Chemical compound
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Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.
Common side effects of high-dose CPA in men include gynecomastia (breast development) and feminization. In both men and women, possible side effects of CPA include low sex hormone levels, reversible infertility, sexual dysfunction, fatigue, depression, weight gain, and elevated liver enzymes. With prolonged use, brain tumors prompting surgery are common, from 5% at high doses to 2% at low doses. At very high doses in older individuals, significant cardiovascular complications can occur. Rare but serious adverse reactions of CPA include blood clots, and liver damage. CPA can also cause adrenal insufficiency as a withdrawal effect if it is discontinued abruptly from a high dosage. CPA blocks the effects of androgens such as testosterone in the body, which it does by preventing them from interacting with their biological target, the androgen receptor (AR), and by reducing their production by the gonads, hence their concentrations in the body. In addition, it has progesterone-like effects by activating the progesterone receptor (PR). It can also produce weak cortisol-like effects at very 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 and as the prototypical antiandrogen. CPA is available widely throughout the world. An exception is the United States, where it is not approved for use. 
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Medical uses.
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. Treatment dosages range from 2mg or less, to 100mg or more daily.
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 inhibitors finasteride and dutasteride. The steroidal antiandrogen and progestin chlormadinone acetate is used as an alternative to CPA in Japan, South Korea, and a few other countries.
In 2020, the European 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 of prostate carcinoma.
Birth control.
CPA is used with ethinylestradiol as a combined birth control pill to prevent pregnancy. 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. 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.
Skin and hair conditions.
Females.
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 higher doses. A birth control pill containing low-dose CPA in combination with ethinylestradiol to treat acne has been found to result in overall improvement in 75 to 90% of women, with responses approaching 100% improvement. High-dose CPA alone likewise has been found to improve symptoms of acne by 75 to 90% in women. Discontinuation of CPA has been found to result in marked recurrence of symptoms in up to 70% of women. CPA is one of the most commonly used medications in the treatment of hirsutism, hyperandrogenism, and polycystic ovary syndrome in women throughout the world.
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. The efficacy of such dosages of CPA in the treatment of hirsutism in women appear to be similar to that of spironolactone, flutamide, and finasteride. Randomized controlled trials have found that higher dosages of CPA (e.g., 20 mg/day or 100 mg/day) added cyclically to a birth control pill containing ethinylestradiol and 2 mg/day CPA were no more effective or only marginally more effective in the treatment of severe hirsutism in women than the birth control pill alone. 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. CPA has typically been combined with ethinylestradiol, but it can alternatively be used in combination with hormone replacement therapy dosages of estradiol instead. 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.
The efficacy of the combination of an estrogen and CPA in the treatment of hirsutism in women appears to be due to marked suppression of total and free androgen levels as well as additional blockade of the androgen receptor.
Males.
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. It can also halt further progression of scalp hair loss in men. Increased head hair and decreased body hair has been observed with CPA in men with scalp hair loss. However, its side effects in men, such as demasculinization, gynecomastia, sexual dysfunction, bone density loss, and reversible infertility, make the use of CPA in males impractical in most cases. In addition, lower dosages of CPA, such as 25 mg/day, have been found to be better-tolerated in men. But such doses also show lower effectiveness in the treatment of acne in men.
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. It is almost always combined with an estrogen, such as ethinylestradiol, when it is used in the treatment of PCOS in women.
Menopausal hormone therapy.
CPA is used at low doses in menopausal hormone therapy in combination with an estrogen to provide endometrial protection and treat menopausal symptoms. It is used in menopausal hormone therapy under the brand name Climen, which is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA. Climen was the first product for use in menopausal hormone therapy containing CPA to be marketed. It is available in more than 40 countries.
Transgender hormone therapy.
CPA is widely used as an antiandrogen and progestogen in feminizing hormone therapy for transgender individuals. 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. 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.
Studies have found that 10, 25, 50, and 100 mg/day CPA in combination with estrogen all result in equivalent and full testosterone suppression in transgender women. In light of risks of CPA such as fatigue, blood clots, benign brain tumors, and liver damage, the use of lower dosages of CPA may help to minimize such risks. As a result, a CPA dosage of 10mg/day and no greater is now recommended by the World Professional Association for Transgender Health (WPATH) "Standards of Care for the Health of Transgender and Gender Diverse People, Version 8" (SOC8).
CPA has an advantage over spironolactone as an antiandrogen in transgender people, as the combination of estrogen and CPA consistently suppresses testosterone levels into the normal female range whereas estrogen with spironolactone does not. 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.
Aside from adult transgender people, CPA has also been used as a puberty blocker and hence as an antiandrogen and antiestrogen to suppress puberty in transgender adolescents, although GnRH modulators are primarily used and more effective for this purpose.
Prostate cancer.
CPA is used as an antiandrogen monotherapy and means of androgen deprivation therapy in the palliative treatment of prostate cancer in men. 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. CPA has similar effectiveness to GnRH modulators and surgical castration, high-dose estrogen therapy (e.g., with diethylstilbestrol), and high-dose nonsteroidal antiandrogen monotherapy (e.g., with bicalutamide), but has significantly inferior effectiveness to combined androgen blockade with a GnRH modulator and a nonsteroidal antiandrogen (e.g., with bicalutamide or enzalutamide). 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. Due to its inferior effectiveness, tolerability, and safety, CPA is rarely used in the treatment of prostate cancer today, having largely been superseded by GnRH modulators and nonsteroidal antiandrogens. CPA is the only steroidal antiandrogen that continues to be used in the treatment of prostate cancer.
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. 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. Schröder (1993, 2002) reviewed the issue of CPA dosage and recommended a dosage of 200 to 300 mg/day for CPA as a monotherapy and a dosage of 100 to 200 mg/day for CPA in combined androgen blockade (that is, CPA in combination with surgical or medical castration). However, the combination of CPA with castration for prostate cancer has been found to significantly decrease overall survival compared to castration alone. Hence, the use of CPA as the antiandrogen component in combined androgen blockade would appear not to be advisable. When used by intramuscular injection to treat prostate cancer, CPA is used at a dosage of 300 mg once a week.
The combination of CPA with an estrogen such as ethinylestradiol sulfonate or low-dose diethylstilbestrol has been used as a form of combined androgen blockade and as an alternative to the combination of CPA with surgical or medical castration.
Sexual deviance.
CPA is used as an antiandrogen and form of chemical castration in the treatment of 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 used to reduce sexual behavior diagnosed as self-harmful, such as masochism. CPA has comparable effectiveness to medroxyprogesterone acetate in suppressing sexual urges