which may persist to an extent in some tissues such as the prostate gland. in accordance with its albeit weak capacity for activation of the ar, cpa has been found to stimulate androgen-sensitive carcinoma growth in the absence of other androgens, an effect which could be blocked by co-treatment with flutamide. in one study in rodents, dht-stimulated prostate weight remained 40% above controls with administration of cpa even at the highest dosage, while flutamide was able to completely block the stimulatory effects of dht. in addition, cpa alone increased prostate weight by 60%, whereas flutamide had no effect. as a result of its weak intrinsic androgenicity, cpa may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to nonsteroidal antiandrogens with a silent antagonist profile at the ar. indeed, cpa has never been found to extend life in prostate cancer patients when added to castration relative to castration alone, unlike nonsteroidal antiandrogens. as such, it is thought that the partial androgenic activity of cpa and other steroidal antiandrogens underlies the superior antiandrogenic efficacy of silent-antagonist nonsteroidal antiandrogens like flutamide. however, the clinical significance of the weak androgenic activity of cpa has also been disputed. in fact, some studies have found little or no stimulating effect of cpa on the prostate gland or seminal vesicles of male rats even with very high circulating concentrations of cpa. nonsteroidal antiandrogens like flutamide and bicalutamide are more efficacious as antiandrogens than cpa in castrated animals due to their superior ar antagonistic activity. conversely, cpa is a much more potent antiandrogen than nonsteroidal antiandrogens like flutamide and bicalutamide in gonadally intact male animals, which is due to its antigonadotropic effects and consequent suppression of testosterone levels (nonsteroidal antiandrogens do not suppress testosterone levels). cpa at high doses (e.g., 25–50 mg/day) has been reported to suppress shbg levels, and may have a partial androgenic effect on hepatic shbg production at such doses. similar effects are known for related androgenic progestins like medroxyprogesterone acetate and megestrol acetate. cpa has also been reported to lower hdl cholesterol levels, another effect associated with androgens. accordingly, cpa shows weak androgenic effects in the liver in rodents which can be blocked by flutamide. other androgenic and antiandrogenic actions a paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their ars. these altered ars can be activated, rather than inhibited, by cpa. in such cases, withdrawal of cpa may result in a reduction in cancer growth, rather than the reverse. this is known as antiandrogen withdrawal syndrome. cpa may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting. most studies however suggest that cpa does not produce important inhibition of 5α-reductase. the combination of birth control pills containing cpa with finasteride, a well-established, selective 5α-reductase inhibitor, has been found to result in significantly improved effectiveness in the treatment of hirsutism relative to cpa-containing birth control pills alone. in addition to its ar antagonistic activity and suppression of gonadal sex-hormone production, high-dose cpa has been found to suppress the levels of the adrenal androgen dehydroepiandrosterone sulfate (dhea-s), which is due to exertion of negative feedback by cpa on adrenocorticotropic hormone (acth) secretion via the glucocorticoid activity of cpa. progestogenic activity cpa is a highly potent progestogen. it is described as the most potent progestin of the 17α-hydroxyprogesterone group, being about 1,200-fold more potent than hydroxyprogesterone acetate, 12-fold more potent than medroxyprogesterone acetate, and 3-fold more potent than chlormadinone acetate in animal bioassays. based on results in the animal bioassays, cpa has also been said to be the most potent progestin known, with 1,000 times the potency of progesterone. with oral administration in humans however, cpa is distinctly less potent as a progestogen than various other progestins such as the 19-nortestosterone derivatives. the effective dosage of cpa needed to inhibit ovulation by itself in women (i.e., to act as a contraceptive) is 1 mg/day, and the medication is marketed as a contraceptive (combined with low-dose ethinylestradiol) at a dosage of 2 mg/day. for comparison, the ovulation-inhibiting dosage of levonorgestrel is 50 μg/day. at the dosages typically used clinically, cpa is described as a "strong" and "powerful" progestogen. its endometrial transformation dosage is 20 to 30 mg per cycle and its menstrual delay test dosage has been estimated to be less than 1 mg/day. cpa is not well-balanced in terms of its activities; relative to the progestogenic potency of cpa, its potency as an androgen receptor antagonist is quite weak. in order to take full advantage of its antiandrogenic activity, cpa must be administered at a dosage of 50 to 100 mg per day, which is 2 to 3 times the cyclical endometrial transformation dose per day. as such, the total dosage of cpa per month is as much as 30 times the physiological equivalent of progesterone production during the normal menstrual cycle, and is notably equivalent to the total production of progesterone by a corpus luteum throughout the course of a woman's entire cyclic life. consequently, there is profound overdosage of progestogenic effect (and by extension progestogenic side effects) when cpa is used as an antiandrogen at high doses. for this reason, it has been said that cpa cannot be considered an ideal antiandrogen. through its action as a progestogen, cpa has been found to significantly increase prolactin secretion and to induce extensive lobuloalveolar development of the mammary glands of female rhesus macaques. in accordance, a study found that cpa, in all cases, induced full lobuloalveolar development of the breasts in transgender women treated with the medication in combination with estrogen for a prolonged period of time. pregnancy-like breast hyperplasia was observed in two of the subjects. in contrast, the same study found that men with prostate cancer treated with a non-progestogenic antiandrogen like flutamide or bicalutamide and no estrogen produced moderate but incomplete lobuloalveolar development of the breasts. based on the above research, it was concluded by the study authors that combined estrogenic and progestogenic action is required in transgender women