Cyproterone acetate

Source: Wikipedia, the free encyclopedia.

Cyproterone acetate
Clinical data
Trade namesAndrocur, Androcur Depot, Cyprostat, Siterone, others
Other namesSH-80714; SH-714; NSC-81430; 1α,2α-Methylene-6-chloro-17α-hydroxy-δ6-progesterone acetate; 1α,2α-Methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione acetate
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • X
Progestin; Progestogen ester; Antigonadotropin
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityOral: 68–100%[1][2]
Protein bindingAlbumin: 93%
Free: 7%[3][4][5][6]
MetabolismHepatic (CYP3A4)[11][12]
Metabolites• 15β-OH-CPATooltip 15β-Hydroxycyproterone acetate (major)[1][7]
• Cyproterone (minor)[8]
• Acetic acid (minor)[8]
Elimination half-lifeOral: 1.6–4.3 days[8][9][10]
IM: 3–4.3 days[2][8][10]
ExcretionFeces: 70%[8]
Urine: 30%[8]
Identifiers
  • (2aR,3aS,3bS,3cS,5aS,6R,8aS,8bR)-6-acetyl-10-chloro-3b,5a-dimethyl-2-oxo-2,2a,3,3a,3b,3c,4,5,5a,6,7,8,8a,8b-tetradecahydrocyclopenta[a]cyclopropa[g]phenanthren-6-yl acetat
JSmol)
Melting point200 to 201 °C (392 to 394 °F)
  • CC(=O)[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2C=C(C4=CC(=O)[C@@H]5C[C@@H]5[C@]34C)Cl)C)OC(=O)C
  • InChI=1S/C24H29ClO4/c1-12(26)24(29-13(2)27)8-6-16-14-10-20(25)19-11-21(28)18(15)23(19,4)17(14)5-7-22(16,24)3/h10-11,14-18H,5-9H2,1-4H3/t14-,15+,16-,17-,18-,22-,23-,24-/m0/s1
  • Key:UWFYSQMTEOIJJG-FDTZYFLXSA-N
  (verify)

Cyproterone acetate (CPA), sold alone under the brand name Androcur or

birth control pills.[1][9][13][14][15] It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth
one to three times per day.

Common

blood clots, liver damage and brain tumors. CPA can also cause adrenal insufficiency as a withdrawal effect if it is discontinued abruptly from a high dosage. CPA blocks the effects of androgens such as testosterone in the body, which it does by preventing them from interacting with their biological target, the androgen receptor (AR), and by reducing their production by the gonads, hence their concentrations in the body.[1][13][16] In addition, it has progesterone-like effects by activating the progesterone receptor (PR).[1][13] It can also produce weak cortisol-like effects at very high doses.[1]

CPA was discovered in 1961.[17] It was originally developed as a progestin.[17] In 1965, the antiandrogenic effects of CPA were discovered.[18] CPA was first marketed, as an antiandrogen, in 1973, and was the first antiandrogen to be introduced for medical use.[19] A few years later, in 1978, CPA was introduced as a progestin in a birth control pill.[20] It has been described as a "first-generation" progestin[21] and as the prototypical antiandrogen.[22] CPA is available widely throughout the world.[23][24] An exception is the United States, where it is not approved for use.[25][26]

Medical uses

CPA is used as a

sex drive in sex offenders or men with paraphilias or hypersexuality, to treat early puberty, and for other uses.[27] It is used both at low doses and at higher doses.[citation needed
]

In the United States, where CPA is not available, other medications with antiandrogenic effects are used to treat androgen-dependent conditions instead.

