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 transgendered 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, its acetate form (cyproterone acetate) has weak progestational activity (e.g., it acts like progesterone) and can be used to treat hot flushes. As part of some contraceptive pills (Diane®) it decreases acne and hirsutism (male-pattern hair growth).

Side effects

The most serious potential side effect is liver toxicity, and patients should be monitored for changes in liver enzymes, especially if taking a high dose (200-300 mg/day).^* Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.

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 oral contraceptives) 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.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12851669&dopt=Abstract

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.

Cyproterone acetate suppresses production of estrogen due to its antigonadotrophic effect, and long-term use without estrogen replacement may result in osteoporosis.

Side-effects in men which directly result from its antiandrogenic action include gynecomastia (breast growth), galactorrhea (milk outflow), and erectile dysfunction.

Withdrawal effects

Abrupt withdrawal of cyproterone can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg, at intervals of several weeks. The primary concern is the manner in which cyproterone affects the adrenal gland. Although cyproterone reduces androgen production in the gonads, it increases adrenal androgen production, in some cases resulting in an overall rise in testosterone levels. Androgens, especially DHT, normally act as an inhibitor of adrenal function, but cyproterone blocks this.^*" target="_blank" >and the DHT metabolite 3beta-diol may still have an effect.cortisol and aldosterone production, apparently due to a blockade of the 21-hydroxylase enzyme.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6237971&dopt=Abstract" target="_blank" >^*

Sudden withdrawal of cyproterone may lead to disruption of the hypothalamic-pituitary-adrenal axis, as well as a transient exacerbation of whatever androgen-dependant condition was originally being treated. High levels of DHT are a particular concern because of the tendency of DHT to further reduce cortisol production, which was already impaired by cyproterone. The effects of the increased adrenal androgen production can be mitigated with 5-alpha-reductase inhibitors such as finasteride and dutasteride, which prevent the conversion of testosterone to the more potent DHT, but changes in the amount of cortisol and aldosterone production will remain a concern. The relatively short elimination half-life of finasteride (6 hours) may require frequent dosing to maintain control of adrenal DHT production. This is less of a concern with dutasteride due to its long elimination time.

Treatment with hydrocortisone will reduce adrenal androgen production, as is commonly done in patients with congenital deficiency of 21-hydroxylase, but the inhibition of 21-hydroxylase by cyproterone is seldom severe enough to necessitate this. Such deliberate adrenal suppression increases the risk of acute adrenal insufficiency in the event that the patient is unable to comply with the dosing schedule.

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.^*

Pharmacokinetics

The pharmacokinetics of cyproterone are complicated due to its lipophilic nature. Although the mean elimination half-life is usually estimated at around 40 hours, this primarily reflects its accumulation in fat cells. Elimination from the bloodstream is considerably faster, and the amount stored in fat may be affected by food intake. Therefore it is recommended that this medication be given in divided doses 2-3 times per day, or in the form of a long-acting injection.

Dosage and Administration

As an oral contraceptive, 2mg cyproterone acetate is combined with 35 or 50 mcg ethinylestradiol and taken once daily for 21 days, followed by 7-day interval with placebo pills.

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-dependant, 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.

Antiandrogens