|Systematic (IUPAC) name|
|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; abbreviated as CPA), 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 this country 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.
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.
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.
Dosage and administration
As an oral contraceptive, 2 mg CPA is combined with 35 or 50 mcg 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, 25 mg twice daily is usually sufficient, although up to 100 mg 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.
Doses up to 300 mg/day are 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 acetate is made from 17α-hydroxyprogesterone acetate.
Dehydrating this using chloranil (tetrachloro-p-benzoquinone) results in formation of an additional double bond at position C6–C7, and subsequent dehydration using selenium dioxide to form the corresponding divinyl ketone, 17α-acetoxy-1,4,6-pregnatrien-3,20-dione. Reacting this with diazomethane results in a 1,3-dipolar addition reaction at C1–C2 of the double bond of the steroid system, which forms a derivative of dihydropyrazole. This compound cleaves when reacted with perchloric acid, releasing nitrogen molecules and forming a cyclopropane derivative. Next, the double bond at C6–C7 is selectively oxidized by benzoyl peroxide, and the resulting epoxide undergoes a reaction with hydrochloric acid in acetic acid, resulting in the formation of chlorine and its subsequent dehydration, and a simultaneous opening of the cyclopropane ring. Heating this in collidine results in intramolecular alkylation, causing cyclization into a cyclopropane ring, which forms cyproterone acetate.
- 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.
- Jonathan S. Berek (2007). Berek & Novak's Gynecology. Lippincott Williams & Wilkins. p. 1085. ISBN 978-0-7817-6805-4.
- Sarah H. Wakelin (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. p. 32. ISBN 978-1-84076-013-2.
- Dr Marius Duker; Dr Marijke Malsch (28 January 2013). Incapacitation: Trends and New Perspectives. Ashgate Publishing, Ltd. p. 77. ISBN 978-1-4094-7151-6.
- Mario Maggi (17 November 2011). Hormonal Therapy for Male Sexual Dysfunction. John Wiley & Sons. p. 104. ISBN 978-1-119-96380-6.
- J. Larry Jameson; David M. de Kretser; John C. Marshall; Leslie J. De Groot (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN 978-0-323-22152-8.
- William Figg; Cindy H. Chau; Eric J. Small (14 September 2010). Drug Management of Prostate Cancer. Springer. p. 71. ISBN 978-1-60327-829-4.
- Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain RE, 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.
- 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.
- Lehmann JM, McKee DD, Watson MA, Willson TM, Moore JT, Kliewer SA (September 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.
- Christians U, Schmitz V, Haschke M (December 2005). "Functional interactions between P-glycoprotein and CYP3A in drug metabolism". Expert Opin Drug Metab Toxicol 1 (4): 641–54. doi:10.1517/17425255.1.4.641. PMID 16863430.
- Rabe T, Kowald A, Ortmann J, Rehberger-Schneider S (2000). "Inhibition of skin 5 alpha-reductase by oral contraceptive progestins in vitro". Gynecol. Endocrinol. 14 (4): 223–30. doi:10.3109/09513590009167685. PMID 11075290.
- Stárka L, Sulcová J, Broulík P (1976). "Effect of cyproterone acetate on the action and metabolism of testosterone in the mouse kidney". Endokrinologie 68 (2): 155–63. PMID 1009901.
- Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
- Tartagni M, Schonauer LM, De Salvia MA, Cicinelli E, De Pergola G, D'Addario V (2000). "Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism". Fertil. Steril. 73 (4): 718–23. doi:10.1016/s0015-0282(99)00633-0. PMID 10731531.
- Sahin Y, Dilber S, Keleştimur F (2001). "Comparison of Diane 35 and Diane 35 plus finasteride in the treatment of hirsutism". Fertil. Steril. 75 (3): 496–500. doi:10.1016/s0015-0282(00)01764-7. PMID 11239530.
- Gutiérrez M, Menéndez L, Ruiz-Gayo M, Hidalgo A, Baamonde A (1997). "Cyproterone acetate displaces opiate binding in mouse brain". Eur. J. Pharmacol. 328 (1): 99–102. doi:10.1016/s0014-2999(97)83034-8. PMID 9203575.
- Luthy IA, Begin DJ, Labrie F (1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". J. Steroid Biochem. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
- Térouanne B, Tahiri B, Georget V, Belon C, Poujol N, Avances C, Orio F, Balaguer P, Sultan C (2000). "A stable prostatic bioluminescent cell line to investigate androgen and antiandrogen effects". Mol. Cell. Endocrinol. 160 (1-2): 39–49. doi:10.1016/s0303-7207(99)00251-8. PMID 10715537.
