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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Last Update: July 5, 2017.



Cyproterone is a steroidal antiandrogen that has been used in the treatment of prostate cancer in many countries of the world, but not in the United States. Cyproterone therapy can be associated with serum enzyme elevations during therapy and has been linked to many instances of clinically apparent acute liver injury, some of which were fatal.


Cyproterone (sye pro' ter one) is a synthetic steroidal antiandrogen that has been used to treat prostate cancer in many countries of the world, but was never approved for this use in the United States. Cyproterone is a derivative of hydroxyprogesterone and has mild progesterone-like effects. Its mechanism of action, however, appears to be via blocking of the androgen receptor. Alone or when combined with other agents, cyproterone has been found to be palliative in patients with advanced prostate cancer. Cyproterone has also been evaluated for hormonally sensitive benign conditions such as endometriosis, precocious puberty and infertility, but has not been formally recommended for these uses. Because of its potential to cause liver injury and its inferior efficacy in comparison to other antiandrogens, cyproterone is now rarely used. The typical dose regimen is 50 to 100 mg two to three times daily, often in combination with a gonadotropin releasing hormone agonist such as leuprolide, goserelin, histrelin or triptorelin. Common side effects include hot flashes, sexual dysfunction, nausea, diarrhea, weight change and fluid retention.


Cyproterone has been associated with serum enzyme elevations during therapy in 10% to 14% of patients, but these elevations are usually transient and mild and often resolve even without dose modification. More importantly, cyproterone has been associated with many instances of clinically apparent liver injury with jaundice. The time to onset has ranged from a few months to as long as a year, but typically arises within 3 to 6 months of starting treatment. The liver injury is almost always hepatocellular with moderate to marked elevations in serum aminotransferase levels and minimal increases in alkaline phosphatase. Mixed and more cholestatic injury occurs occasionally and may have a more favorable prognosis. Importantly, the hepatocellular injury associated with cyproterone use is often severe and the mortality rate of patients presenting with jaundice is at least 10% (these patients frequently being elderly men with advanced prostate cancer and not qualifying for emergency liver transplantation). Immunoallergic features (fever, rash, eosinophilia) are uncommon, as are autoantibodies. Some patients, however, appear to respond to corticosteroid therapy and rare instances of autoimmune-hepatitis like injury have been attributed to cyproterone. Improvement is usually seen within 1 to 2 weeks of stopping cyproterone and resolution within 1 to 3 months. Nevertheless, many examples of progressive liver injury leading to death from hepatic failure despite prompt discontinuation of therapy have been reported. In rare cases, recovery has been incomplete and patients have had residual evidence of chronic liver disease or cirrhosis.

Likelihood score: B (likely cause of clinically apparent liver injury).

Chronic therapy with cyproterone has also been linked to cases of hepatocellular carcinoma, generally arising after years of therapy with high doses of cyproterone or its combination with other hormonal agents such as estrogens or oral contraceptives. Most cases of hepatocellular carcinoma arose in a noncirrhotic liver and without other evidence of chronic liver injury, although sometimes with elevations in alpha-fetoprotein levels. In some instances, liver cancer was found years after use of cyproterone. The association of cyproterone use with hepatocellular carcinoma remains somewhat controversial.

Mechanism of Injury

The acute form of liver injury attributed to cyproterone use is probably due to an idiosyncratic reaction to a metabolite of the medication, rather than its antiandrogen or secondary estrogenic effects. The specific mechanism of liver injury caused by cyproterone is not known, but most antiandrogens have hepatotoxicity potential although some to a greater extent than others (cyproterone and flutamide more than bicalutamide and nilutamide).

Outcome and Management

Cyproterone has been associated with liver injury ranging in severity from asymptomatic or mildly symptomatic elevations in serum enzymes to an acute hepatitis and acute liver failure. At least a dozen instances of fatality from cyproterone acute liver injury have been reported. In some instances, corticosteroids have been used with some evidence of benefit. The most important element is rapid discontinuation of treatment with the first signs of liver injury. Severe and even fatal recurrence of injury upon rechallenge has been reported and restarting of cyproterone after clinically apparent liver injury attributed to its use is inadvisable. Indeed, cross sensitivity to hepatic injury between cyproterone and other antiandrogens (flutamide) has also been reported.

Drug Class: Antineoplastic Agents, Antiandrogens


Case 1. Severe acute hepatitis causing cirrhosis due to cyproterone.

[Modified from: Abenavoli L, Milic N, Beaugrand M. Severe hepatitis induced by cyproterone acetate: role of corticosteroids. A case report. Ann Hepatol 2013; 12: 152-5. PubMed Citation.]

