Cyproterone acetate (Androcur, Cyprostat,Cyproteron, Procur, Cyprone, Cyprohexal, Ciproterona, Cyproteronum,Neoproxil, Siterone) is an antiandrogen, i.e. it suppresses the actions of testosterone (and its metabolite dihydrotestosterone) on tissues. It acts by blocking androgen receptors which prevents androgens from binding to them and suppresses luteinizing hormone (which in turn reduces testosterone levels). Its main indications are prostate cancer, benign prostatic hyperplasia, priapism, hypersexuality and other conditions in which androgen action maintains the disease process. Due to its anti-androgen effect, it can also be used to treat hirsutism, and is a common component in hormone therapy for male-to-female transgender people.
Until the development of leuprolide, cyproterone was one of the few drugs used to treat precocious puberty. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation.
In addition, cyproterone acetate has weak progestational activity (e.g., it acts like progesterone) and can be used to treat hot flashes. As part of some combined oral contraceptive pills (Dianette in UK and Diane-35 in other countries) it decreases acne and hirsutism (male-pattern hair growth).
Cyproterone acetate inhibits the steroidogenic enzyme 21-hydroxylase and to a lesser extent 3beta-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol. The blockade of 21-hydroxylase can also result in reduced production of aldosterone, the primary mineralcorticoid hormone. Mutations in the gene encoding 21-hydroxylase are fairly common in the human population, therefore some patients may be affected more than others. Although cyproterone has some glucocorticoid activity, this is offset by the fact that cyproterone acetate inhibits cortisol production and can act as a competitive inhibitor of cortisol at the glucocorticoid receptor, thus its adrenosuppressive effects are usually fairly minor. However, since the glucocorticoid effects appear to be due to metabolites, rather than cyproterone acetate itself, the net effect may vary depending on the rate at which cyproterone acetate is metabolized. The progestational and glucocorticoid effects reduce production of gonadotropins, which usually results in lower testosterone levels, however the blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, reducing the efficacy of the antiandrogen treatment. Due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5-alpha-reductase inhibitor finasteride, and studies of hirsutism treatment show increased efficacy of this combination over cyproterone acetate alone. Some in vitro studies have suggested that cyproterone or cyproterone acetate may have a slight inhibitory effect on 5-alpha-reductase, however no significant reduction in DHT production has been observed in vivo.
Cyproterone acetate is metabolized by the CYP3A4 enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestational activity. Therefore, use of cyproterone acetate in combination with substances which inhibit CYP3A4 may increase the progestational effects. Cyproterone acetate increases production of CYP3A4 by activating the pregnane x receptor.
Suppression of adrenal function and reduced response to ACTH have been reported. Low cortisol levels may impair carbohydrate metabolism, and patients with diabetes mellitus may require adjustments in insulin dosage. Low aldosterone levels may lead to salt loss and hyperkalemia (excess potassium). Patients taking cyproterone should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, reduce the consumption of food having a high potassium content.
Used alone, cyproterone acetate does not appear to have a significant effect on blood clotting factors, however in combination with ethinylestradiol (as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis. There are conflicting reports as to whether there is a significant difference in the risk of thrombosis between oral contraceptives containing cyproterone acetate versus other types of combined oral contraceptives.
Cyproterone has been associated with depressive mood changes in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant effects. This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone.
A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptors. These altered androgen receptors can be stimulated, rather than inhibited, by cyproterone. In such cases, withdrawal of cyproterone results in a reduction in cancer growth, rather than the opposite.
For the treatment of hypersexuality, severe hirsutism, or for the treatment of male-to-female transsexuals, 25mg twice daily is usually sufficient, although up to 100mg/day is permitted. As side effects are dose-dependent, treatment with the lowest effective dose is advisable.
Use during pregnancy is contraindicated, and for women of childbearing age, cyproterone should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional cyproterone should be taken only on days 1-10 of a 28-day package of birth control pills.
Doses up to 300 mg/day are used for the treatment of metastatic prostate cancer, however at high doses the risk of serious hepatic toxicity or adrenal suppression requires careful monitoring. In treatment of prostate cancer, cyproterone is often co-administered with a GnRH agonist and a 5-alpha-reductase inhibitor.