of individuals at a dosage of 20 to 50 mg/day, in 10.2% of individuals at a dosage of 50 to 100 mg/day, and in 11.1 to 25.0% of individuals at a dosage of greater than 100 mg/day (up to more than 200 mg/day). in a trial of 89 men with prostate cancer who received 50 mg/day cpa for 4 years, elevated liver enzymes occurred in 28.2%. a study of 105 patients treated with 150 mg/day cpa reported a hepatotoxicity rate of 9.5%, with serious liver injury occurring in 3.8% (4/105). a study of 303 transgender women treated with high-dose estrogen and 100 mg/day cpa reported an incidence of elevated liver enzymes of 7.2% (22/303). in 2002, it was reported that there were 18 published case reports of cpa-associated hepatitis in the literature, with 6 of these cases resulting in death. in addition however, a 1995 publication by the united kingdom medicines control agency/committee on safety of medicines in its journal current problems in pharmacovigilance described an additional 96 spontaneous reports of hepatotoxicity (91 males, 5 females), with 33 of these cases resulting in death. the manifestations of hepatotoxicity described in this publication included hepatitis, cholestatic jaundice, and liver failure. the majority of cases were men being treated with very high doses of cpa (300 mg/day) for prostate cancer. a 2014 review found that 9 cases specifically of cpa-induced fulminant (sudden-onset and severe) liver failure had been reported to date, with only one of these cases not being fatal. as such, the prognosis of cpa-induced liver failure is death. however, serious hepatotoxicity occurs mostly in prostate cancer patients who take very high doses of cpa, and serious liver toxicity has not been reported in transgender women. all 14 reported cases of serious hepatotoxicity (acute liver failure and acute hepatitis) with cpa described in the 2014 review were in a dosage range of 100 to 300 mg/day and were in elderly men with prostate cancer (age range 65 to 92 years). a 2015 publication reported an additional 22 new cases of hepatotoxicity in association with cpa, including one case at 50 mg/day. 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. in any case, liver toxicity with cpa occurs mostly in prostate cancer patients who take very high doses of the medication (200–300 mg/day), and liver toxicity has not been reported in cisgender or transgender women, who usually take lower doses (25–100 mg/day). however, in 2021, a case report of liver failure and death with 25 mg/day cpa in a young cisgender woman taking it for treatment of hirsutism was published. the hepatotoxicity of the nonsteroidal antiandrogen flutamide is greater than that of cpa. in a randomized controlled trial and direct head-to-head comparison for prostate cancer, overall rates of liver function deterioration were 9.9% in the 750 mg/day flutamide group (n = 151) and 5.3% in the 300 mg/day oral cpa group (n = 152) (p = 0.128), while liver toxicity requiring discontinuation occurred in 8.6% (13 of 151) in the flutamide group and 2.0% (3 of 152) in the cpa group. findings were similar in another randomized controlled trial and direct head-to-head comparison of 750 mg/day flutamide and 150 mg/day oral cpa; the rates of hepatotoxicity were 15.3% (19 of 124) for flutamide and 9.5% (10 of 105) for cpa (p = 0.034) and the rates of serious hepatotoxicity were 4.8% (6 of 124) for flutamide and 3.8% (4 of 105) for cpa. a 2004 review cited 46 published cases of hepatotoxicity