alone then in combination with transdermal testosterone followed by discontinuation and recovery in healthy young men. levels decreased by about 65% with cyproterone acetate alone. there were no differences in gonadotropin levels with 10 versus 20 mg/day cyproterone acetate and testosterone levels for the two groups were combined. testosterone levels with 5 or 10 mg/day oral cyproterone acetate in men. levels of testosterone decreased by 52% with 5 mg/day and by 51% with 10 mg/day. testosterone levels with 10 mg/day oral cyproterone acetate in men. levels of testosterone decreased by about 70%. androgen (mainly testosterone) levels with 10 or 20 mg/day oral cyproterone acetate in men. levels of androgens decreased by about 60% with both 10 mg/day and 20 mg/day. testosterone levels with 100 to 300 mg/day oral cyproterone acetate and low-dose oral estrogen in men. the estrogen used was 0.1 mg/day diethylstilbestrol (des), which has been described as an "extremely low" dosage. levels of testosterone were decreased by about 95% with the combination and by about 61% with cyproterone acetate only. hormone levels with 1 to 2 mg/day transdermal estradiol gel and 50 mg/day oral cyproterone acetate in transgender women. the mean dosage of estradiol gel increased between 6 and 12 months. testosterone levels with estradiol (e2) alone or in combination with an antiandrogen (aa) in the form of spironolactone (spl) or cyproterone acetate (cpa) in transfeminine people. estradiol was used in the form of oral estradiol valerate (ev) in almost all cases. the dashed horizontal line is the upper limit of the female/castrate range (~50 ng/dl). glucocorticoid activity cpa is an agonist of the glucocorticoid receptor (gr), and has weak and partial glucocorticoid activity at high doses. in animals, cpa suppresses the secretion of adrenocorticotropic hormone (acth) from the pituitary gland, suppresses the production of corticosteroids like cortisol and corticosterone by the adrenal cortices, and decreases the weights of the adrenal glands and thymus. conversely however, cpa shows no anti-inflammatory or eosinophilic effects in animals. as such, cpa, as well as related antiandrogens, show only some of the typical effects of glucocorticoids. cpa may produce mild glucucorticoid actions at high doses of more than 100 mg/day in humans. clinically, the glucocorticoid effects of cpa appear to be relevant only at high doses in people with small body sizes (cpa exposure of more than 80 to 100 mg/m2), namely in the treatment of children with precocious puberty. no signs of secondary adrenal insufficiency have been observed with cpa. while various studies have clearly shown reduced cortisol and acth levels and acth responsiveness in humans with cpa therapy, some studies contradict these findings and report no such effects even with high doses of cpa. due to negative feedback on the hypothalamic–pituitary-adrenal (hpa) axis, administration of exogenous glucocorticoids such as prednisone and dexamethasone suppress the secretion of adrenocorticotropic hormone (acth) from the pituitary gland and the production of cortisol from the adrenal glands. this results in adrenal suppression and atrophy and, upon glucocorticoid discontinuation, temporary adrenal insufficiency. similarly, cpa both in animals and humans can weakly reduce acth and cortisol levels and decrease adrenal gland weight as well as cause adrenal insufficiency with discontinuation. these findings suggest that cpa possesses weak glucocorticoid properties. cpa has been reported to be an antagonist of the glucocorticoid receptor (gr) in vitro and may reduce adrenal cortisol and corticosterone production by weakly inhibiting the enzymes 3β-hydroxysteroid dehydrogenase and 21-hydroxylase. these are antiglucocorticoid actions. however, metabolites of cpa, for instance 15β-hydroxycyproterone acetate, may have differing activities. both cyproterone and cpa have been found to possess glucocorticoid effects, and based on studies in mice, it has been suggested that cpa has approximately one-fifth of the potency of prednisone as a glucocorticoid. the glucocorticoid effects of cpa in humans appear to be less significant than those in animals. megestrol acetate, medroxyprogesterone acetate, and chlormadinone acetate are all steroidal progestins of the 17α-hydroxyprogesterone family and close analogues of cpa which similarly possess glucocorticoid properties and the potential for producing adrenal insufficiency upon discontinuation. estrogenic and antiestrogenic activities cpa does not bind to the estrogen receptors. accordingly, pre-treatment with cpa does not block the retention of estradiol in the brain in mice. cpa has no estrogenic or direct antiestrogenic activity. however, cpa has been reported to produce weak estrogenic effects in rodents. in any case, cpa has prominent indirect antiestrogenic effects via its progestogenic activity. this includes pr-mediated antiestrogenic activity in certain tissues like the uterus and vagina as well as suppression of estrogen levels via its pr-mediated antigonadotropic activity. cpa also has indirect estrogenic activity in the breasts via its antiandrogenic activity, as androgens have strong functional antiestrogenic effects in this part of the body. this underlies the slight gynecomastia that can occur with cpa in men. opioid receptors cpa has been found to bind to several of the opioid receptors, including the μ-, δ-, and κ-opioid receptor subtypes. however, this binding is very weak relative to its other actions (ic50 for inhibition of diprenorphine binding = 1.62 ± 0.33 μm). it has been suggested that activation of opioid receptors might be involved in the sedation that is reportedly sometimes seen with high doses of cpa or in its reported effectiveness in the treatment of cluster headaches. aryl hydrocarbon receptor antagonist cpa has been identified