5α-reductase inhibitors finasteride and dutasteride.[28] The steroidal antiandrogen and progestin chlormadinone acetate is used as an alternative to CPA in Japan, South Korea, and a few other countries.[citation needed
]

Birth control

CPA is used with

combined birth control pill to prevent pregnancy. This birth control combination has been available since 1978.[20] The formulation is taken once daily for 21 days, followed by a 7-day free interval.[29] CPA has also been available in combination with estradiol valerate (brand name Femilar) as a combined birth control pill in Finland since 1993.[30][31] High-dose CPA tablets have a contraceptive effect and can be used as a form of birth control, although they are not specifically licensed as such.[32]

Skin and hair conditions

Females

CPA is used as an antiandrogen to treat

scalp hair loss, and hidradenitis suppurativa in women.[33][34][35][36][37][38][39] These conditions are worsened by the presence of androgens, and by suppressing androgen levels and blocking their actions, CPA improves the symptoms of these conditions. CPA is used to treat such conditions both at low doses as a birth control pill and on its own at higher doses.[33][34][35][36][40] A birth control pill containing low-dose CPA in combination with ethinylestradiol to treat acne has been found to result in overall improvement in 75 to 90% of women, with responses approaching 100% improvement.[41] High-dose CPA alone likewise has been found to improve symptoms of acne by 75 to 90% in women.[42] Discontinuation of CPA has been found to result in marked recurrence of symptoms in up to 70% of women.[43] CPA is one of the most commonly used medications in the treatment of hirsutism, hyperandrogenism, and polycystic ovary syndrome in women throughout the world.[44][45]

Higher dosages of CPA are used in combination with an estrogen specifically at doses of 25 to 100 mg/day cyclically in the treatment of hirsutism in women.

birth control pill containing ethinylestradiol and 2 mg/day CPA were no more effective or only marginally more effective in the treatment of severe hirsutism in women than the birth control pill alone.[45][47][44][48][49][50] Maintenance therapy with lower doses of CPA, such as 25 mg/day, has been found to be effective in preventing relapse of symptoms of hirsutism.[43] CPA has typically been combined with ethinylestradiol, but it can alternatively be used in combination with hormone replacement therapy dosages of estradiol instead.[45] CPA at a dosage of 50 mg/day in combination with 100 μg/day transdermal estradiol patches has been found to be effective in the treatment of hirsutism similarly to the combination of CPA with ethinylestradiol.[47][51]

The efficacy of the combination of an estrogen and CPA in the treatment of hirsutism in women appears to be due to marked suppression of total and free androgen levels as well as additional blockade of the androgen receptor.[44][45][52]

Males

CPA has been found to be effective in the treatment of acne in males, with marked improvement in symptoms observed at dosages of 25, 50, and 100 mg/day in different studies.

bone density loss, and reversible infertility, make the use of CPA in males impractical in most cases.[57][58][54][55][61][62][63] In addition, lower dosages of CPA, such as 25 mg/day, have been found to be better-tolerated in men.[55] But such doses also show lower effectiveness in the treatment of acne in men.[53]

High androgen levels

CPA is used as an antiandrogen to treat

masculinization due to conditions like polycystic ovary syndrome (PCOS) and congenital adrenal hyperplasia (CAH) in women.[34][39][64][65][66][67] It is almost always combined with an estrogen, such as ethinylestradiol, when it is used in the treatment of PCOS in women.[68]

Menopausal hormone therapy

CPA is used at low doses in

menopausal symptoms.[69][1][70][71] It is used in menopausal hormone therapy under the brand name Climen, which is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA.[69][70][71] Climen was the first product for use in menopausal hormone therapy containing CPA to be marketed.[70] It is available in more than 40 countries.[69]

Transgender hormone therapy

CPA is widely used as an antiandrogen and progestogen in feminizing hormone therapy for transgender individuals.[72][73][74][75][76][77][78] It has been historically used orally at a dosage of 10 to 100 mg/day and by intramuscular injection at a dosage of 300 mg once every 4 weeks.[79][80] Many transgender individuals seeking feminizing hormone therapy have breast growth as one of the goals for undergoing feminizing hormone therapy, making this particular side effect of CPA generally viewed as a beneficial outcome rather than an issue.[58]

Studies have found that 10, 25, 50, and 100 mg/day CPA in combination with estrogen all result in equivalent and full testosterone suppression in

Standards of Care for the Health of Transgender and Gender Diverse People, Version 8 (SOC8).[85]

CPA has an advantage over spironolactone as an antiandrogen in transgender people, as the combination of estrogen and CPA consistently suppresses testosterone levels into the normal female range whereas estrogen with spironolactone does not.[86][87][88][89][90][91][92] Spironolactone is the most widely used antiandrogen in transgender women in the United States, whereas CPA is widely used in Europe and throughout the rest of the world.[87][85]