A 66 year old man with advanced prostate cancer developed fatigue and dark urine followed by jaundice approximately 9 months after starting cyproterone (200 mg daily). He had previously undergone prostatectomy and radiotherapy followed by a two year course of bicalutamide and goserelin. Because of evidence of progression, this regimen was switched to cyproterone. He had no previous history of liver disease and was known to have had normal liver tests in the past. He denied a history of alcohol abuse or risk factors for viral hepatitis and was taking no other medications or herbal products. On presentation, he was jaundiced but had no signs of chronic liver disease. Laboratory tests showed a total bilirubin of 22.3 mg/dL, ALT 2044 U/L, AST 1487 U/L, GGT 335 U/L and alkaline phosphatase 223 U/L (Table). The prothrombin index was 43%. Cyproterone was discontinued and he was admitted for evaluation and monitoring. Tests for hepatitis A, B, C and E and for EBV, HSV and CMV were negative. Autoantibodies were not present. Abdominal ultrasound showed increased hepatic echogenicity, but no evidence of biliary obstruction or gallstones. A liver biopsy showed acute hepatocellular injury, portal and periportal inflammation, bridging necrosis and areas of regeneration. He was started on prednisone (60 mg daily) and ursodiol. Serum bilirubin and ALT levels began to decline, but a repeat liver biopsy showed evidence of active cirrhosis. Because of hyperglycemia, the prednisone dose was decreased and then stopped, which was followed by reappearance of jaundice. Prednisone and ursodiol were restarted and he again improved. Thereafter, the dose of prednisone was decreased slowly and ultimately withdrawn. Two years after the initial presentation he was asymptomatic, although liver tests were still slightly abnormal.

Key Points

Medication:Cyproterone (200 mg daily)
Pattern:Hepatocellular (R=24)
Severity:4+ (jaundice, hospitalization, cirrhosis)
Latency:9 months
Other medications:None mentioned

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin (mg/dL)Other
9 months0204422322.3Cyproterone stopped; Prednisone started
1 week165524229.1First liver biopsy
10 months1 month~300Prednisone 20 mg/day
11 months2 months~500.6Second liver biopsy; prednisone stopped
12 months3 months7928814.1Prednisone restarted
14 months5 months~60~5.0
18 months9 months~501.7Prednisone stopped
24 months15 months~501.7
Normal Values<40<110<1.2

*Some values estimated from Figure 1.


An elderly man developed a severe and protracted hepatitis 9 months after starting cyproterone. He was treated with prednisone and ursodiol, but improvement was slow. An initial attempt to withdraw corticosteroids was unsuccessful, but ultimately he was able to stop treatment. However, a liver biopsy showed cirrhosis and he had mild elevations in liver tests in follow up. Typical of cyproterone hepatotoxicity was the delayed latency, the hepatocellular pattern of injury and severe course. In several reports, corticosteroid therapy was considered to be beneficial, but controlled observations have not been made and remarkable spontaneous recovery can occur.



Cyproterone – Generic, Androcur®


Antineoplastic Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Cyproterone Chemical Structure
17-Hydroxyprogesterone Chemical Structure


References updated: 05 July 2017

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    (70 year old man developed jaundice 3 months after starting cyproterone for prostate cancer [bilirubin 14 mg/dL, ALT 1311 U/L, AST 82 U/L, protime 15 sec], which recurred within 2 months of reexposure 1 year later [bilirubin 6.2 mg/dL, ALT 399 U/L, AST 268 U/L, Alk P 115 U/L], imaging showing cirrhosis with ascites; death from multiorgan failure one month later).
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    (66 year old man with prostate cancer developed jaundice 4 months after starting cyproterone [bilirubin 22.3 mg/dL, ALT 2044 U/L, Alk P 223 U/L], with a prolonged course, corticosteroid therapy, but ultimate recovery).
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    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none of the 96 were attributed to cyproterone).
  • Kim JH, Yoo BW, Yang WJ. Hepatic failure induced by cyproterone acetate: A case report and literature review. Can Urol Assoc J 2014; 8 (5-6): E458-61. [PMC free article: PMC4081269] [PubMed: 25024808]
    (87 year old man developed jaundice 3 months after starting cyproterone and a GnRH agonist for prostate cancer [bilirubin 10.6 mg/dL, ALT 223 U/L, GGT 85 U/L, INR 2.4], progressing to hepatic failure and death 20 days after presentation; the authors also summarize results from 15 fatal cases in literature).
  • Vodička M, Sálek T, Röderová E, Cerný D. Hepatotoxicity induced by cyproterone acetate in the prostate carcinoma treatment - a case report]. Klin Onkol 2013; 26 (1): 47-8. Czech. [PubMed: 23528173]
    (75 year old man with prostate cancer developed jaundice 9 months after starting cyproterone [bilirubin 10.3 mg/dL, ALT 994 U/L, Alk P 193 U/L, GGT 1128 U/L, INR 1.23]).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18], nitrofurantoin [n=17], antituberculosis drugs [n=13] and flutamide [n=12: 7%]).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one was attributed to bicalutamide, but none to other antiandrogens such as flutamide, nilutamide and cyproterone).
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