as an antagonist of the aryl hydrocarbon receptor and this action may be involved in its liver toxicity. pharmacokinetics absorption the oral bioavailability of cpa is 68 to 100%. the absorption of oral cpa is slow but complete, and the medication is not subject to a significant first-pass effect. the mean absorption half-life of oral cpa is about 1.5 hours. steady-state levels of cpa occur with oral cpa after about 8 days of continuous administration, with a 2- to 3-fold gradual accumulation in cpa levels. oral cpa is taken daily and intramuscular cpa is administered weekly or biweekly. following a single low oral dose of 2 mg cpa in combination with 35 or 50 μg ethinylestradiol in premenopausal women, mean peak levels of cpa of 7.2 to 15.2 ng/ml (17–36.5 nmol/l) have been recorded after 1.6 to 3.7 hours. in healthy men, a single high oral dose of 100 mg cpa produced maximal cpa levels of 254 ng/ml (609 nmol/l) after 2.6 hours. in aged men with prostate cancer, continuous oral cpa therapy resulted in cpa levels of 132 ± 18 ng/ml at 25 mg/day, 246 ± 13 ng/ml at 50 mg/day, and 348 ± 23 ng/ml at 100 mg/day. similarly, in healthy young women, a single high oral dose of 100 mg cpa resulted in peak cpa levels of 255 ng/ml (612 nmol/l) within 2 to 3 hours. during continuous treatment with high oral doses of cpa in women with hirsutism, levels of cpa were 199 to 228 ng/ml (477–547 nmol/l) with 50 mg/day cpa and were 436 to 520 ng/ml (1050–1250 nmol/l) with 100 mg/day cpa. after a single intramuscular injection of 300 mg cpa in healthy young women, maximal levels of cpa of 191 ng/ml (458 nmol/l) and of 15β-oh-cpa of 164 ng/ml occurred after 2 to 4 days. during continuous weekly intramuscular injections of cpa in men with prostate cancer, mean levels of cpa roughly doubled from 170 ng/ml (408 nmol/l) after the first injection to 310 ng/ml (744 nmol/l) after the fifth injection, and were projected to increase to 350 to 400 ng/ml (840–960 nmol/l) after around 8 to 12 injections. the area-under-the-curve (auc; total exposure) levels of cpa with 100 mg/day oral cpa and 300 mg/week intramuscular cpa may be approximately equivalent. cyproterone acetate levels with oral and intramuscular cyproterone acetate cpa levels after a single oral dose of 100 mg cpa in men. cpa levels after a single oral dose of 100 mg cpa (androcur or ciproterone) in men. cyproterone acetate levels with 100 mg oral cyproterone acetate per day in women. administration was stopped at day 10. cpa and testosterone levels with continuous 300 mg/week cpa in oil solution by intramuscular injection in men. five injections were administered total but cpa and testosterone levels were determined only for the 1st, 3rd, and 5th injections. cpa levels with continuous 300 mg/week cpa in oil solution by intramuscular injection in men. the first injection was at week 1 and the injection for week 23 was skipped. the dashed line shows average levels. distribution with oral cpa, there is a probable distribution phase of cpa into tissues which lasts about 12 hours and has a half-life of 3 hours. cpa is very lipophilic, and it is sequestered into fat, which provides a depot effect. the volume of distribution of cpa is 20.6 ± 3.5 l/kg. cpa crosses the blood–brain barrier, which is evidenced by the suppression of gonadotropin secretion that is observed during therapy with it (the site of action of this effect being the pituitary gland, a part of the brain). in terms of plasma protein binding, cpa does not bind to shbg or corticosteroid-binding globulin and is instead bound exclusively to albumin (93%), with the remainder (7%) circulating free or unbound. the affinity of cpa for shbg is very low at about 0.006% of that of testosterone or dht. metabolism metabolism of cpa. cpa is metabolized primarily by hydroxylation via cyp3a4, forming the major active metabolite 15β-hydroxycyproterone acetate. this metabolite circulates at concentrations approximately twice those of cpa, and has similar antiandrogen activity to that of cpa but only 10% of its activity as a progestogen. as a result, the co-administration of cpa with drugs which inhibit cyp3a4 may increase its potency as a progestogen. some cpa is reportedly metabolized by hydrolysis into cyproterone and acetic acid. however, unlike many other steroid esters, cpa is not extensively hydrolyzed, and much of the pharmacological activity of the drug is attributable to cpa itself in its unchanged form. cyproterone has approximately one-third the potency of cpa as an antiandrogen and is devoid of progestogenic activity. the elimination half-life of oral cpa is relatively long at approximately 1.6 to 2.2 days (38 to 53 hours), but possibly as long as 3.6 to 4.3 days (86 to 100 hours). the half-life of 15β-oh-cpa with oral administration of cpa is 2.6 days. the elimination half-life of cpa is prolonged in obese patients, which may be due to relatively greater storage of cpa in fat. the elimination half-life of cpa is also longer in older individuals; it is approximately twice as long in elderly men than in younger men (95 hours and 45 hours, respectively). when given via depot intramuscular injection, cpa has an elimination half-life of 3 to 4.3 days while 15β-oh-cpa has a half-life of 5.2 days. the duration of action of a single intramuscular injection of cpa is about 14 to 20 days. the serum total clearance of cpa is approximately 2.32 ± 0.38 ml/min/kg. levels of cpa and 15β-oh-cpa with oral administration decrease biphasically over a period of 24 to 120 hours. the elimination of cpa appears to be biphasic. in one study, a peak at 3.4 hours post-dose with an initial half-life of 3.4 hours and later half-life of 1.6 days was observed following a single 50 mg oral dose of cpa. the high lipophilicity and fat storage of cpa may be the reason for its longer subsequent half-life. excretion cpa is excreted 70% in feces and 30% in urine.