Aside from adult transgender people, CPA has also been used as a

GnRH modulators are primarily used and more effective for this purpose.[93][94][74][95][96]

Prostate cancer

CPA is used as an antiandrogen monotherapy and means of

safety, CPA is rarely used in the treatment of prostate cancer today, having largely been superseded by GnRH modulators and nonsteroidal antiandrogens.[108][109] CPA is the only steroidal antiandrogen that continues to be used in the treatment of prostate cancer.[103]

overall survival compared to castration alone.[115] Hence, the use of CPA as the antiandrogen component in combined androgen blockade would appear not to be advisable.[115] When used by intramuscular injection to treat prostate cancer, CPA is used at a dosage of 300 mg once a week.[63]

The combination of CPA with an estrogen such as ethinylestradiol sulfonate or low-dose diethylstilbestrol has been used as a form of combined androgen blockade and as an alternative to the combination of CPA with surgical or medical castration.[114][116][117][118][119]

Sexual deviance

CPA is used as an antiandrogen and form of

GnRH modulators like leuprorelin and has more side effects.[121]

High-dose CPA significantly decreases

sexual activity in 80 to 90% of men with paraphilias.[125] In addition, it has been found to decrease the rate of reoffending in sex offenders from 85% to 6%, with most of the reoffenses being committed by individuals who did not follow their CPA treatment prescription.[125] It has been reported that in 80% of cases, 100 mg/day CPA is adequate to achieve the desired reduction of sexuality, whereas in the remaining 20% of cases, 200 mg/day is sufficient.[129] When only a partial reduction in sexuality is desired, 50 mg/day CPA can be useful.[129] Reduced sexual desire and erectile function occurs with CPA by the end of the first week of treatment, and becomes maximal within three to four weeks.[129][63] The dosage range is 50 to 300 mg/day.[63][129]

Early puberty

CPA is used as an antiandrogen and antiestrogen to treat

gonadotropin-independent precocious puberty.[132] CPA has been used at dosages of 50 to 300 mg/m2 to treat precocious puberty.[63][13]

Other uses

CPA is useful in the treatment of hot flashes, for instance due to androgen deprivation therapy for prostate cancer.[104][133][134][135]

CPA is useful for suppressing the testosterone flare at the initiation of GnRH agonist therapy.[136][104][137][9][65][138][139][140][141] It has been used successfully both alone and in combination with estrogens such as diethylstilbestrol for this purpose.[136][142]

Available forms

See also: Estradiol valerate/cyproterone acetate and Ethinylestradiol/cyproterone acetate

CPA is available in the form of oral tablets alone (higher-dose; 10 mg, 50 mg, 100 mg) or in combination with ethinylestradiol or estradiol valerate (low-dose; 1 or 2 mg CPA) and in the form of ampoules for intramuscular injection (higher-dose; 100 mg/mL, 300 mg/3 mL; brand name Androcur Depot).[143][144][145][146][147]

The higher-dose formulations are used to treat prostate cancer and certain other androgen-related indications while the low-dose formulations which also have an estrogen are used as

symptoms.[146][148]

Contraindications

Contraindications of CPA include:[149][150][52]

When CPA is used in combination with an estrogen, contraindications for

birth control pills should also be considered.[52]

Side effects

Main article: Side effects of cyproterone acetate

CPA is generally well-

quantitative data are available on many of the potential side effects of CPA.[154] Pooled tolerability data for CPA is not available in the literature.[155] Cyproterone is also known to suppress adrenocortical function.[156]

At very high doses in aged men with prostate cancer, CPA can cause

discontinuation from high doses, CPA can produce adrenal insufficiency as a withdrawal
effect.

