Cyproterone Acetate: Antiandrogen with Progestational Component in Hirsutism, Acne and Prostate Cancer
Cyproterone acetate (CPA) is a synthetic steroid hormone with antiandrogenic and progestational activity. In Germany, it has been approved since 1973 and is marketed under brand names such as Androcur, Diane 35 (in fixed combination with ethinyl estradiol), and numerous generics. The active substance competitively occupies the androgen receptor both centrally and peripherally and simultaneously reduces pituitary secretion of LH and FSH, thereby lowering endogenous testosterone production.
Cyproterone acetate has a checkered history. High-dose use in men (prostate cancer, hypersexuality) has been established for decades. In women, the active substance is used at low doses within hormonal contraceptives against androgenetic acne and mild hirsutism. Since 2020, however, the EMA has significantly restricted its use following increased reports of intracranial meningiomas at cumulatively high doses. CPA exemplifies how risk assessments over decades can lead to fundamentally new therapeutic recommendations.
Mechanism of Action
Cyproterone acetate possesses two pharmacologically relevant effects. First, it binds competitively to the androgen receptor in target tissues such as sebaceous glands, hair follicles, and prostate, blocking the binding of testosterone and dihydrotestosterone and suppressing their biological effects. Second, CPA acts as a progesterone receptor agonist on the hypothalamus and pituitary gland, inhibiting GnRH and thus LH and FSH secretion. The result is a reduction in gonadal testosterone production by up to 75 percent.
In women, this combined effect leads to improvement of androgenized skin manifestations such as severe acne, seborrhea, and mild hirsutism. In men, CPA reduces libido, reduces spermatogenesis, and is the basis for chemical castration in metastatic prostate cancer or in the treatment of paraphilic disorders.
Pharmacokinetically, CPA is hepatically metabolized (predominantly CYP3A4) and eliminated via feces. The half-life is approximately 38 hours, allowing once-daily administration.
Indications
- Severe androgenetic acne and moderate hirsutism in women: in combination with ethinyl estradiol (e.g., Diane 35), when topical and systemic acne standard therapies fail
- Inoperable advanced prostate cancer: as monotherapy or in combination with GnRH analogs to prevent flare-up phenomenon
- Polycystic ovary syndrome (PCOS): off-label in clinically dominant hyperandrogenemia
- Sexual deviation treatment: chemical reduction of sexual drive intensity in paraphilic disorders
- Gender-affirming hormone therapy: as antiandrogen in female-to-male transition (off-label, increasingly replaced by spironolactone or GnRH analogs)
Dosage and Administration
Acne and hirsutism (Diane 35): One tablet daily, 21 days of administration, 7 days off; CPA dose per tablet 2 mg. High-dose indications (Androcur): 50 to 200 mg daily, in individual cases up to 300 mg. Due to the meningioma risk, cumulative lifetime dose should be kept as low as possible and the indication should be regularly critically reviewed.
EMA Recommendation 2020: Use CPA at doses of 10 mg daily or higher only for clear indications and after failure of other options, use the lowest possible effective dose, regularly monitor for neurological symptoms (headaches, visual disturbances, hearing loss, seizures), and perform MRI if indicated.
Adverse Effects
Common: Weight gain, fatigue, depressive mood, loss of libido, breast tenderness, gynecomastia and erectile dysfunction in men, hot flashes.
Occasional to rare, but important: Hepatotoxicity up to fulminant liver failure (especially at high doses), thromboembolic events particularly in combination with estrogens, hyperprolactinemia, anemia, bone density loss with long-term use.
Important, meningioma risk: Since 2018, studies show a clear dose-dependent relationship between cumulative CPA exposure and intracranial meningioma. At cumulative doses exceeding 10 g (corresponding to approximately 50 mg daily over six months), the risk increases significantly. Patients on long-term therapy require comprehensive counseling and neurological symptom monitoring.
Drug Interactions
- CYP3A4 Inducers (Rifampicin, Carbamazepine, Phenytoin, St. John's Wort): Accelerated metabolism, reduced efficacy
- CYP3A4 Inhibitors (Ketoconazole, Itraconazole, Ritonavir): Elevated plasma levels, increased adverse effects
- Statins (Simvastatin, Atorvastatin): Rarely increased myopathy incidence under high-dose CPA
- Alcohol: Additive hepatotoxicity, preferably avoided
- Oral antidiabetic agents and insulin: Dose adjustment if needed due to altered glucose metabolism
Special Precautions
Pregnancy: Contraindicated. CPA crosses the placenta and can cause feminization in male fetuses. Breastfeeding: Contraindicated, passes into breast milk.
Liver monitoring: Liver transaminases before initiation, at three and six months, then annually. If elevation exceeds three times the upper limit of normal, consider discontinuing therapy. Currently existing or previous liver disease is a contraindication.
Meningioma counseling: Patients on moderate and high doses must be informed about the risk. With new headaches, visual disturbances, hearing loss, dizziness, or seizures, MRI diagnostics is indicated. If a meningioma is found, CPA must usually be discontinued, which frequently leads to size stagnation or even regression.
Thrombosis risk: In combination with estrogens (Diane 35), there is an increased thrombosis risk. Before prescribing, risk factors such as smoking, overweight, migraine with aura, and family thrombosis history should be carefully assessed.
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- Leuprolide, GnRH agonist in prostate cancer
Frequently Asked Questions
Why is cyproterone acetate in Diane 35 now considered critical?
Diane 35 was long used as a combined acne and contraceptive pill. Due to higher thrombosis risk compared to modern micropills and meningioma data at higher cumulative doses, current guidelines recommend using Diane 35 only for moderate acne and hirsutism when other therapies have failed, and not as a primary contraceptive.
How high is the meningioma risk under Androcur?
French registry data (CNAM, approximately 250,000 women) showed approximately twenty-fold increased frequency of intracranial meningiomas at cumulative doses starting from 60 g. At low doses (Diane 35), the risk is significantly lower. With signs of neurological symptoms, MRI diagnostics is indicated. If a meningioma is detected, CPA must usually be discontinued.
Does CPA help with hair loss?
In androgenetic hair loss (especially in women with hyperandrogenemia), CPA can slow progression. However, there is no approved indication for this in Germany; its use is off-label. First-line treatment for androgenetic hair loss in women remains topical minoxidil, supplemented by spironolactone in the indication of hyperandrogenemia.
What happens in men under CPA?
High-dose CPA reduces libido and spermatogenesis, reduces erectile function, and leads to hot flashes, gynecomastia, and fatigue. In metastatic prostate cancer, this chemical castration is therapeutically desired and prolongs disease control. In indications outside oncology (e.g., paraphilic disorder), CPA is used only after comprehensive counseling and within specialist medical treatment.
Sources
- EMA Referral Cyproterone 2020 (Meningioma)
- Gelbe Liste, Cyproterone Acetate Active Substance Profile
- AWMF Guideline Acne and PCOS
- BfArM Dear Health Care Professional Letter Cyproterone 2020
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