pharmacology of cyproterone acetate pharmacology of cyproterone acetate the pharmacology of cyproterone acetate (cpa) concerns the pharmacology (pharmacodynamics, pharmacokinetics, and routes of administration) of the steroidal antiandrogen and progestin medication cyproterone acetate. pharmacology of cyproterone acetateclinical dataroutes ofadministrationby mouth, intramuscular injectiondrug classsteroidal antiandrogen; progestin; progestogen; progestogen ester; antigonadotropinpharmacokinetic databioavailabilityoral: 68–100%protein bindingalbumin: 93%free: 7%metabolismhepatic (cyp3a4)metabolites• 15β-oh-cpa (major) • cyproterone (minor)• acetic acid (minor)elimination half-lifeoral: 1.6–4.3 daysim: 3–4.3 daysexcretionfeces: 70%urine: 30% cpa blocks the effects of androgens like testosterone in the body, which it does by preventing them from interacting with their biological target, the androgen receptor (ar), and by reducing their production by the gonads and hence their concentrations in the body. in addition, it has progesterone-like effects by activating the progesterone receptor (pr). by activating the pr, cpa has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both men and women. cpa can also produce weak and partial cortisol-like effects at very high doses under certain circumstances by activating the glucocorticoid receptor (gr). cpa can be taken by mouth or by injection into muscle. it has near-complete oral bioavailability, is highly and exclusively bound to albumin in terms of plasma protein binding, is metabolized in the liver by hydroxylation and conjugation, has 15β-hydroxycyproterone acetate (15β-oh-cpa) as a single major active metabolite, has a long elimination half-life of about 2 to 4 days regardless of route of administration, and is excreted in feces primarily and to a lesser extent in urine. pharmacodynamics cpa has antiandrogenic activity, progestogenic activity, weak partial glucocorticoid activity, weak steroidogenesis inhibitor activity, and agonist activity at the pregnane x receptor. it has no estrogenic or antimineralocorticoid activity. in terms of potency, cpa is described as a highly potent progestogen, a moderately potent antiandrogen, and a weak glucocorticoid. relative affinities (%) of cyproterone acetate progestogenprarergrmr cyproterone acetate906068 notes: values are percentages (%). reference ligands (100%) were promegestone for the pr, metribolone for the ar, estradiol for the er, dexamethasone for the gr, and aldosterone for the mr. sources: parenteral potencies and durations of progestogens compound form dose for specific uses (mg) doa tfd poicd cicd algestone acetophenideoil soln.-–75–15014–32 d gestonorone caproateoil soln.25–50––8–13 d hydroxyprogest. acetateaq. susp.350––9–16 d hydroxyprogest. caproateoil soln.250–500–250–5005–21 d medroxyprog. acetateaq. susp.50–1001502514–50+ d megestrol acetateaq. susp.-–25>14 d norethisterone enanthateoil soln.100–2002005011–52 d progesteroneoil soln.200––2–6 d aq. soln. ?––1–2 d aq. susp.50–200––7–14 d notes and sources: sources: all given by intramuscular or subcutaneous injection. progesterone production during the luteal phase is ~25 (15–50) mg/day. the oid of ohpc is 250 to 500 mg/month. duration of action in days. usually given for 14 days. usually dosed every two to three months. usually dosed once monthly. never marketed or approved by this route. in divided doses (2 × 125 or 250 mg for ohpc, 10 × 20 mg for p4). antiandrogenic activity affinities compound rba metribolone 100 dihydrotestosterone 85 cyproterone acetate 7.8 bicalutamide 1.4 nilutamide 0.9 hydroxyflutamide 0.57 flutamide <0.0057 notes: at androgen receptors; measured in human prostate tissue. relative to metribolone, which is by definition 100% relative potencies of selected antiandrogens antiandrogenrelative potency bicalutamide4.3 hydroxyflutamide3.5 flutamide3.3 cyproterone acetate1.0 zanoterone0.4 description: relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. higher values mean greater potency. sources: see template. cpa is a potent competitive antagonist of the androgen receptor (ar), the biological target of androgens such as testosterone and dihydrotestosterone (dht). it was at one time the most potent known ar antagonist of the steroidal antiandrogens, out of hundreds of other compounds. cpa has the highest antiandrogenic activity of any other clinically used progestin. it directly blocks endogenous androgens like