrated animals, due to their superior AR antagonistic activity.
CPA is an agonist of the glucocorticoid receptor (GR), and has weak and partial glucocorticoid activity at high doses. In animals, CPA suppresses the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland, suppresses the production of corticosteroids like cortisol and corticosterone by the adrenal cortices, and decreases the weights of the adrenal glands and thymus. Conversely however, CPA shows no anti-inflammatory or eosinophilic effects in animals. As such, CPA, as well as related antiandrogens, show only some of the typical effects of glucocorticoids. Clinically, the glucocorticoid effects of CPA appear to be relevant only at high doses in people with small body sizes (CPA exposure of more than 80–100 mg/m2), namely in the treatment of children with precocious puberty. No signs of secondary adrenal insufficiency have been observed with CPA.
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. Paradoxically however, in vitro, CPA is an antagonist of the glucocorticoid receptor (GR) and a suppressor of adrenal cortisol and corticosterone production by inhibiting the enzymes 3β-hydroxysteroid dehydrogenase and 21-hydroxylase, 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), are, contrarily, agonists of the GR, 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.
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.
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.
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). 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 or its effectiveness in the treatment of cluster headaches.
The oral bioavailability of CPA is 88 to 100%. The absorption of oral CPA is slow but complete, and the medication is not subject to a significant first-pass effect. The mean absorption half-life of oral CPA is about 1.5 hours. Steady-state levels of CPA occur with oral CPA after about 8 days of continuous administration, with a 2- to 3-fold gradual accumulation in CPA levels. Oral CPA is taken daily and intramuscular CPA is administered weekly or biweekly.
Following a single low oral dose of 2 mg CPA in combination with 35 or 50 µg EE in premenopausal women, mean peak levels of CPA of 7.2 to 15.2 ng/mL (17–36.5 nmol/L) have been recorded after 1.6 to 3.7 hours. In healthy men, a single high oral dose of 100 mg CPA produced maximal CPA levels of 254 ng/mL (609 nmol/L) after 2.6 hours. Similarly, in healthy young women, a single high oral dose of 100 mg CPA resulted in peak CPA levels of 255 ng/mL (612 nmol/L) within 2 to 3 hours. During continuous treatment with high oral doses of CPA in women with hirsutism, levels of CPA were 199 to 228 ng/mL (477–547 nmol/L) with 50 mg/day CPA and were 436 to 520 ng/mL (1050–1250 nmol/L) with 100 mg/day CPA.
After a single intramuscular injection of 300 mg CPA in healthy young women, maximal levels of CPA of 191 ng/mL (458 nmol/L) occurred after 2 to 3 days. During continuous weekly intramuscular injections of CPA in men with prostate cancer, mean levels of CPA roughly doubled from 170 ng/mL (408 nmol/L) after the first injection to 310 ng/mL (744 nmol/L) after the fifth injection, and was projected to increase to 350 to 400 ng/mL (840–960 nmol/L) after around 8 to 12 injections. The area-under-the-curve (AUC; total exposure) levels of CPA with 100 mg/day oral CPA and 300 mg/week intramuscular CPA may be approximately equivalent.
With oral CPA, there is a probable distribution phase of CPA into tissues which lasts about 12 hours and has a half-life of 3 hours. CPA is very lipophilic, and it is sequestered into fat, which provides a depot effect. CPA crosses the blood–brain barrier, which is evidenced by the suppression of gonadotropin secretion that is observed during therapy with it (the site of action of this effect being the pituitary gland, a part of the brain). In terms of plasma protein binding, CPA does not bind to SHBG or corticosteroid-binding globulin and is instead bound exclusively to albumin (93%), with the remainder (7%) circulating free or unbound. The affinity of CPA for SHBG is very low at about 0.006% of that of testosterone or DHT.
CPA is metabolized primarily by hydroxylation via CYP3A4, forming the major active metabolite 15β-hydroxycyproterone acetate. This metabolite circulates at concentrations approximately twice those of CPA, and has similar antiandrogen activity to that of CPA but only 10% of its activity as a progestogen. As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.
A portion of ingested CPA is metabolized by hydrolysis into cyproterone and acetic acid. However, unlike many other steroid esters, CPA is not extensively hydrolyzed, and much of the pharmacological activity of the drug is attributable to CPA itself in its unchanged form. Cyproterone has approximately one-third the potency of CPA as an antiandrogen and is devoid of progestogenic activity.