in association with flutamide, 21 cases with cpa, 4 cases with nilutamide, and 1 case with bicalutamide, all between 1986 and 2003. it should be noted however that some of these antiandrogens, like nilutamide and bicalutamide, were introduced after 1986 and hence were launched more recently than the others. there are case reports of suspected cross-hepatotoxicity between cpa and flutamide. as such, cpa and flutamide may be cross-reactive in terms of hepatotoxicity. the hepatotoxicity of cpa may be dependent on age, with greater risk in older people. published case reports of cyproterone acetate-associated liver toxicity #sexagedosagetypeonsetoutcomesurvivalareflink 1female73 years400 mg/dayah2.5 monthssurvivedn/ameijers et al. (1986) 2female85 years200 mg/dayah4.8 monthssurvivedn/ameijers et al. (1986) 3male78 years200 mg/dayalf6 monthsdeath2 weekslévesque et al. (1989) 4male71 years300 mg/dayah5.3 monthssurvivedn/ablake et al. (1990) 5male79 years200–300 mg/dayah2.5 monthssurvivedn/adore et al. (1990) 6male80 years200 mg/dayalf7 monthsdeath~1–2 monthsantoni et al. (1991) 7male75 years300 mg/dayhcc1.5 yearsndndohri et al. (1991) 8male72 years300 mg/dayalfndsurvivedn/aparys et al. (1991) 9male65 years300 mg/dayalf1 yeardeath1.6 monthsparys et al. (1991) 10male83 years300 mg/dayalf1.25 yearsdeath2 weeksparys et al. (1991) 11male78 years150 mg/dayah~3 monthssurvivedn/adrakos et al. (1992) 12female24 years100 mg/day (rs)ch3 monthssurvivedn/ahassler et al. (1992) 13male74 years200 mg/dayah11 monthssurvivedn/aroila et al. (1993) 14male79 years300 mg/dayalf10 monthsdeath2 weeksbressollette et al. (1994) 15male92 years100 mg/dayalf4 monthsdeath5 weekshirsch et al. (1994) 16male65 years600 mg/dayhcc4 monthssurvivedn/akattan et al. (1994) 17female22 years100–250 mg/dayhcc10 yearsdeath9 monthswatanabe et al. (1994) 18female19 years200–300 mg/dayhcc9 yearssurvivedn/awatanabe et al. (1994) 19female19 years200 mg/dayhcc~10 yearssurvivedn/awatanabe et al. (1994) 20male87 years200 mg/dayalf4 monthsdeath~3.5 weekspinganaud et al. (1995) 21male78 years150 mg/dayalf1 yeardeath3 weekspinganaud et al. (1995) 22female45 years2 mg/day (bcp)hcc14 yearsdeath9 monthsrüdiger et al. (1995) 23male78 years200–300 mg/dayalf3 monthsdeath9 monthscastellani et al. (1996) 24male73 years300 mg/dayalf4 monthssurvivedn/amurphy et al. (1996) 25male64 years100 mg/dayah6 monthssurvivedn/aruiz-rebollo et al. (1997) 26female≥8 years200–300 mg/dayhcc>4 yearssurvivedn/awatanabe et al. (1997) 27male21 years100–350 mg/dayhcc15 yearssurvivedn/awatanabe et al. (1997) 28male84 yearsndalfnddeath1 weeklombardi et al. (1998) 29male81 years300 mg/dayalf6 monthsdeath1.6 monthsfriedman et al. (1999) 30male66 years300 mg/dayalf2 monthsdeath4 weeksfriedman et al. (1999) 31male14 years100 mg/daycirrhosis~7.5 yearsdeath~1 yeargarty et al. (1999) 32male84 years100–300 mg/dayhcc10 yearsdeath6 daysmanfredi et al. (2000) 33male87 years300 mg/dayahndsurvivedn/agiordano et al. (2001) 34female17 years2 mg/day (bcp)aih/cirrhosis2 monthssurvivedn/akacar et al. (2002) 35male76 years150 mg/dayah7 monthssurvivedn/amanolakopoulos et al. (2004) 36male78 years200 mg/dayalf3 monthsdeath1.0 monthsfamularo et al. (2005) 37male82 years200 mg/dayah12 monthssurvivedn/asavidou et al. (2006) 38male83 years300 mg/dayah7 monthsdeath1.4 monthssavidou et al. (2006) 39male78 years300 mg/dayah3 monthssurvivedn/asavidou et al. (2006) 40male78 years150 mg/dayalf2 monthssurvivedn/amiquel et al. (2007) 41bfemale22 years2 