Side effects of high-dose cyproterone acetate
Frequency
System Organ Class
 Side effect
Very common (≥10%)
administration site conditions
  • Tiredness
Psychiatric disorders
  • Reduced ejaculate volume
    (men)
breast disorders
Hepatobiliary disorders
Elevated liver enzymes
Common (≥1% and <10%)
nutrition disorders
fluid retention
)
Psychiatric disorders
breast disorders
administration site conditions
  • Sweating
mediastinal disorders
 Shortness of breath
Gastrointestinal disorders
  • Gastrointestinal complaints
Uncommon (≥0.1% and <1%)
Psychiatric disorders
Decreased libido
(women)
Skin and subcutaneous tissue disorders
 Rash
Rare (≥0.01% and <0.1%)
Immune system disorders
itching, shortness of breath
)
Psychiatric disorders
Increased libido
(women)
Very rare (<0.01%)
malignant
malignant liver tumors
connective tissue disorders
 Osteoporosis
Cardiovascular disorders
breast disorders
 Galactorrhea
administration site conditions
Sleep disturbances
Unspecified Unsorted
Notes: Side effects are for dosages of cyproterone acetate (Androcur) of 10 to 300 mg/day. Sources: See template.

Overdose

CPA is relatively safe in acute

symptom-based.[150] Gastric lavage can be used in the event of oral overdose within the last 2 to 3 hours.[150]

Interactions

St. John's wort.[150] Certain anticonvulsant medications can substantially reduce levels of CPA, by as much as 8-fold.[36]

Pharmacology

Pharmacodynamics

Main article: Pharmacology of cyproterone acetate § Pharmacodynamics

CPA has

antigonadotropic effects, and is able to suppress fertility and sex-hormone levels in both males and females.[1][13][52]

Pharmacokinetics

Main article: Pharmacology of cyproterone acetate § Pharmacokinetics

CPA can be taken

elimination half-life of about 2 to 4 days regardless of route of administration, and is excreted in feces primarily and to a lesser extent in urine.[1][4][10]

Chemistry

See also: List of progestogens, Progestogen ester, List of progestogen esters, Steroidal antiandrogen, and List of steroidal antiandrogens

CPA, also known as 1α,2α-methylene-6-chloro-17α-acetoxy-δ6-progesterone or as 1α,2α-methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione acetate, is a

17α-hydroxyprogesterone.[165][166] It is structurally related to other 17α-hydroxyprogesterone derivatives such as chlormadinone acetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate.[166]

Synthesis

Chemical syntheses of CPA have been published.[144][167][168] The following is one such synthesis:[169][170]

Partial synthesis of CPA, using hydroxyprogesterone acetate as a starting material, by Wiechert & Neumann (1965) and Wiechert (1966).[169][170]

The dehydrogenation of

17α-hydroxyprogesterone acetate [302-23-8] (1) with chloranil (tetrachloro-p-benzoquinone) gives a compound that has been called melengestrol acetate [425-51-4] (2). Dehydrogenation with selenium dioxide gives 17-acetoxy-1,4,6-pregnatriene-3,20-dione [2668-75-9] (3). 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, CID:134990386 (4). This compound cleaves when reacted with perchloric acid,[171]
releasing nitrogen molecules and forming a cyclopropane derivative, 6-deschloro cyproterone acetate [2701-50-0] (5). Selective oxidation of the C6=C7 olefin with benzoyl peroxide gives the epoxide, i.e. 6-deschloro-6,7-epoxy cyproterone [15423-97-9] (6). The penultimate step involves 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 giving 1α-(chloromethyl) chlormadinone acetate [17183-98-1] (7). The heating of this in collidine reforms the cyclopropane ring, completing the synthesis of CPA (8).

History

CPA was first synthesized in 1961 by Rudolf Wiechert, a Schering employee, and together with Friedmund Neumann in Berlin, they filed for a patent for CPA as "progestational agent" in 1962.[17][172] The antiandrogenic activity of CPA was discovered serendipitously by Hamada, Neumann, and Karl Junkmann in 1963.[173][63] Along with the steroidal antiandrogens benorterone (17α-methyl-B-nortestosterone; SKF-7690), cyproterone, BOMT (Ro 7–2340), and trimethyltrienolone (R-2956) and the nonsteroidal antiandrogens flutamide and DIMP (Ro 7–8117), CPA was one of the first antiandrogens to be discovered and researched.[41][174][175][176]