The elimination half-life of oral CPA is relatively long at approximately 1.6 to 1.8 days (38 to 43 hours), but possibly as long as 4.3 days (100 hours). The elimination half-life of CPA is prolonged in obese patients, which may be due to relatively greater storage of CPA in fat. The elimination half-life of CPA is also longer in older individuals; it is approximately twice as long in elderly men than in younger men (95 hours and 45 hours, respectively). When given via depot intramuscular injection, the medication has an elimination half-life of 3 to 4.3 days.
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. It is structurally related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate.
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. The antiandrogenic activity of CPA was discovered shortly thereafter. CPA was initially developed as a progestogen for the prevention of threatened abortion. As part of its development, CPA was assessed for androgenic activity to ensure that it would not produce teratogenic effects in female fetuses. It was administered to pregnant rats and its effects on the rat fetuses were studied. However, the experiment was complicated by the fact that all of the rat pups born appeared to be female. After 20 female rat pups in a row had been counted however, it was clear that this was no coincidence. The rat pups were further evaluated and it was found that, in terms of karyotype, about 50% were actually males. CPA had feminized the male rat pups, and the antiandrogenic activity of CPA had been discovered. A year after patent approval in 1965, Neumann published the first evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain". During the same year, in 1966, a publication by a group in Lund, Sweden described for the first time that prenatal exposure to CPA caused urogenital malformations in male rats. 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, rates of spermatogenesis, and hair growth in women. Starting in 1972, psychiatrists trialed "sexually deviant" persons with CPA. In 1973, CPA was first approved in Europe, under the brand name Androcur. Until the development of leuprolide, CPA was one of the few drugs used to treat precocious puberty. CPA was first marketed in combination with EE as an oral contraceptive in 1978 under the brand name Diane.
Along with the steroidal benorterone (17α-methyl-B-nortestosterone; SKF-7690), cyproterone, BOMT (Ro 7-2340), and trimethyltrienolone (R-2956) and the nonsteroidal flutamide and DIMP (Ro 7-8117), CPA was one of the first antiandrogens to be discovered and studied.
Society and culture
The English and generic name of CPA is cyproterone acetate and this is its USAN, BAN, and JAN. The English and generic name of unacetylated cyproterone is cyproterone and this is its INN and BAN, while cyprotérone is the DCF and French name and ciproterone is the DCIT and Italian name. The name of unesterified cyproterone in Latin is cyproteronum, in German is cyproteron, and in Spanish is ciproterona. 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, cyproteronacetaat in Dutch, and ciproteron acetat in Slavic.
CPA is marketed under brand names including Androcur, Androcur Depot, Androcur-100, Androstat, Asoteron, Cyprone, Cyproplex, Cyprostat, Cysaxal, Imvel, and Siterone. When CPA is formulated in combination with EE, 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. CPA is also marketed in combination with estradiol valerate as Climen, Climene, Elamax, and Femilar.
CPA is widely available throughout the world, and is marketed in almost every advanced country, with the notable major exceptions of the United States and Japan. In Japan, the closely related medication chlormadinone acetate is used instead. CPA is marketed both alone and in combination with EE or estradiol valerate. Specific places in which CPA is marketed include the United Kingdom, elsewhere throughout Europe, Canada, Australia, New Zealand, South Africa, Latin America, Asia.
Progestins in birth control pills are sometimes grouped by generation. 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". 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.
CPA has been studied for use as a potential male hormonal contraceptive in combination with testosterone in men. CPA was under development by Barr Pharmaceuticals in the 2000s for the treatment of hot flashes in prostate cancer patients in the United States. It reached phase III clinical trials for this indication and had the tentative brand name CyPat but development was ultimately discontinued in 2008. CPA has been studied as a form of androgen deprivation therapy for the treatment of benign prostatic hyperplasia (enlarged prostate). CPA is not satisfactorily effective as an antiandrogen when used as a topical medication.
CPA has been investigated for use in reducing aggression and self-injurious behavior via its antiandrogenic effects in conditions like autism spectrum disorders and dementias like Alzheimer's disease. CPA may be effective in the treatment of obsessive–compulsive disorder (OCD). In very limited clinical research, it has been reported to be "considerably" effective in the treatment of OCD in women. CPA has been studied in the treatment of cluster headaches in men.
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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 . 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].
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