|Systematic (IUPAC) name|
|Legal status||℞ Prescription only|
|Half-life||about 40 hours|
|Excretion||60% bile, 33% renal|
|Mol. mass||416.94 g/mol|
|(what is this?)|
Cyproterone acetate (INN, USAN, BAN, JAN), sometimes abbreviated as CPA, and sold under brand names such as Androcur and Cyprostat, is a synthetic steroidal antiandrogen drug with additional progestogen and antigonadotropic properties. Its primary action is to suppress the activity of the androgen hormones such as testosterone and its more potent metabolite dihydrotestosterone (DHT) in the body, effects which it mediates via competitive antagonism of the androgen receptor and inhibition of enzymes in the androgen biosynthesis pathway. The main therapeutic indications of cyproterone acetate are prostate cancer, benign prostatic hyperplasia, priapism, hypersexuality (e.g., as a form of chemical castration), and other conditions in which androgen action maintains the disease process. In addition, it can also be used to treat acne and hirsutism in females, and is a common component in hormone therapy for transsexual women.
In addition to its antiandrogen properties, cyproterone acetate has weak progestogen activity (i.e., it acts like progesterone). Accordingly, it can be used to treat hot flashes, and is also a component of some combined oral contraceptive pills such as Dianette in the United Kingdom and Diane-35 in other countries such as Canada. It is called Dixi-35 in Chile. No form of cyproterone acetate is available in the United States.
Until the development of leuprorelin, cyproterone acetate 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.
Cyproterone acetate is a synthetic derivative of 17-hydroxyprogesterone, and acts as an androgen receptor antagonist as well as a weak progesterone receptor agonist with weak progestational and glucocorticoid activity. Some portion is metabolized by hydrolysis to cyproterone and acetic acid. However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form. Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone.
Cyproterone acetate inhibits the steroidogenic enzyme 21-hydroxylase and to a lesser extent 3β-hydroxysteroid dehydrogenase, both of which are needed to synthesize endogenous corticosteroids such as cortisol and aldosterone, and it may reduce cortisol production, though there is great individual variability in this effect. 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 is thought to have some glucocorticoid activity, this is offset by the facts that cyproterone acetate inhibits the enzymes responsible for glucocorticoid production, markedly suppresses ACTH (which positively modulates glucocorticoid secretion), and is a weak competitive antagonist of the glucocorticoid receptor (of which its affinity for is similar to that of the progesterone receptor, and effects on the adrenal cortex are usually negligible. 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.
Cyproterone has potent antigonadotropic effects, blunting the GnRH-induced secretion of gonadotropins such as luteinizing hormone and follicle-stimulating hormone and accordingly decreasing their levels significantly. This usually results in lower testosterone levels, however the concurrent blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, potentially reducing the efficacy of the antiandrogen treatment. Though, cyproterone has also been shown to inhibit 17α-hydroxylase and 17,20-lyase, enzymes in the androgen biosynthesis pathway, which may offset this. In any case, due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5α-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 5α-reductase. However, studies have shown mixed results of cyproterone acetate's effects on observed dihydrotestosterone (DHT) production in vivo, with some showing a reduction and others showing no change. As mentioned above, cyproterone acetate has also been found to inhibit 17α-hydroxylase and 17,20-lyase, enzymes in the androgen biosynthesis pathway, and this could also account for any observed decreases in DHT or other androgens. Indeed, it has been found to decrease testosterone and androstenedione levels. With all of that having been said however, whether the inhibition of any of these enzymes by cyproterone is significant enough in humans to cause any physiological effects is unknown, and any observed reductions in androgen levels could simply be the pure result of its antigonadotropic actions.
Cyproterone acetate is metabolized by the CYP3A4 enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestogen 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.
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, but in combination with ethinylestradiol (as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis. Women who take contraceptive pills containing cyproterone acetate have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.
Cyproterone acetate is also associated with striae (stretch mark) formation, due to its glucocorticoid activity and drying of the skin.
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.
Abrupt withdrawal of cyproterone acetate 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 acetate affects the adrenal gland. Due to its glucocorticoid activity, high levels of cyproterone acetate may reduce ACTH, resulting in adrenal insufficiency if discontinued suddenly. In addition, although cyproterone acetate reduces androgen production in the gonads, it can increase adrenal androgen production, in some cases resulting in an overall rise in testosterone levels. Thus the sudden withdrawal of cyproterone acetate may result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing cortisol production. In theory, 5-alpha-reductase inhibitors such as finasteride and dutasteride may be able to mitigate this effect somewhat by preventing the conversion of testosterone to the more potent DHT.
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.
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, 2 mg cyproterone acetate is combined with 35 or 50 mcg ethinylestradiol and taken once daily for 21 days, followed by 7-day interval (Co-cyprindiol (BAN) sold as Dianette in UK, Diane-35 in Canada, Bella Hexal in Germany, and Diane in Sweden. It is not available in the USA). In Canada, Diane-35 is not used as an oral contraceptive, but as a treatment for severe acne.
For the treatment of hypersexuality, severe hirsutism, or for the treatment of transsexual women, 25 mg twice daily is usually sufficient, although up to 100 mg/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, but 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.
- Medroxyprogesterone acetate
- Megestrol acetate
- Chlormadinone acetate
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