Cyproterone acetate

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Cyproterone acetate
Systematic (IUPAC) name
(1R,3aS,3bR,7aR,8aS,8bS,8cS,10aS)-1-Acetyl-5-chloro-8b,10a-dimethyl-7-oxo-1,2,3,3a,3b,7,7a,8,8a,8b,8c,9,10,10a-tetradecahydrocyclopenta[a]cyclopropa[g]phenanthren-1-yl acetate
Clinical data
Trade names Androcur
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy cat. X
Legal status ℞ Prescription only
Routes oral, intramuscular
Pharmacokinetic data
Bioavailability 100%
Protein binding 96%
Metabolism hepatic
Half-life about 40 hours
Excretion 60% bile, 33% renal
Identifiers
CAS number 427-51-0 YesY
ATC code G03HA01
PubChem CID 9880
ChemSpider 9496 YesY
UNII 4KM2BN5JHF YesY
ChEBI CHEBI:50743 YesY
ChEMBL CHEMBL142130 YesY
Chemical data
Formula C24H29ClO4 
Mol. mass 416.94 g/mol
 YesY (what is this?)  (verify)

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.[1] 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.

Pharmacology

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.[2] However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form.[3] Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone.[4]

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,[5] and it may reduce cortisol production, though there is great individual variability in this effect.[6] 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,[7] this is offset by the facts that cyproterone acetate inhibits the enzymes responsible for glucocorticoid production, markedly suppresses ACTH (which positively modulates glucocorticoid secretion),[8] and is a weak competitive antagonist of the glucocorticoid receptor (of which its affinity for is similar to that of the progesterone receptor,[9][10] and effects on the adrenal cortex are usually negligible.[8][11][12] 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.[13]

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.[6][14] 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.[15]

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.[6][16] 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.[17] Indeed, it has been found to decrease testosterone and androstenedione levels.[6][18][19] 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.[20][21][22] 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.[23]

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).[3] Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.[24]

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.[25] 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.[26]

Cyproterone acetate is also associated with striae (stretch mark) formation, due to its glucocorticoid activity and drying of the skin.[27]

Cyproterone has been associated with depressive mood changes in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant effects.[28] This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone.[29]

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 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.[30] 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.[31] 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.[32]

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, 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,[33] 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.

