the same regimen was used but transdermal estradiol had become the standard therapy for those over the age of 40, the risk of vte was still increased overall by 20-fold (45 cases, 5.5% incidence). however, there was only a single case of vte in the group of 138 transgender women treated with transdermal estradiol (0.7% incidence). in accordance, the combination of transdermal estradiol and 50 mg/day cyproterone acetate appears to be relatively safe in terms of vte risk. the vte risk was initially attributed exclusively to ethinylestradiol, and the use of ethinylestradiol has largely been abandoned in transgender women in favor of other estrogens such as estradiol because of it. however, cpa is now known to significantly increase the risk of vte as well, and it may have contributed also. cpa should be discontinued in transgender women after sex reassignment surgery or orchiectomy to reduce the risk of vte. it should also be discontinued at least 2 weeks before undergoing surgery to reduce the risk of vte. a large pharmacoepidemiological study in the united kingdom using the general practice research database assessed the risk of vte with various forms of androgen deprivation therapy for prostate cancer. the study had a sample of 11,199 men, of whom 229 (2.0%) experienced vte and in whom 14% this was fatal. the incidence rates for vte were 3.46 for cpa monotherapy relative to nonsteroidal antiandrogen monotherapy with flutamide or bicalutamide; 3.35 for cpa monotherapy relative to gnrh agonist/orchiectomy monotherapy; 1.25 for cpa monotherapy relative to estrogen monotherapy with diethylstilbestrol or estramustine phosphate; and 0.60 for cpa monotherapy relative to combined androgen blockade with a gnrh agonist/orchiectomy and cpa. the adjusted odds ratios for vte were 1.00 for no treatment; 1.29 for nonsteroidal antiandrogen therapy; 3.35 for combined androgen blockade with cpa and a gnrh agonist/orchiectomy; 5.23 for cpa monotherapy; and 5.67 for estrogen monotherapy. the adjusted odds ratios for vte of different dosages of cpa with or without a gnrh agonist relative to gnrh agonist monotherapy were 3.49 for 25 or 50 mg/day, 4.93 for 100 or 150 mg/day, and 4.54 for greater than or equal to 200 mg/day. in addition to cpa and other medications used to treat prostate cancer, metastatic prostate cancer is itself a risk factor for vte. in large randomized controlled trials of cpa versus other medications for the treatment of prostate cancer, the following incidences of vte have been observed: 5.3% for 100 mg/day oral cpa (n = 95) vs. 4.2% for 100 mg/month intramuscular estradiol undecylate (n = 96); 2.4% for 250 mg/day oral cpa (n = 82) vs. 6.1% for 200 mg/day oral medroxyprogesterone acetate (n = 73) vs. 8.2% for 3 mg/day oral diethylstilbestrol (n = 114) (eortc trial 30761); and 4.5% for 300 mg/day oral cpa (n = 130) vs. 0% for 750 mg/day flutamide (n = 134). however, the final analysis of the last study (eortc trial 30892) indicated that vte ultimately ended up occurring in 3 patients (2.0%) in the flutamide group (n = 151) and 7 patients (4.6%) in the cpa group (n = 152). for further comparison, in another similar and closely related trial (eortc trial 30762), the incidence of vte was 6.3% with 3 mg/day oral diethylstilbestrol (n=112) and 7.9% with 280–560 mg/day oral estramustine phosphate (n = 114). premenopausal women using depot injectable medroxyprogesterone acetate, a progestin related to cpa, as a form of progestogen-only birth control, have been observed to have a 2.2- to 3.6-fold increased risk of vte. however, this could have reflected preferential prescription of dmpa to