Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others.
It is an antiandrogen and progestin medication
It is used in the treatment of androgen-dependent conditions such as acne, excessive hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender women, and in birth control pills.
CPA has antiandrogenic activity,progestogenic activity, weak partial glucocorticoid activity, weak steroidogenesis inhibitor activity, and agonist activity at the pregnane X receptor.
CPA has progesterone-like effects by activating the progesterone receptor (PR).
It produces weak cortisol-like effects at very high doses.
In the the United States, it is not approved for use.
CPA is taken by mouth one to three times per day.
Pregnancy category X
Routes of administration
By mouth, intramuscular injection
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.
Taken by mouth one to three times per day or given by injection once or twice per week.
Drug class
Steroidal antiandrogen; Progestogen
Oral: 68–100% oral bioavailability.
Protein binding Albumin: 93%
Free: 7%
Metabolism
Hepatic (CYP3A4)
Metabolites
• 15β-OH-CPA (major)
• Cyproterone (minor)
• Acetic acid (minor)
Elimination half-life
Oral: 1.6–4.3 days
IM: 3–4.3 days
Excretion
Feces: 70%
Urine: 30%
Common side effects of high-dose CPA in men include gynecomastia and feminization.
In both men and women, possible side effects of CPA include low sex hormone levels, reversible infertility, sexual dysfunction, fatigue, depression, weight gain, and elevated liver enzymes.
At very high doses in older individuals, significant cardiovascular complications can occur.
Rare but serious adverse reactions of CPA include blood clots, liver damage, and meningiomas.
Can cause adrenal insufficiency as a withdrawal effect if it is discontinued abruptly from a high dosage.
CPA blocks the effects of androgens 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.
CPA has progesterone-like effects by activating the progesterone receptor.
It can also produce weak cortisol-like effects at very high doses.
CPA is used as a progestin and antiandrogen in hormonal birth control and in the treatment of androgen-dependent conditions:
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, and to treat early puberty.
CPA is used with ethinylestradiol as a combined birth control pill to prevent pregnancy.
CPA is used as an antiandrogen to treat androgen-dependent skin and hair conditions such as acne, seborrhea, hirsutism, scalp hair loss, and hidradenitis suppurativa in women.
Such processes are worsened by the presence of androgens, and by suppressing androgen levels and blocking their actions, CPA improves the symptoms of these conditions.
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 improves androgen related 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.
It is a commonly used medication 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 in the treatment of hirsutism in women.
Its efficacy in the treatment of hirsutism in women appear to be similar to that of spironolactone, flutamide, and finasteride.
Maintenance therapy with low doses of CPA, such as 25 mg/day, has been found to be effective in preventing relapse of symptoms of hirsutism.
The combination of an estrogen and CPA in the treatment of hirsutism in women appears causes marked suppression of total and free androgen levels as well as additional blockade of the androgen receptor.
CPA has been found to be effective in the treatment of acne in males.
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.
Its side effects in men:
demasculinization, gynecomastia, sexual dysfunction, bone density loss, and reversible infertility, use of CPA in males impractical in most cases.
CPA is used as an antiandrogen to treat high androgen levels and associated symptoms such as masculinization: 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.
CPA is used at low doses in menopausal hormone therapy in combination with an estrogen to provide endometrial protection and treat menopausal symptoms.
CPA is widely used as an antiandrogen and progestogen in feminizing hormone therapy for transgender women.
Risks of CPA: fatigue, blood clots, benign brain tumors, and liver damage, the use of lower dosages of the medication may help to minimize such risks.
CPA has also been used as a puberty blocker and hence as an antiandrogen and antiestrogen to suppress puberty in transgender youth, although now GnRH modulators are primarily used for this purpose.
In the United States, other medications with antiandrogenic effects are used to treat androgen-dependent conditions instead: GnRH modulators, nonsteroidal antiandrogens like flutamide and bicalutamide, the diuretic and steroidal antiandrogen spironolactone, the progestin medroxyprogesterone acetate, and the 5α-reductase inhibitors finasteride and dutasteride.
CPA is used as an antiandrogen monotherapy and means of androgen deprivation therapy in the palliative treatment of prostate cancer.
CPA is rarely used in the treatment of prostate cancer today, having largely been superseded by GnRH modulators and nonsteroidal antiandrogens.
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.
Decreases sex drive and sexual arousal and producing sexual dysfunction.
Can be used to reduce sex drive in individuals with inappropriate sexual behaviors, such as people with intellectual disability and dementia.
CPA 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.
CPA is less effective than GnRH modulators like leuprorelin and has more side effects in suppressing sexual urges and function.
CPA significantly decreases sexual fantasies and sexual activity in 80 to 90% of men with paraphilias.
It decreases the rate of reoffending in sex offenders from 85% to 6%, with most of the reoffenses being committed by individuals were not compliant.
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, but it is not able to completely suppress puberty: now superseded by GnRH agonists
It is useful in the treatment of hot flashes, for instance due to androgen deprivation therapy for prostate cancer.
CPA is useful for suppressing the testosterone flare at the initiation of GnRH agonist therapy.
Higher-dose formulations are used to treat prostate cancer and certain other androgen-related indications while the low-dose formulations which also have an estrogen are used as combined birth control pills and are used in menopausal hormone therapy for the treatment of menopausal symptoms.
