|Systematic (IUPAC) name|
|Half-life||about 40 hours|
|Excretion||60% bile, 33% renal|
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Cyproterone acetate (abbreviated as CPA) (INN, USAN, BAN, JAN), also known as 1,2α-methylene-6-chloro-δ6-17α-acetoxyprogesterone and sold under brand names such as Androcur and Cyprostat, is a synthetic, steroidal antiandrogen, progestin, and antigonadotropin. It is primarily used in the treatment of androgen-related conditions by virtue of its ability to suppress androgenic activity in the body, an effect which it mediates by preventing endogenous androgens from interacting with the androgen receptor and by suppressing androgen biosynthesis. CPA is also used for its progestogenic effects, for instance, as a component of some combined oral contraceptive pills, such as in Dianette in the United Kingdom, Diane-35 in Canada, Bella Hexal in Germany, Diane in Sweden, and Dixi-35 in Chile.
CPA has been in use as an antiandrogen since 1964, and was the first antiandrogen introduced for clinical use. It is widely used throughout Europe, and is also used in Canada, Mexico, and other countries. It is not FDA-approved for use in the United States, due to concerns about hepatotoxicity; medroxyprogesterone acetate has been used in the US instead. CPA has been approved for the treatment of prostate cancer, precocious puberty, androgen-related dermatological conditions (such as acne, seborrhea, hirsutism, and androgenic alopecia), and to reduce sex drive in sex offenders. Combination formulations of CPA with ethinyl estradiol (a formulation sometimes referred to as co-cyprindiol) have been available as contraceptives since 1997.
Other uses of CPA include the treatment of benign prostatic hyperplasia, priapism, hypersexuality, paraphilias, hot flashes, and hyperandrogenism in women. In addition, with the exception of the United States (where CPA is not available and spironolactone is generally employed instead), CPA is widely used as a component of hormone replacement therapy for trans women.
The most serious potential side effect of CPA is hepatotoxicity (liver damage), and patients should be monitored for changes in liver enzymes, especially if taking a high dose (e.g., above 50–100 mg/day, and especially at the range of 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 taking insulin may require adjustments in their dosage. Low aldosterone levels may lead to hyponatremia (sodium loss) and hyperkalemia (excess potassium). Patients taking CPA should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, should reduce the consumption of foods with high potassium content.
Used alone, CPA does not appear to have a significant effect on blood clotting factors, but in combination with ethinyl estradiol (as in combined oral contraceptive pills), presents an increased risk of deep vein thrombosis. Women who take contraceptive pills containing CPA have a six- to seven-fold increased risk of developing thromboembolism compared to women not taking a contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel.
CPA has been associated with the incidence of depression, which can reportedly occur in up to 30% of patients. Paradoxically however, antidepressant effects have also been reported. This may be due to the effect of CPA on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone.
Side effects in males resulting directly from the antiandrogen properties of CPA include physical demasculinization, physical feminization (including gynecomastia (breast enlargement)), breast tenderness, galactorrhea (milk outflow), sexual dysfunction (including loss of libido and erectile dysfunction), impaired spermatogenesis, and reversible infertility.
Abrupt withdrawal of CPA 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 CPA affects the adrenal glands. Due to its glucocorticoid activity, high levels of CPA may reduce ACTH, resulting in adrenal insufficiency if discontinued abruptly. In addition, although CPA reduces androgen production in the gonads, it can increase the production of adrenal androgens, in some cases resulting in an overall rise in testosterone levels. Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production. In theory, 5α-reductase inhibitors such as finasteride could, to some extent, mitigate this effect by preventing the conversion of testosterone to its more potent relative DHT.
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.
CPA is known to possess the following pharmacological activity:
- Androgen receptor (AR) antagonist/very weak partial agonist
- Progesterone receptor (PR) agonist (Kd = 15 nM; IC50 = 79 nM)
- Glucocorticoid receptor (GR) antagonist (Kd = 45 nM; IC50 = 360 nM)
- 21-hydroxylase, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase, and 17,20-lyase inhibitor
- Pregnane X receptor (PXR) agonist (and thus indirect CYP3A4 and P-glycoprotein inducer)
CPA may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting. In any case, the combination of CPA and 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 alone, suggesting that if CPA does have any direct inhibitory effects on 5α-reductase, they must not be particularly marked.
Interestingly, CPA has been found to bind non-selectively to the opioid receptors, including the μ-, δ-, and κ-opioid subtypes. It has been suggested that activation of opioid receptors could have the potential to explain the side effect of sedation sometimes seen with CPA treatment and/or the effectiveness of CPA in the treatment of cluster headaches.