women considered to be at an increased risk of vte. dmpa has little or no effect on coagulation and fibrinolytic factors. in addition, progestogens by themselves at physiological doses normally do not increase the risk of thrombosis. risk of venous thromboembolism (vte) with hormone therapy and birth control (qresearch/cprd) typeroutemedicationsodds ratio (95% ci) menopausal hormone therapyoralestradiol alone ≤1 mg/day >1 mg/day1.27 (1.16–1.39)*1.22 (1.09–1.37)*1.35 (1.18–1.55)* conjugated estrogens alone ≤0.625 mg/day >0.625 mg/day1.49 (1.39–1.60)*1.40 (1.28–1.53)*1.71 (1.51–1.93)* estradiol/medroxyprogesterone acetate1.44 (1.09–1.89)* estradiol/dydrogesterone ≤1 mg/day e2 >1 mg/day e21.18 (0.98–1.42)1.12 (0.90–1.40)1.34 (0.94–1.90) estradiol/norethisterone ≤1 mg/day e2 >1 mg/day e21.68 (1.57–1.80)*1.38 (1.23–1.56)*1.84 (1.69–2.00)* estradiol/norgestrel or estradiol/drospirenone1.42 (1.00–2.03) conjugated estrogens/medroxyprogesterone acetate2.10 (1.92–2.31)* conjugated estrogens/norgestrel ≤0.625 mg/day cees >0.625 mg/day cees1.73 (1.57–1.91)*1.53 (1.36–1.72)*2.38 (1.99–2.85)* tibolone alone1.02 (0.90–1.15) raloxifene alone1.49 (1.24–1.79)* transdermalestradiol alone ≤50 μg/day >50 μg/day0.96 (0.88–1.04)0.94 (0.85–1.03)1.05 (0.88–1.24) estradiol/progestogen0.88 (0.73–1.01) vaginalestradiol alone0.84 (0.73–0.97) conjugated estrogens alone1.04 (0.76–1.43) combined birth controloralethinylestradiol/norethisterone2.56 (2.15–3.06)* ethinylestradiol/levonorgestrel2.38 (2.18–2.59)* ethinylestradiol/norgestimate2.53 (2.17–2.96)* ethinylestradiol/desogestrel4.28 (3.66–5.01)* ethinylestradiol/gestodene3.64 (3.00–4.43)* ethinylestradiol/drospirenone4.12 (3.43–4.96)* ethinylestradiol/cyproterone acetate4.27 (3.57–5.11)* notes: (1) nested case–control studies (2015, 2019) based on data from the qresearch and clinical practice research datalink (cprd) databases. (2) bioidentical progesterone was not included, but is known to be associated with no additional risk relative to estrogen alone. footnotes: * = statistically significant (p < 0.01). sources: see template. cardiovascular health high-dose cpa for prostate cancer in men is associated with incidence of relatively mild cardiovascular side effects. these include coagulation changes and blood clots (5%), fluid retention (4%), ischemic cardiomyopathy (4–40%), and undesirable effects on serum lipid profiles. severe cardiovascular complications occur in up to 10% at such doses and are sometimes fatal. a large randomized controlled trial that compared cpa and flutamide in men with prostate cancer found that the rates of cardiovascular problems were not significantly different between the two therapies. the cardiovascular toxicity of 250 mg/day cpa is significantly lower than that of 3 mg/day diethylstilbestrol. breast cancer the women's health initiative randomized controlled trials demonstrated a significantly increased risk of breast cancer with 0.625 mg/day conjugated estrogens and 2.5 mg/day medroxyprogesterone acetate (a progestin closely related to cpa) for menopausal hormone therapy relative to 0.625 mg/day conjugated estrogens alone and placebo in peri- and postmenopausal women. similarly, estrogen plus low-dose cpa for menopausal hormone therapy has been associated with a significantly higher risk of breast cancer relative to estrogen alone and no use. in addition, a nationwide observational study found that estrogen plus high-dose cpa was associated with a 46-fold increased risk of breast cancer in transgender women relative to the expected incidence for cisgender men. risk of breast cancer with menopausal hormone therapy in large