CPA was initially developed as a progestogen for the prevention of

teratogenic effects in female fetuses.[63] The drug was administered to pregnant rats and its effects on the rat fetuses were studied.[63] To the surprise of the researchers, all of the rat pups born appeared to be female.[63] After 20 female rat pups in a row had been counted, it was clear that this could not be a chance occurrence.[63] The rat pups were further evaluated and it was found that, in terms of karyotype, about 50% were actually males.[63] The male rat pups had been feminized, and this resultant finding constituted the discovery of the powerful antiandrogenic activity of CPA.[63] A year after patent approval in 1965, Neumann published additional evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain".[18] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation.[177]

The first clinical use of CPA in the treatment of

off-label indication, was reported as early as 1977.[188][189] The use of CPA in transgender women was well-established by the early 1990s.[190]

The history of CPA, including its discovery, development, and marketing, has been reviewed.[191][13]

Society and culture

Generic names

The

Latin is cyproteronum, in German is cyproteron, and in Spanish is ciproterona.[23][24] These names of cyproterone correspond for CPA to acétate de cyprotérone in French, acetato de ciproterona in Spanish, ciproterone acetato in Italian, cyproteronacetat in German, siproteron asetat in Turkish, and cyproteronacetaat in Dutch. CPA is also known by the developmental code names SH-80714 and SH-714, while unacetylated cyproterone is known by the developmental code names SH-80881 and SH-881.[23][24][192][193]

Brand names

CPA is marketed under brand names including Androcur, Androcur Depot, Androcur-100, Androstat, Asoteron, Cyprone, Cyproplex, Cyprostat, Cysaxal, Imvel, and Siterone.[23][24] When CPA is formulated in combination with ethinylestradiol, it is also known as co-cyprindiol, and brand names for this formulation include Andro-Diane, Bella HEXAL 35, Chloe, Cypretil, Cypretyl, Cyproderm, Diane, Diane Mite, Diane-35, Dianette, Dixi 35, Drina, Elleacnelle, Estelle, Estelle-35, Ginette, Linface, Minerva, Vreya, and Zyrona.[23][24] CPA is also marketed in combination with estradiol valerate as Climen, Climene, Elamax, and Femilar.[23]

Availability

Availability of CPA in countries throughout the world (as of March 2018). Turquoise is combined with an estrogen at a low dose, dark blue is alone at a high dose, and light blue is both available.

CPA is widely available throughout the world, and is marketed in almost every developed country,[195] with the notable major exceptions of the United States and Japan.[23][24][25][196][197] In almost all countries in which CPA is marketed, it is available both alone and in combination with an estrogen in birth control pills.[23][196][197] CPA is marketed widely in combination with both ethinylestradiol and estradiol valerate.[23][24][196][197] CPA-containing birth control pills are available in South Korea, but CPA as a standalone medication is not marketed in this country.[23][24][196][197] In Japan and South Korea, the closely related antiandrogen and progestin chlormadinone acetate, as well as other medications, are used instead of CPA.[198] Specific places in which CPA is marketed include the United Kingdom, elsewhere throughout Europe, Canada, Australia, New Zealand, South Africa, Latin America, and Asia.[23][24][196][197] CPA is not marketed in most of Africa and the Middle East.[23][24][196][197]

It has been said that the lack of availability of CPA in the United States explains why there are relatively few studies of it in the treatment of androgen-dependent conditions such as hyperandrogenism and hirsutism in women.[151]

Generation

Progestins in birth control pills are sometimes grouped by generation.

19-nortestosterone progestins are consistently grouped into generations, the pregnane progestins that are or have been used in birth control pills are typically omitted from such classifications or are grouped simply as "miscellaneous" or "pregnanes".[199][200] In any case, CPA has been described as a "first-generation" progestin similarly to closely related progestins like chlormadinone acetate, medroxyprogesterone acetate, and megestrol acetate.[21][201]

Research

CPA has been studied and used in combination with low-dose diethylstilbestrol in the treatment of prostate cancer.[116][118][117] The combination results in suppression of testosterone levels into the castrate range, which normally cannot be achieved with CPA alone.[118] CPA has been studied as a form of androgen deprivation therapy for the treatment of benign prostatic hyperplasia (enlarged prostate).[202][203][204] The medication has been studied in the treatment of breast cancer as well.[205][206]