testosterone and dht from binding to and activating the ar, and thus prevents them from exerting their androgenic effects, such as masculinization and prostate gland growth, in the body. a comparative study of binding inhibition to the ar in rat prostate cytosol ar found ic50 values of 3 nm for dht, 24 nm for cyproterone acetate, and 67 nm for spironolactone. affinities of selected ligands at the androgen receptor compoundar rba (%)ar ki (nm) metribolone1001.18 dihydrotestosterone1360.87 testosterone1171.01 spironolactone67.01.76 trimethyltrienolone14.88.0 megestrol acetate13.68.7 cyproterone acetate12.59.5 progesterone6.618 estradiol4.924 androstenedione2.058 canrenone0.84140 flutamide0.0791200 cimetidine0.00084140,000 notes: (1) human skin fibroblasts used for assays. (2) situation in vivo is different for flutamide and spironolactone due biotransformation. (3) conflicting findings for spironolactone. sources: main: related: antiandrogenic efficacy and potency androgen receptor antagonistic potency of spironolactone, cpa, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight). the antiandrogenic activity of cpa is dose-dependent. although cpa is a potent antiandrogen, relatively high doses of cpa are nonetheless required for clinically important ar antagonism. the clinical antiandrogenic efficacy of birth control pills containing cpa, which have only low doses of cpa in them (2 mg/day), often can't be distinguished from that of birth control pills containing other progestins. it is likely that the antiandrogenic effects of cpa-containing birth control pills are due mostly to the ethinylestradiol component and/or suppression of androgen levels, rather than the antiandrogenic activity of the small doses of cpa present in them. cpa has been found to decrease inflammatory acne lesions in males by about 15% at 5 mg/day, by 45% at 25 mg/day, and by 73% at 100 mg/day. a dosage of 100 mg/day cpa can achieve a 65 to 70% reduction in sebum excretion rate in males within 4 weeks of treatment, but doses of 10 mg/day cpa or less are said to have a negligible effect. on the basis of these findings, it has estimated that the threshold dosage of cpa to reduce sebum production may be 5 mg/day in males. in other studies, 25 mg/day cpa resulted in substantial improvement or complete clearance of severe acne in almost all males, whereas 12.5 mg/day was ineffective. cpa has been found to be strongly catabolic in young healthy males. it was shown to result in a mean negative nitrogen balance of 1.2 g at 50 mg/day, 1.4 g at 100 mg/day, and 2.5 g at 200 mg/day. this corresponded to mean losses of lean tissue of 780, 945, and 1,515 g, respectively. conversely, the catabolic effect was much less in an older male, and no such effect was observed in adult females consuming a diet with sufficient calories and protein. the catabolic effects of cpa were found to be greater than those of corticosteroids. although higher doses of cpa are necessary for considerable systemic ar antagonistic activity, it is notable that even low doses of oral cpa appear to be able to significantly antagonize ar signaling in the liver in women. this may be related to the hepatic first-pass effect of oral administration, and is evidenced by the fact that whereas combined birth control pills containing cpa increase shbg levels by 300 to 400%, combined birth control pills containing various other progestins, with either androgenic or antiandrogenic activity, increase shbg levels by only 50 to 300%. this is relevant as estrogens stimulate hepatic shbg production while androgens inhibit hepatic shbg production, and vice versa for their antagonists. the antiandrogenic activity of cpa may also be responsible for the relatively greater risk of venous thromboembolism with cpa-containing birth control pills compared to those containing other progestins. in rats, a dosage of cpa of 25 mg/kg/day results in complete regression of prostate gland growth in gonadally intact males. the equivalent dosage in humans, on the basis of body surface (conversion factor from rat to human of 6), was estimated to be approximately 4 mg/kg/day, or around 300 mg/day cpa for a 75 kg (165 lb) man. other techniques for determining the dosage of cpa have validated this extrapolation, for instance affinity studies and prostatic cpa levels. the affinity of cpa for the ar is around 20-fold lower than that of dht, and an excess of cpa levels of around 20 to 30 times those of dht