observational studies (mirkin, 2018) studytherapyhazard ratio (95% ci) e3n-epic: fournier et al. (2005)estrogen alone1.1 (0.8–1.6) estrogen plus progesterone transdermal estrogen oral estrogen0.9 (0.7–1.2)0.9 (0.7–1.2)no events estrogen plus progestin transdermal estrogen oral estrogen1.4 (1.2–1.7)1.4 (1.2–1.7)1.5 (1.1–1.9) e3n-epic: fournier et al. (2008)oral estrogen alone1.32 (0.76–2.29) oral estrogen plus progestogen progesterone dydrogesterone medrogestone chlormadinone acetate cyproterone acetate promegestone nomegestrol acetate norethisterone acetate medroxyprogesterone acetatenot analyzeda0.77 (0.36–1.62)2.74 (1.42–5.29)2.02 (1.00–4.06)2.57 (1.81–3.65)1.62 (0.94–2.82)1.10 (0.55–2.21)2.11 (1.56–2.86)1.48 (1.02–2.16) transdermal estrogen alone1.28 (0.98–1.69) transdermal estrogen plus progestogen progesterone dydrogesterone medrogestone chlormadinone acetate cyproterone acetate promegestone nomegestrol acetate norethisterone acetate medroxyprogesterone acetate1.08 (0.89–1.31)1.18 (0.95–1.48) 2.03 (1.39–2.97)1.48 (1.05–2.09)not analyzeda1.52 (1.19–1.96)1.60 (1.28–2.01)not analyzedanot analyzeda e3n-epic: fournier et al. (2014)estrogen alone1.17 (0.99–1.38) estrogen plus progesterone or dydrogesterone1.22 (1.11–1.35) estrogen plus progestin1.87 (1.71–2.04) cecile: cordina-duverger et al. (2013)estrogen alone1.19 (0.69–2.04) estrogen plus progestogen progesterone progestins progesterone derivatives testosterone derivatives1.33 (0.92–1.92)0.80 (0.44–1.43)1.72 (1.11–2.65)1.57 (0.99–2.49)3.35 (1.07–10.4) footnotes: a = not analyzed, fewer than 5 cases. sources: see template. other long-term effects in terms of ovulation inhibition, the effective dosage of cpa is 1.0 mg/day while that of medroxyprogesterone acetate is 10 mg/day. based on ovulation inhibition, a dosage of 50 mg/day cyproterone acetate has on the order of 200 times the progestogenic potency of 2.5 mg/day medroxyprogesterone acetate. in addition to its progestogenic activity, cpa produces androgen and estrogen deficiency when used as a monotherapy, and this influences health as well. the health effects of high-dose cpa with long-term therapy have not been well-studied. a meta-analysis of high-dose cpa for the treatment of prostate cancer in men found that cpa was associated with a slight excess of non-prostate cancer deaths. in addition, the combination of cpa with surgical or medical castration for prostate cancer has been found to significantly decrease overall survival relative to castration alone. results of the women's health initiative (whi) menopausal hormone therapy randomized controlled trials clinical outcome hypothesized effect on risk estrogen and progestogen(ces 0.625 mg/day p.o. + mpa 2.5 mg/day p.o.)(n = 16,608, with uterus, 5.2–5.6 years follow up) estrogen alone(ces 0.625 mg/day p.o.)(n = 10,739, no uterus, 6.8–7.1 years follow up) hr 95% ci ar hr 95% ci ar coronary heart disease decreased 1.24 1.00–1.54 +6 / 10,000 pys 0.95 0.79–1.15 −3 / 10,000 pys stroke decreased 1.31 1.02–1.68 +8 / 10,000 pys 1.37 1.09–1.73 +12 / 10,000 pys pulmonary embolism increased 2.13 1.45–3.11 +10 / 10,000 pys 1.37 0.90–2.07 +4 / 10,000 pys venous thromboembolism increased 2.06 1.57–2.70 +18 / 10,000 pys 1.32 0.99–1.75 +8 / 10,000 pys breast cancer increased 1.24 1.02–1.50 +8 / 10,000 pys 0.80 0.62–1.04 −6 / 10,000 pys colorectal cancer decreased 0.56 0.38–0.81 −7 / 10,000 pys 1.08 0.75–1.55 +1 / 10,000 pys endometrial cancer – 0.81 0.48–1.36 −1 / 10,000 pys – – – hip fractures decreased 0.67 0.47–0.96 −5 / 10,000 pys 0.65 0.45–0.94 −7 / 10,000 pys total fractures decreased 0.76 0.69–0.83 −47 / 10,000 pys 0.71 0.64–0.80 −53 / 