Contraindications of CPA include:
Hypersensitivity to CPA
Pregnancy, lactation, and breastfeeding
Puberty, except if being used to treat precocious puberty or delay puberty.
Liver diseases and liver dysfunction
Chronic kidney disease
Dubin–Johnson syndrome and Rotor syndrome
History of jaundice or persistent pruritus during pregnancy
History of herpes during pregnancy
Previous or existing liver tumors
Previous or existing meningioma, hyperprolactinemia, or
Wasting syndromes
Severe depression
Previous or existing thromboembolic processes, as well as stroke and myocardial infarction
Severe diabetes with vascular changes
Sickle-cell anemia
CPA is generally well-tolerated and has a mild side-effect profile:
hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis, breast changes such as breast tenderness, breast enlargement, and gynecomastia in men, emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes.
Weight gain can occur with CPA.
Some of the side effects of CPA can be improved or fully prevented combined with an estrogen to prevent estrogen deficiency.
Contraindications of CPA include:
Hypersensitivity, pregnancy, lactation, and breastfeeding, puberty except to treat precocious puberty or delay puberty,
Liver diseases and liver dysfunction
Chronic kidney disease
Dubin–Johnson syndrome and Rotor syndrome
History of jaundice or persistent pruritus during pregnancy
History of herpes during pregnancy
Previous or existing liver tumors
Previous or existing meningioma
Hyperprolactinemia, or prolactinoma
Wasting syndromes
Severe depression
Previous or existing thromboembolic processes.
Severe diabetes with vascular changes
Sickle-cell anemia
CPA is generally well-tolerated and has a mild side-effect profile regardless of dosage when it is used in combination with an estrogen in women.
Side effects of CPA: hypogonadism and associated symptoms such as demasculinization, sexual dysfunction, infertility, and osteoporosis, breast changes such as breast tenderness, breast enlargement, and gynecomastia, emotional changes such as fatigue and depression; and other side effects such as vitamin B12 deficiency, weak glucocorticoid effects, and elevated liver enzymes.
Weight gain occurs with CPA when it is used at high doses.
At high doses in aged men with prostate cancer, CPA can cause cardiovascular side effects.
CPA can produce blood clots, liver toxicity, excessively high prolactin levels, and meningiomas and prolactinomas.
When discontinuing high dose CPA adrenal insufficiency as a withdrawal effect can occur.
Very common (≥10%):
Headache
Tiredness
Psychiatric disorders
Decreased libido in men
Erectile dysfunction
Reduced ejaculate volume
Reproductive system and breast disorders
Reversible inhibition of spermatogenesis
Inhibition of ovulation and reversible infertility
Elevated liver enzymes
Inhibitors and inducers of the cytochrome P450 enzyme CYP3A4 may interact with CPA.[
CYP3A4 inhibitors include ketoconazole, itraconazole, clotrimazole, and ritonavir.
Strong CYP3A4 inducers include rifampicin, rifampin, phenytoin, carbamazepine, phenobarbital, and St. John’s wort.
Certain anticonvulsant medications can reduce levels of CPA, by as much as 8-fold.
CPA has antigonadotropic effects, and is able to suppress fertility and sex-hormone levels in both males and females.
CPA can be taken by mouth or by injection into muscle.
It has near-complete oral bioavailability
It is highly bound to albumin and is metabolized in the liver by hydroxylation and conjugation.
It has 15β-hydroxycyproterone acetate (15β-OH-CPA) as a single major active metabolite, has a long elimination half-life of about 2 to 4 days.
15β-hydroxycyproterone acetate is excreted in feces primarily and to a lesser extent in urine.
It is marketed in almost every developed country, with the notable major exceptions of the United States and Japan.
There is an increased risk of developing intracranial meningiomas after prolonged use of the hormonal product cyproterone acetate (BMJ).
Among women using cyproterone acetate, the rate of meningiomas was 23.8 per 100,000 person years vs. 4.5 per 100,000 in the control group: a sevenfold increased risk of meningioma.
Confirms the risk but also the measurement of the dose-effect relationship, the decrease in the risk after stopping use, and the preferential anatomical localization of meningiomas.
A large proportion of meningiomas involve the skull base, which is of considerable importance because skull base meningioma surgery is one of the most challenging forms of surgery and is associated with a much higher risk than surgery for convexity meningiomas.
It is recommended that cyproterone products with daily doses of 10 mg or more be restricted because of the risk of developing meningioma.
Studies document risk for high-dose cyproterone acetate in men, women, and transgender people, and the absence of any observed risk for low-dose cyproterone acetate use in women.
A dose-effect relation, with a higher risk associated with a higher cumulative dose.
The hazard ratio was not significant for exposure to less than 12 g of cyproterone acetate.
The risk of meningioma decreased noticeably after treatment was stopped.
At 1 year after discontinuing treatment, the risk of meningioma in the exposed group was 1.8-fold higher than in the control group.
Patients who have used high-dose cyproterone acetate for at least 3-5 years about the increased risk of intracranial meningioma.
The incidence of meningiomas are more frequent in women than men, and there is an association between breast cancer and the occurrence of meningiomas.
Progesterone and androgen receptors have been found in meningiomas.
Hormonal therapy to inhibit estrogen or progesterone receptors has not produced any decrease in meningiomas growth.