for fully mature female-like histologic breast development (i.e., that includes complete lobuloalveolar maturation). also, it was observed that lobuloalveolar maturation reverses upon discontinuation of cpa after surgical castration, similarly to the case of mammary gland involution in postpartum women, indicating that continued progestogen treatment is necessary to maintain the histology. it should be noted however that although these findings may have important implications in the context of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue, and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a type of epithelial tissue) contributes to breast size or shape. cpa has been found to increase prolactin levels in humans both alone and in combination with an estrogen. antigonadotropic effects cpa has potent antigonadotropic effects via its progestogenic activity. it blunts the gonadotropin releasing hormone (gnrh)-induced secretion of gonadotropins, and accordingly, markedly suppresses circulating levels of luteinizing hormone (lh) and follicle-stimulating hormone (fsh) at sufficiently high doses. consequently, levels of progesterone, androstenedione, testosterone, dht, and estradiol are also markedly lowered at sufficiently high dosages, while an elevation in sex hormone-binding globulin (shbg) and prolactin levels is observed. the effective dosage of cpa for inhibition of ovulation in women, this being an antigonadotropic effect, is 1 mg/day. cpa alone has been found to suppress ovulation in 3 of 5 women at a dose of 0.5 mg/day and in 5 of 5 women at a dose of 1 mg/day in studies. ovulation inhibition with 1–2 mg/day cpa in combination with 1–2 mg/day estradiol valerate as a birth control pill (brand name femilar) occurred in 94.4% of 108 women during the third treatment cycle in one study and in almost 100% of 26 women over 12 treatment cycles in another study (except for one woman who ovulated during her first treatment cycle). oral cpa has been studied at low dosages of 5 to 20 mg/day as a potential male hormonal contraceptive. a dosage of as low as 5 to 10 mg/day oral cpa has been found to suppress circulating testosterone levels in men by 50 to 70%. for comparison with lower dosages, the suppression of circulating testosterone levels in men with a dosage of 100 mg/day oral cpa was 77% and with a dosage of 300 mg/week intramuscular cpa was 76%. dosages of cpa of 12.5 to 25 mg/day have been used as a maintenance dosage for testosterone suppression in men with sexual deviance after initial administration of higher cpa dosages, without recurrence of symptoms. cpa is generally able to maximally suppress circulating testosterone levels by 70 to 80% in men. however, in spite of strong suppression of testosterone levels, cpa, at least by itself (e.g., without estrogen), is not usually able to reduce testosterone levels into the castrate/female range (<50 ng/dl) at any dosage, and testosterone levels generally remain just above it at levels of roughly 50 to 200 ng/dl. however, studies have reported that a very high dosage of cpa of 300 mg/day may suppress testosterone levels to around 50 ng/dl in men. cpa also suppresses estradiol levels in men, with one study finding about a 65% decrease in estradiol levels (from about 27 pg/ml to around 10 pg/ml) with 100 mg/day cpa. cpa has been found to maximally suppress testosterone and estradiol levels in young men within 7 days of continuous administration. following discontinuation of cpa, the recovery of testosterone levels is variable and may require 14 days to 6 months for completion. an escape or recovery phenomenon, in which testosterone levels increase over time, has been observed with long-term cpa monotherapy. in one study in aged men with prostate cancer, testosterone levels were initially suppressed by 70%, but increased to 50% of baseline levels between 6 and 12 months, remaining stable thereafter up to 24 months of therapy. the combination of progestogens like cpa with an estrogen is synergistic in terms of antigonadotropic effect, and is able to fully suppress gonadal testosterone production even with very small doses of the estrogen. one study found that 100 to 300 mg/day cpa combined with an "extremely low" dosage of diethylstilbestrol (0.1 mg/day), a nonsteroidal estrogen, suppressed testosterone levels into the castrate range (to 30 ng/dl) in men with prostate cancer. discontinuation of diethylstilbestrol at 5 months resulted in a rapid 6-fold increase in testosterone levels (to 135 ng/dl) and then further (to almost 200 ng/dl) by 12 months. another study likewise found that the combination of 160 mg/day oral megestrol acetate, a progestin closely related to cpa, with 0.5 to 1.5 mg/day oral estradiol suppressed testosterone levels into the castrate range in men with prostate cancer. a study by fung and colleagues (2017) found no difference in suppression of circulating testosterone levels (~95% suppression) in transgender women by the combination of either 25 mg/day oral cpa or 50 mg/day oral cpa with a moderate dosage of oral or transdermal estradiol (mean 3.3 mg/day oral, 3.4 g/day gel, or 95.6 μg/day patches). a high dosage of cpa given starting 7 days prior to initiation of gnrh agonist therapy was found to prevent the gnrh agonist-induced flare in testosterone levels. the combination of 100 mg/day cpa and 0.1 mg/day diethylstilbestrol given starting 4 weeks before gnrh-agonist introduction has also been found to prevent the gnrh agonist-induced testosterone flare. cpa should be given continuously for at least a week prior to gnrh agonist initiation for an optimal preventative effect on the gnrh agonist-induced testosterone flare. testosterone levels with cyproterone acetate testosterone and luteinizing hormone levels with 100 mg/day oral cyproterone acetate in men. levels of testosterone decreased by about 80%. testosterone levels with 300 mg/week cyproterone acetate or 100 mg/month estradiol undecylate both by intramuscular injection in men. solid lines are average and dashed lines highest and lowest levels. levels of testosterone decreased by 75% with cyproterone acetate and by 91% with estradiol undecylate. testosterone levels with 10 mg/day oral cyproterone acetate, different doses of oral dienogest, or placebo in healthy young men. levels of testosterone decreased by 66 ± 4%, from 600 ng/dl to 185 ng/dl. testosterone levels with different doses of cyproterone acetate (cpa), segesterone acetate (sga), norethisterone acetate (neta), and levonorgestrel (lng)