mg/day (bcp)bcs7 daysndndhe et al. (2009) 42male89 years150–300 mg/dayalf3.2 monthsdeath28 dayskim et al. (2009) 43male71 years100–200 mg/dayalf2–3 monthsdeath20 dayshsu et al. (2011) 44male66 years200 mg/dayah/cirrhosis4 monthssurvivedn/aabenavoli et al. (2013) 45male75 years200 mg/dayalf9 monthssurvivedn/avodička et al. (2013) 46male87 years200 mg/dayalf6 monthsdeath20 dayskim et al. (2014) 47male80 years150 mg/dayah4.0 monthssurvivedn/abessone et al. (2016) 48male73 years200 mg/dayah2.1 monthssurvivedn/abessone et al. (2016) 49male54 years200 mg/dayaih4.0 monthssurvivedn/abessone et al. (2016) 50male60 years200 mg/dayah1.1 monthssurvivedn/abessone et al. (2016) 51male74 years200 mg/dayah5.1 monthssurvivedn/abessone et al. (2016) 52male66 years150 mg/dayalf3.2 monthsdeathndbessone et al. (2016) 53male77 years100 mg/dayah8.1 monthssurvivedn/abessone et al. (2016) 54male72 years200 mg/dayah5.0 monthssurvivedn/abessone et al. (2016) 55male80 years200 mg/dayah1.9 monthssurvivedn/abessone et al. (2016) 56male69 years100 mg/dayah4.1 monthssurvivedn/abessone et al. (2016) 57male58 years200 mg/dayah10.1 monthssurvivedn/abessone et al. (2016) 58male83 years100 mg/dayah2.1 monthssurvivedn/abessone et al. (2016) 59male75 years200 mg/dayah4.9 monthssurvivedn/abessone et al. (2016) 60male72 years100 mg/dayah8.0 monthssurvivedn/abessone et al. (2016) 61male72 years50 mg/dayah5.9 monthssurvivedn/abessone et al. (2016) 62male66 years100 mg/dayah/ch1.2 yearssurvivedn/abessone et al. (2016) 63male58 years200 mg/dayalf5.0 monthsdeathndbessone et al. (2016) 64male75 years200 mg/dayalf7.9 monthsdeathndbessone et al. (2016) 65male74 years150 mg/dayah9.9 monthssurvivedn/abessone et al. (2016) 66male64 years100 mg/dayah3.3 monthssurvivedn/abessone et al. (2016) 67male64 years150 mg/dayah/ch4.9 monthssurvivedn/abessone et al. (2016) 68male64 years150 mg/dayah/cirrhosis4.9 monthssurvivedn/abessone et al. (2016) 69male61 years300 mg/dayalf3 monthsdeath2.6 monthsnour et al. (2017) 70female30 years25 mg/dayalf6 monthsdeath4 dayskumar et al. (2021) abbreviations: bcp = birth control pill. rs = reverse sequential (days 5–25 of cycle). alf = acute liver failure (fulminant liver failure). ah = acute hepatitis. ch = cholestatic hepatitis. aih = autoimmune hepatitis. hcc = hepatocellular carcinoma. bcs = budd–chiari syndrome. nd = no data. n/a = not applicable. footnotes: a = time until death after onset of liver toxicity. b = probably related to ethinylestradiol rather than to cyproterone acetate. notes: many additional cases have been described in spontaneous adverse drug reaction reporting systems of individual countries. these include 19 cases (5 deaths) by late 1988 and 96 cases (91 males, 5 females; 33 deaths) by early 1995 in the united kingdom; 32 cases (deaths not given) in australia by 2004; and 15 cases (no deaths) in spain by 2006. the cases from bessone et al. (2016) were reported between 1993 and 2013 and were from spanish and latin american drug-induced liver injury databases (17 cases in argentina, 2 cases in uruguay, 3 cases in spain). worldwide, 153 cases of liver abnormalities were reported to schering, the manufacturer, between 1982 and 1987. in a large observational study of 2,506 patients, heinemann et al. (1997) reported 7 cases of benign liver tumors and no cases of serious liver toxicity or hcc. large observational studies have found no increased risk of liver toxicity or hcc with cyproterone acetate at bcp doses. a fatal case of alf in