CPA has been studied for use as a potential

estrogen hypersensitivity vulvovaginitis in women.[210]

CPA has been investigated for use in reducing

autism spectrum disorders, dementias like Alzheimer's disease, and psychosis.[211][212][213][214] CPA may be effective in the treatment of obsessive–compulsive disorder (OCD).[215][216][217][218] CPA has been studied in the treatment of cluster headaches in men.[219]

See also

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    S2CID 79095497
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  85. ^
    PMID 36238954
    .
  86. S2CID 254818114
    .
  87. ^
    S2CID 235335361
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  88. S2CID 221724686
    .
  89. S2CID 253707685
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  90. S2CID 236092532
    .
  91. S2CID 225334013
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  92. PMID 31234145
    .
  93. S2CID 52009542
    .
  94. PMID 25140398
    .
  95. S2CID 10690853
    .
  96. S2CID 31089247
    .
  97. ^
    PMID 16372511
    .
  98. ISBN 978-3-642-45747-0
    .
  99. ^
    S2CID 221762
    .
  100. S2CID 22747185
    .
  101. PMID 1825143
    .
  102. ISBN 978-0-7817-6879-5
    .
  103. ^
    S2CID 23128641
    .
  104. ^
    ISBN 978-0-12-800592-7. Archived
    from the original on 8 September 2017.
  105. S2CID 22300358
    .
  106. PMID 17007995
    .
  107. PMID 10637363
    . When compared to flutamide, [cyproterone acetate] has significant intrinsic androgenic and estrogenic activities. [...] The effects of flutamide and the steroidal derivatives, cyproterone acetate, chlormadinone acetate, megestrol acetate and medroxyprogesterone acetate were compared in vivo in female nude mice bearing androgen-sensitive Shionogi tumors. All steroidal compounds stimulated tumor growth while flutamide had no stimulatory effect [51]. Thus, CPA due to its intrinsic properties stimulates androgen-sensitive parameters and cancer growth. Cyproterone acetate added to castration has never been shown in any controlled study to prolong disease-free survival or overall survival in prostate cancer when compared with castration alone [152-155].
  108. PMID 18506331. Archived
    (PDF) from the original on 10 May 2017.
  109. ISBN 978-1-60547-431-1
    . From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
  110. ISBN 978-0-19-956142-1
    .
  111. S2CID 8639102
    .
  112. S2CID 25366526
    .
  113. ISBN 978-3-642-45745-6
    .
  114. ^
    ISBN 978-1-60761-471-5
    .
  115. ^
    PMID 17956709
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  116. ^
    PMID 7500443
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  117. ^
    PMID 8677581
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  118. ^
    PMID 2973529
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  119. ISBN 978-3-642-60064-7
    .
  120. PMID 25692326
    .
  121. ^
    PMID 26428645
    .
  122. PMID 10986575
    .
  123. S2CID 21981060
    .
  124. PMID 18996306
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  125. ^
    PMID 24877704
    .
  126. PMID 19161930
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  127. S2CID 37808515
    .
  128. PMID 3895195
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  129. ^
    PMID 1177426
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  130. PMID 18345393
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  131. ISBN 978-93-5025-777-7
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  132. PMID 1903104
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  133. PMID 19962840
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  134. PMID 15334868
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  135. PMID 2149457
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  136. ^
    PMID 16986003
    .