- Marc A. Fritz; Leon Speroff (20 December 2010). Clinical Gynecologic Endocrinology and Infertility. Lippincott Williams & Wilkins. p. 80. ISBN 978-0-7817-7968-5. Retrieved 27 May 2012.
- Lewis J. Kampel (20 March 2012). Dx/Rx: Prostate Cancer: Prostate Cancer. Jones & Bartlett Publishers. p. 169. ISBN 978-1-4496-8695-6.
- 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.
- Moltz L, Römmler A, Post K, Schwartz U, Hammerstein J (1980). "Medium dose cyproterone acetate (CPA): effects on hormone secretion and on spermatogenesis in men". Contraception 21 (4): 393–413. doi:10.1016/s0010-7824(80)80017-5. PMID 6771095.
- Rost A, Schmidt-Gollwitzer M, Hantelmann W, Brosig W (1981). "Cyproterone acetate, testosterone, LH, FSH, and prolactin levels in plasma after intramuscular application of cyproterone acetate in patients with prostatic cancer". Prostate 2 (3): 315–22. doi:10.1002/pros.2990020310. PMID 6458025.
- Jeffcoate WJ, Matthews RW, Edwards CR, Field LH, Besser GM (1980). "The effect of cyproterone acetate on serum testosterone, LH, FSH, and prolactin in male sexual offenders". Clin. Endocrinol. (Oxf) 13 (2): 189–95. doi:10.1111/j.1365-2265.1980.tb01041.x. PMID 6777092.
- 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 (in German) 54 (11): 634–45. doi:10.1055/s-2007-1022355. PMID 8719011.
- Salva P, Morer F, Ordoñez J, Rodriguez J (1983). "Treatment of idiopathic hirsute women with two combinations of cyproterone acetate". Int J Clin Pharmacol Res 3 (2): 129–35. PMID 6237068.
- Schürenkämper P, Lisse K (1982). "Effects of cyproterone on the steroid biosynthesis in the human ovary in vitro". Endokrinologie 80 (3): 281–6. PMID 7166160.
- Pham-Huu-Trung MT, 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.
- 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.
- Städtler FA, 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.
- Girard J, Baumann JB, Bühler U, Zuppinger K, Haas HG, Staub JJ, Wyss HI (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.
- Honer C, Nam K, Fink C, Marshall P, Ksander G, Chatelain RE, 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.
- 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.
- Holdaway IM, Croxson MS, Evans MC, France J, Sheehan A, Wilson T, Ibbertson HK (1983). "Effect of cyproterone acetate on glucocorticoid secretion in patients treated for hirsutism". Acta Endocrinol (Copenh) 104 (2): 222–6. PMID 6227191.
- 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.
- Bhargava AS, Kapp JF, Poggel HA, Heinick J, Nieuweboer B, Günzel 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.
- Medicines and Healthcare products Regulatory Authority (2006-04-11). "Cyproterone Acetate" (PDF).
- Berlex Canada, Inc. (2003-02-10). "Cyproterone Acetate Tablets and Injections Product Monographs (revised version)" (PDF).
- Giorgi EP, Shirley IM, Grant JK, Stewart JC (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.
- Frith RG, 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.
- 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.
- New Zealand Medicines and Medical Devices Safety Authority (2005-12-09). "Data Sheet: Diane 35 ED".
- Adverse Drug Reactions Advisory Committee (February 2004). "Australian Adverse Drug Reactions Bulletin, Volume 23, Number 1".
- 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.
- Lidegaard Ø, Nielsen LH, Skovlund CW, Skjeldestad FE, Løkkegaard E; 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. PMID 22027398.
- Mohan D, Taylor R, Mackeith JA (1998). "Cyproterone acetate and striae". International Journal of Clinical Practice 2 (2): 147–148. doi:10.3109/13651509809115348. PMID 24946296.
- James Barrett (2007). Transsexual and Other Disorders of Gender Identity: A Practical Guide to Management. Radcliffe Publishing. p. 174. ISBN 978-1-85775-719-4.
- 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.
- 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.
- van der Vange N, Blankenstein MA, Kloosterboer HJ, Haspels AA, Thijssen JH (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.
- Stalvey JR (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.
- Prostate Cancer Research Institute. "The Anti-Androgen Withdrawal Response". Retrieved 2005-08-31.
- U.S. Patent 3,127,396