a common chimpanzee has also been reported. sources: vitamin b12 deficiency both low-dose (2 mg/day) and high-dose cpa combined with an estrogen have been associated with vitamin b12 deficiency in women in some small studies. vitamin b12 deficiency in turn has been associated with depression, anxiety, irritability, and fatigue due to depletion of central monoamine neurotransmitters. for this reason, it has been suggested that low vitamin b12 levels might be involved in the side effect of depression that has sometimes been associated with cpa. serum vitamin b12 monitoring and supplementation (e.g., 100 to 200 μg/day orally) as necessary may be recommended during cpa therapy. miscellaneous cpa has been associated rarely with retinal vascular disorder, retinal vein thrombosis, and optic neuritis. a case report of symptomatic epidural lipomatosis in association with cpa therapy has been published. a published case report of lymphocytic pneumonitis in associated with cpa also exists. there is a case report of severe stretch marks in association with cpa therapy. dosage dependence belisle and love (1986) directly compared diane (ethinylestradiol 50 μg/day and cpa 2 mg/day) alone versus the combination of diane and cpa 100 mg/day (androcur) in 158 women with hirsutism. they reported no differences in mean incidences of side effects including menometrorrhagia (9.9%), acne (6.5%), decreased libido (9.5%), edema (9.3%), nausea (17.5%), vomiting (4.8%), headache (20.3%), and depression (12.7%). conversely, the incidences of fatigue and amenorrhea were significantly greater in the diane plus androcur group relative to the diane alone group (6.7% vs. 2.5% and 5.4–32.6% vs. 0–4.2%, respectively), the incidence of breast tenderness was significantly lower in the diane plus androcur group than in the diane alone group (3.6–26.3% vs. 12.5–46.4%), and the percent gain in body weight relative to baseline was significantly greater in the diane plus androcur group than in the diane alone group (6.3% vs. 1.1% at 12 months). cpa at relatively low doses, for instance 10–20 mg/day, has been reported in small studies to cause few to no side effects in men. conversely, cpa at higher doses, for instance 100 mg/day or greater, has been reported to produce a variety of side effects in men including decreased libido, erectile dysfunction, gynecomastia, tiredness, weakness, decreased efficiency, weight gain, skin dryness, skin peeling, and decreased body hair (e.g., trunk and pubic region). side effects of estrogen plus high- versus low-dose cyproterone acetate in women side effecthigh-dose(n = 602) (%)low-dose(n = 226) (%) fatigue22.013.0 weight gain (>2 kg or >4.4 lbs)18.55.5 decreased libido10.06.0 breast discomfort9.215.0 nausea9.03.9 headaches7.310.4 depression5.12.0 irregular uterine bleeding3.57.2 sleep disturbance3.5– thrombophlebitis1.03.0 chloasma0.9– constipation0.5– thrombosis0.150.9 heavy legs or cramps–4.6 footnotes: average dosage; range less than 10 mg/day to >200 mg/day. liver enzymes monitored in 1,685 individuals, including 1,131 males and 554 females. reverse sequential regimen: in women with hirsutism, cyproterone acetate 100 mg/day from days 5 to 14 of the menstrual cycle and ethinylestradiol 50 μg/day from days 5 to 25 of the cycle. diane: in women with hirsutism, cyproterone acetate 2 mg/day and ethinylestradiol 50 μg/day from days 5 to 25 of the cycle. sources: see template. withdrawal adrenal insufficiency abrupt withdrawal of cpa can