  137. ISBN 978-1-85317-422-3
    .
  138. S2CID 9151853
    .
  139. PMID 2144596
    .
  140. PMID 2949980
    .
  141. ISBN 9783110853674
    .
  142. S2CID 21824595
    .
  143. ISSN 1810-2107
    .
  144. ^
    ISBN 978-3-13-179275-4
    .
  145. ISBN 978-3-7692-2114-5
    .
  146. ^
    ISBN 978-0-7020-5182-1
    .
  147. ISBN 978-3-662-10498-9
    .
  148. ISBN 978-0-8151-5480-8
    .
  149. ^ "Androcur Label" (PDF).
  150. ^ a b c d e f g h "Mylan-Cyproterone Label" (PDF).
  151. ^
    PMID 20096826
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  152. S2CID 29236094
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  153. ^
    PMID 10352926
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  154. PMID 19243704
    . No quantitative data on these adverse events are available, even in the product prescribing information and data sheets.
  155. PMID 10673793
    .
  156. ^ Mylan-Cypersterone Monograph at 4. https://pdf.hres.ca/dpd_pm/00011374.PDF
  157. ISBN 978-0-19-517704-6
    .
  158. ISBN 978-0-7817-7968-5
    .
  159. ^
    ISBN 978-1-60327-829-4
    .
  160. S2CID 23872584
    .
  161. PMID 2956461
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  162. ISBN 978-0-470-57488-1
    .
  163. PMID 9727070
    .
  164. S2CID 17742146
    .
  165. ^
    ISBN 978-3-642-80861-6
    .
  166. ^
    ISBN 978-1-4612-4340-3
    .
  167. ^
    ISBN 978-0-8155-1856-3
    .
  168. ^ EP 1359154A1, Buddhasukh D, Maier R, Manosroi A, Manosroi J, Sripalakit P, Werner R, "Further syntheses of cyproterone acetate", published 5 November 2003 
  169. ^ a b "Verfahren zur Herstellung von 1, 2alpha-Methylen-delta-17alpha-hydroxy-progesteronen".
  170. ^ a b "6-chloro-1, 2alpha-methylene-delta6-17alpha-hydroxyprogesterone compounds and compositions".
  171. ^ Rudolf Wiechert, U.S. patent 3,127,396 (1964).
  172. ^ U.S. patent 3,234,093
  173. PMID 14071315
    .
  174. ISBN 978-1-4471-1300-3
    .
  175. ISBN 978-1-4832-5810-2
    .
  176. ISBN 978-3-642-88429-0
    .
  177. PMID 4949979
    .
  178. S2CID 14949511
    .
  179. PMID 2462132
    .
  180. S2CID 71214286
    .
  181. ISBN 978-1-118-46871-5
    .
  182. ^
    ISBN 978-0-683-04354-9
    .
  183. PMID 7000222
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  184. ^ "Androcur". Drug Product Database Online Query. Health Canada. 25 April 2012.
  185. ^ "Androcur Depot". Drug Product Database Online Query. Health Canada. 25 April 2012.
  186. ^ "DIANE-35". Drug Product Database Online Query. Health Canada. 25 April 2012.
  187. ISBN 978-0-7817-1750-2
    .
  188. S2CID 149168765
    .
  189. S2CID 56512058
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  190. S2CID 144580633
    .
  191. PMID 2967500
    .
  192. ^
    ISBN 978-1-4757-2085-3
    .
  193. ^
    ISBN 978-94-011-4439-1
    .
  194. ISBN 978-3-11-085727-6
    .
  195. ISBN 978-1-118-23277-4
    .
  196. ^ a b c d e f http://www.micromedexsolutions.com/micromedex2/[permanent dead link]
  197. ^
    ISBN 978-0-85369-840-1
    .
  198. ISBN 978-0-08-049789-1
    .
  199. ^
    ISBN 978-1-85070-067-8
    .
  200. ^
    ISBN 978-92-832-1291-1
    .
  201. ISBN 978-0-9645467-7-6
    .
  202. PMID 1702565
    .
  203. PMID 7516371
    .
  204. PMID 7516378
    .
  205. PMID 9767736
    .
  206. PMID 2968261
    .
  207. PMID 20933120
    .
  208. ISBN 9781139003353
    .
  209. ^ a b "Cyproterone acetate - Barr Laboratories - AdisInsight".
  210. S2CID 22365089
    .
  211. S2CID 11909534
    .
  212. S2CID 11479701
    .
  213. S2CID 28557481
    .
  214. PMID 1837749
    .
  215. S2CID 208956450
    .
  216. ISBN 978-0-88048-282-0
    .
  217. PMID 20623923
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  218. ISBN 978-84-7429-200-8
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  219. PMID 3366500
    .

Further reading

External links