CPA is a potent competitive antagonist of the AR. It directly blocks endogenous androgens such as testosterone (T) and dihydrotestosterone (DHT) from binding to and activating the AR, and thus prevents them from exerting their androgenic effects in the body. However, CPA, like spironolactone and other steroidal antiandrogens such as chlormadinone acetate and medroxyprogesterone acetate, is not actually a pure antagonist of the AR – that is, a silent antagonist – but rather is a very weak partial agonist. Clinically, CPA generally behaves purely as an antiandrogen, as it displaces much more efficacious endogenous androgens such as T and DHT from interacting with the receptor and thus its net effect is usually to lower physiological androgenic activity. But unlike silent antagonists of the AR such as flutamide, CPA, by virtue of its slight intrinsic activity at the receptor, is incapable of fully abolishing androgenic activity in the body, and will always maintain at least some degree of it.
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. As a result, CPA may not be as effective in the treatment of certain androgen-sensitive conditions such as prostate cancer compared to non-steroidal antiandrogens with a silent antagonist profile at the AR such as flutamide, bicalutamide, and enzalutamide.
CPA has powerful antigonadotropic effects. In humans, it blunts the gonadotropin releasing hormone (GnRH)-induced secretion of gonadotropins, and accordingly, markedly suppresses the plasma levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Consequently, progesterone (P4), androstenedione, T, DHT, and estradiol (E2) are also markedly lowered, while an elevation in sex hormone-binding globulin (SHBG) and prolactin levels is observed. The antigonadotropic effects of CPA are thought to be mediated by over-stimulation of the PR. However, its inhibition of steroidogenic enzymes may also contribute to its ability to suppress sex hormone levels.
CPA is an inhibitor of the steroidogenic enzymes 21-hydroxylase and, to a lesser extent, 3β-hydroxysteroid dehydrogenase. Both of these enzymes are necessary for the biosynthesis of the endogenous corticosteroids, such as cortisol and aldosterone, and for this reason, it may reduce their production. However, there is great inter-individual variability in this effect, perhaps due to the fact that mutations in the gene encoding 21-hydroxylase are fairly common in the human population. Although CPA is thought to have some glucocorticoid properties, any such activity is likely offset by its inhibition of glucocorticoid production, as well as the fact that CPA markedly suppresses adrenocorticotropic hormone (ACTH), which stimulates glucocorticoid secretion. Also, CPA is a weak antagonist of the GR. In accordance, its effects on the adrenal cortex, which is the primary site of corticosteroid production in the body, are usually negligible. However, since the glucocorticoid properties of CPA appear to be due to its metabolites, rather than CPA itself, the overall effect may vary depending on the metabolism of CPA.
The pharmacokinetics of CPA are complicated due to its lipophilic nature. Although the mean elimination half-life is usually estimated to be around 40 hours, this primarily reflects its accumulation in adipose cells. Elimination from the bloodstream is considerably quicker, and the amount stored in fat may be affected by food intake. Therefore, it is recommended that CPA be given in divided doses 2–3 times per day, or in the form of a long-acting injection.
A portion of ingested CPA is metabolized by hydrolysis into cyproterone and acetic acid. However, unlike many other steroid esters, CPA is not extensively hydrolyzed, and much of its pharmacological activity is attributable to its unchanged form. CPA has approximately three times the potency as an antiandrogen of cyproterone.
CPA is metabolized by CYP3A4, forming the active metabolite 15β-hydroxycyproterone acetate. This metabolite retains antiandrogen activity, but has reduced activity as a progestogen. As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.
Dosage and administration
As an oral contraceptive, CPA is combined with ethinyl estradiol and taken once daily for 21 days, followed by a 7 day free interval.
For the treatment of hypersexuality, severe hirsutism, or for the treatment of trans women, twice daily is usually sufficient, although higher doses per 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, CPA should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional CPA should be taken only on days 1-10 of a 28-day package of birth control pills.
High doses may be used for the treatment of metastatic prostate cancer, but at high doses the risk of serious hepatotoxicity and adrenal suppression requires careful monitoring. In the treatment of prostate cancer, CPA is often co-administered with a GnRH agonist and a 5α-reductase inhibitor.
Cyproterone was discovered in the early 1960s, and Rudolf Wiechert, a Schering employee, together with F. Neumann in Berlin filed for a patent as "progestational agent" in 1962.U.S. Patent 3,234,093 Only one year after patent approval in 1965, Neumann published evidence of cyproterone acetate's antiandrogenic effect in rats; he reported an "organizational effect of cyproterone acetate on the brain".
During the same year, in 1966, its prenatal administration in male rats was shown to cause urogenital malformations by a group in Lund, Sweden. Cyproterone acetate started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation.
In 1970, the first human experiments began by measuring serum levels after oral administration., rates of spermatogenesis and hair growth in women. Starting in 1972, psychiatrists trialed "sexually deviant" persons on it. In the mid seventies, nonprogestational antiandrogens like spironolactone became available. Until the development of leuprolide, cyproterone acetate was one of the few drugs used to treat precocious puberty.
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