10,000 pys total mortality decreased 0.98 0.82–1.18 −1 / 10,000 pys 1.04 0.91–1.12 +3 / 10,000 pys global index – 1.15 1.03–1.28 +19 / 10,000 pys 1.01 1.09–1.12 +2 / 10,000 pys diabetes – 0.79 0.67–0.93 0.88 0.77–1.01 gallbladder disease increased 1.59 1.28–1.97 1.67 1.35–2.06 stress incontinence – 1.87 1.61–2.18 2.15 1.77–2.82 urge incontinence – 1.15 0.99–1.34 1.32 1.10–1.58 peripheral artery disease – 0.89 0.63–1.25 1.32 0.99–1.77 probable dementia decreased 2.05 1.21–3.48 1.49 0.83–2.66 abbreviations: ces = conjugated estrogens. mpa = medroxyprogesterone acetate. p.o. = per oral. hr = hazard ratio. ar = attributable risk. pys = person–years. ci = confidence interval. notes: sample sizes (n) include placebo recipients, which were about half of patients. "global index" is defined for each woman as the time to earliest diagnosis for coronary heart disease, stroke, pulmonary embolism, breast cancer, colorectal cancer, endometrial cancer (estrogen plus progestogen group only), hip fractures, and death from other causes. sources: see template. androgenic or antiandrogenic effects lipid changes high doses of cpa have been found to decrease levels of hdl ("good") cholesterol. unfavorable blood lipid profile changes are a potential risk factor for cardiovascular disease like atherosclerosis or coronary heart disease. cpa has weak androgenic effects in the liver, which may be responsible for its adverse influence on the lipid profile. unfavorable lipid changes have also been seen with other antiandrogens, for instance spironolactone and bicalutamide, and with androgenic medications. the women's health initiative randomized controlled trials demonstrated a significantly increased risk of coronary heart disease with 0.625 mg/day conjugated estrogens and 2.5 mg/day medroxyprogesterone acetate (a progestin closely related to cpa) for menopausal hormone therapy relative to 0.625 mg/day conjugated estrogens alone and placebo in peri- and postmenopausal women. whether or not estrogen plus low-dose cpa alone has similar risks has not been studied and hence is unknown. biomarker research suggests that the lower androgenic activity of cpa and reduced unfavorable effects on blood lipids may confer less or no coronary heart disease risk, but this has yet to be evaluated in clinical studies. other side effects liver toxicity incidences of elevated liver enzymes with different dosages of cyproterone acetate in 1,685 healthy males and females of all ages in a large active surveillance study. the most serious potential side effect of cpa is hepatotoxicity. a variety of manifestations of liver disease in association with cpa treatment have been documented, including immunoallergic cytotoxic reactions, cholestasis, autoimmune hepatitis, acute hepatitis, fulminant liver failure, and cirrhosis, as well as an increased risk of hepatocellular carcinoma. clinical features may include jaundice, fatigue, nausea, elevated liver enzymes, hepatic necrosis and inflammation, and features of hepatic decompensation. hepatotoxicity due to cpa therapy is most common in elderly patients who are treated with high dosages of the drug for prolonged periods of time, but has also occurred in younger patients. the hepatotoxicity of cpa is related to its c1α,2α methylene group. in an uncontrolled open-label active surveillance study of 1,685 healthy males and females of all ages (3 to 75 years for the full sample of 2,506 individuals) treated with cpa for an average of 6.7 years (but in 602 individuals for up to more than 10 years), elevated liver enzymes were seen in 2.6 to 3.1% of individuals at a dosage of 1 to 20 mg/day, in 8.1%