would hence be expected to maximally neutralize androgen signaling. in accordance, different publications have stated based on preclinical experiments that a 2- to 5-fold excess of cpa can inhibit the effects of testosterone by 50%, a 3- to 10-fold excess of cpa can reduce the effects of "potent androgens" (presumably testosterone and/or dht) by 50%, and a 10-fold excess of cpa can inhibit the effects of testosterone by "almost 100%". high-dose cpa has been found to achieve prostatic levels that are at least 30-fold those of dht. one study found that levels of cpa in the prostate gland in men being treated with 200 mg/day oral cpa were about 28 times those of dht. in accordance with the preceding findings, it has been stated that oral doses of cpa of at least 300 mg/day may achieve a combined androgen blockade action in the treatment of prostate cancer. at a dosage of cpa of 100 mg/day in men with prostate cancer, circulating levels of cpa (e.g., 350 ng/ml) are on the order of 200-fold higher than circulating levels of testosterone (e.g., 100 ng/dl). in men who have undergone orchiectomy, 50 mg/day oral cpa results in a 500-fold excess of circulating cpa relative to circulating testosterone. in accordance with such findings, high-dose cpa shows equivalent effects on the prostate gland in men relative to high-dose diethylstilbestrol or buserelin, which both achieve castrate levels of testosterone. however, a lower dosage of 50 mg/day cpa has been found to produce a reduction in prostate volume in men with benign prostatic hyperplasia that is reportedly comparable to that observed with surgical or medical castration. in accordance, the dosage of cpa that achieves complete inhibition of the secretory function of the healthy prostate gland is around 50 to 100 mg/day, which is less than the dosage of 200 to 300 mg/day cpa that is used to treat prostate cancer. it has been said that in combined androgen blockade regimens with castration and cpa as the ar antagonist for prostate cancer, due to the marked reduction in androgen levels, lower dosages of cpa than those used as a monotherapy would seem to be equally effective. relative to the 200 to 300 mg/day dosage of cpa used as a monotherapy in prostate cancer, the recommended dosage in combined androgen blockade is 100 to 200 mg/day. it has been stated that this dosage should be more than necessary to inhibit the effects of the remaining adrenal androgens in castrated men. despite considerable suppression of testosterone levels, only a modest suppression of spermatogenesis typically occurs with 5 to 10 mg/day cpa, and azoospermia occurs only occasionally. conversely, a combination of testosterone enanthate injections with 12.5 to 100 mg/day cpa results in azoospermia in most men. the rates of azoospermia increased with greater cpa dosage, which was attributed to the additional ar antagonism of higher doses of cpa. significant spermatogenesis still occurs with 50 mg/day cpa alone, but spermatogenesis is significantly reduced compared to normal. at a dosage of 200 mg/day, cpa has been found to produce azoospermia (sperm count of less than 1 million/ml) in men within 8 to 10 weeks of treatment. however, fertility is generally lost even at a lower dosage of cpa of 100 mg/day because there is complete inhibition of the accessory sex glands and hence an absence of semen production and ejaculate upon orgasm. ejaculate volume decreases at a dosage of 50 mg/day and decreases to almost zero after 6 weeks of high-dose cpa therapy. the effects of cpa on fertility are completely reversible. this has been demonstrated in clinical studies of male adolescents and adults treated with cpa continuously for 6 to 7 years. weak partial androgenic activity cpa, like spironolactone and other steroidal antiandrogens such as chlormadinone acetate and megestrol acetate, is actually not a pure antagonist of the ar – that is, a silent antagonist – but rather appears to be a very weak partial agonist. clinically, cpa generally functions purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as testosterone and dht from interacting with the receptor and thus its net effect is virtually always to lower physiological androgenic activity. but unlike silent antagonists of the ar like nonsteroidal antiandrogens such as flutamide, bicalutamide, and enzalutamide, cpa, by virtue of its slight intrinsic activity at the ar, may be unable to fully inhibit androgenic signaling in the body,