See also

References

  1. ↑ Neumann F, Töpert M (November 1986). "Pharmacology of antiandrogens". Journal of Steroid Biochemistry 25 (5B): 885–95. doi:10.1016/0022-4731(86)90320-1. PMID 2949114. 
  2. ↑ Medicines and Healthcare products Regulatory Authority (2006-04-11). "Cyproterone Acetate" (PDF). 
  3. ↑ 3.0 3.1 Berlex Canada, Inc. (2003-02-10). "Cyproterone Acetate Tablets and Injections Product Monographs (revised version)" (PDF). 
  4. ↑ Giorgi E, Shirley I, Grant J, Stewart J (1 March 1973). "Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate". Biochem J 132 (3): 465–74. PMC 1177610. PMID 4125095. 
  5. ↑ Pham-Huu-Trung M, de Smitter N, Bogyo A, Girard F (1984). "Effects of cyproterone acetate on adrenal steroidogenesis in vitro". Horm Res 20 (2): 108–15. doi:10.1159/000179982. PMID 6237971. 
  6. ↑ 6.0 6.1 6.2 6.3 de la Torre B, Norén S, Hedman M, Diczfalusy E (October 1979). "Effect of cyproterone acetate (CPA) on gonadal and adrenal function in men". Contraception 20 (4): 377–96. doi:10.1016/S0010-7824(79)80048-7. PMID 228907. 
  7. ↑ Städtler F, Langner V (1985). "The effect of cyproterone and gonadotrophins on the adrenal gland of juvenile and adult rats. A morphological and morphometrical study". Pathol Res Pract 179 (4–5): 493–8. doi:10.1016/S0344-0338(85)80189-8. PMID 4001026. 
  8. ↑ 8.0 8.1 Girard J, Baumann JB, Bühler U, et al. (September 1978). "Cyproteroneacetate and ACTH adrenal function". The Journal of Clinical Endocrinology and Metabolism 47 (3): 581–6. doi:10.1210/jcem-47-3-581. PMID 233676. 
  9. ↑ Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain R, Cornell W, Steele R, Schweitzer R, Schumacher C (2003). "Glucocorticoid receptor antagonism by cyproterone acetate and RU486". Mol Pharmacol 63 (5): 1012–20. doi:10.1124/mol.63.5.1012. PMID 12695529. 
  10. ↑ Poulin R, Baker D, Poirier D, Labrie F (1991). "Multiple actions of synthetic 'progestins' on the growth of ZR-75-1 human breast cancer cells: an in vitro model for the simultaneous assay of androgen, progestin, estrogen, and glucocorticoid agonistic and antagonistic activities of steroids". Breast Cancer Research and Treatment 17 (3): 197–210. doi:10.1007/BF01806369. PMID 1645605. 
  11. ↑ Holdaway I, Croxson M, Evans M, France J, Sheehan A, Wilson T, Ibbertson H (1983). "Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism". Acta Endocrinol (Copenh) 104 (2): 222–6. PMID 6227191. 
  12. ↑ H. J. T. Coelingh Bennink; H. M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. Taylor & Francis. p. 151. ISBN 978-1-85070-322-8. Retrieved 26 May 2012. 
  13. ↑ Bhargava AS, Kapp JF, Poggel HA, Heinick J, Nieuweboer B, Gunzel P (1981). "Effect of cyproterone acetate and its metabolites on the adrenal function in man, rhesus monkey and rat". Arzneimittelforschung 31 (6): 1005–9. PMID 6266428. 
  14. ↑ Donald RA, Espiner EA, Cowles RJ, Fazackerley JE (April 1976). "The effect of cyproterone acetate on the plasma gonadotrophin response to gonadotrophin releasing hormone". Acta Endocrinologica 81 (4): 680–4. PMID 769466. 
  15. ↑ Welsh National Public Health Service, ATTRACT project. "What therapies are available for women with PCOS with hirsutism other than Dianette?". 
  16. ↑ Grunwald K, Rabe T, Schlereth G, Runnebaum B (1994). "[Serum hormones before and during therapy with cyproterone acetate and spironolactone in patients with androgenization]". Geburtshilfe Frauenheilkd 54 (11): 634–45. doi:10.1055/s-2007-1022355. PMID 8719011. 
  17. ↑ Ayub M, Levell MJ (July 1987). "Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro". Journal of Steroid Biochemistry 28 (1): 43–7. doi:10.1016/0022-4731(87)90122-1. PMID 2956461. 
  18. ↑ O'Brien RC, Cooper ME, Murray RM, Seeman E, Thomas AK, Jerums G (May 1991). "Comparison of sequential cyproterone acetate/estrogen versus spironolactone/oral contraceptive in the treatment of hirsutism". The Journal of Clinical Endocrinology and Metabolism 72 (5): 1008–13. doi:10.1210/jcem-72-5-1008. PMID 1827125. 
  19. ↑ Grunwald K, Rabe T, Schlereth G, Runnebaum B (November 1994). "[Serum hormones before and during therapy with cyproterone acetate and spironolactone in patients with androgenization]". Geburtshilfe Und Frauenheilkunde (in German) 54 (11): 634–45. doi:10.1055/s-2007-1022355. PMID 8719011. 
  20. ↑ Frith R, Phillipou G (1985). "15-Hydroxycyproterone acetate and cyproterone acetate levels in plasma and urine". J Chromatogr 338 (1): 179–86. doi:10.1016/0378-4347(85)80082-7. PMID 3160716. 
  21. ↑ Fischl FH. (2001). "Pharmacology of Estrogens and Gestagens." (PDF). In Krause & Pachemegg. Menopause andropause. Gablitz: Krause und Pachernegg. pp. 33–50. ISBN 3-901299-34-3. 
  22. ↑ New Zealand Medicines and Medical Devices Safety Authority (2005-12-09). "Data Sheet: Diane 35 ED". 
  23. ↑ Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (1998). "The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions". J Clin Invest 102 (5): 1016–23. doi:10.1172/JCI3703. PMC 508967. PMID 9727070. 
  24. ↑ Adverse Drug Reactions Advisory Committee (February 2004). "Australian Adverse Drug Reactions Bulletin, Volume 23, Number 1". 
  25. ↑ Vasilakis-Scaramozza C, Jick H (2001). "Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives". Lancet 358 (9291): 1427–9. doi:10.1016/S0140-6736(01)06522-9. PMID 11705493. 
  26. ↑ Lidegaard et al.; Nielsen, L. H.; Skovlund, C. W.; Skjeldestad, F. E.; Lokkegaard, E. (2011). "Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses". BMJ 343: 1–15. doi:10.1136/bmj.d6423. 
  27. ↑ Mohan, Taylor & Mackeith (1998). "Cyproterone acetate and striae". International Journal of Clinical Practice 2 (2): 147–148. doi:10.3109/13651509809115348. 
  28. ↑ Itil TM (1983). "The discovery of antidepressant drugs by computer-analyzed human cerebral bio-electrical potentials (CEEG)". Prog Neurobiol 20 (3–4): 185–249. doi:10.1016/0301-0082(83)90003-5. PMID 6142498. 
  29. ↑ Healy DG, Harkin A, Cryan JF, Kelly JP, Leonard BE (1999). "Metyrapone displays antidepressant-like properties in preclinical paradigms". Psychopharmacology 145 (3): 303–8. doi:10.1007/s002130051062. PMID 10494579. 
  30. ↑ van der Vange N, Blankenstein M, Kloosterboer H, Haspels A, Thijssen J (1990). "Effects of seven low-dose combined oral contraceptives on sex hormone binding globulin, corticosteroid binding globulin, total and free testosterone". Contraception 41 (4): 345–52. doi:10.1016/0010-7824(90)90034-S. PMID 2139843. 
  31. ↑ Stalvey J (2002). "Inhibition of 3beta-hydroxysteroid dehydrogenase-isomerase in mouse adrenal cells: a direct effect of testosterone". Steroids 67 (8): 721–31. doi:10.1016/S0039-128X(02)00023-5. PMID 12117620. 
  32. ↑ Prostate Cancer Research Institute. "The Anti-Androgen Withdrawal Response". Retrieved 2005-08-31. 
  33. ↑ BNF 54 September 2007


Androgens (G03B)
Androgens
Agonists
Antiandrogens
Antagonists

M: ♂ MRS

anat/phys/devp

noco/cong/tumr, sysi/epon

proc, drug (G3B/4BE/4C)

Estrogens and progestogens (G03C-D, L02)
Progestogens
Agonist
1st
2nd
3rd
4th
17-OH
Other/
ungrouped
Antiprogestogens/
SPRMs
Estrogens
Agonists
Steroidal
Nonsteroidal
Antiestrogens/
SERMs
Aromatase inhibitors

M: ♀ FRS

anat/phys/devp

noco/cong/npls, sysi/epon

proc/asst, drug (G1/G2B/G3CD)

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