Cyproterone

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Cyproterone
Cyproterone.svg
Clinical data
Other namesSH-80881; SH-881; NSC-758636; 1α,2α-Methylene-6-chloro-17α-hydroxy-δ6-progesterone; 1α,2α-Methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione
Routes of
administration
By mouth, topical
Drug class Steroidal antiandrogen
ATC code
Identifiers
  • (1S,2S,3S,5R,11R,12S,15R,16S)-15-acetyl-9-chloro-15-hydroxy-2,16-dimethylpentacyclo[9.7.0.02,8.03,5.012,16]octadeca-7,9-dien-6-one
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.218.313 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H27ClO3
Molar mass 374.91 g·mol−1
3D model (JSmol)
  • 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)O
  • InChI=1S/C22H27ClO3/c1-11(24)22(26)7-5-14-12-9-18(23)17-10-19(25)13-8-16(13)21(17,3)15(12)4-6-20(14,22)2/h9-10,12-16,26H,4-8H2,1-3H3/t12-,13+,14-,15-,16-,20-,21-,22-/m0/s1 Yes check.svgY
  • Key:DUSHUSLJJMDGTE-ZJPMUUANSA-N Yes check.svgY
   (verify)

Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. [1] [2] [3] It is a precursor of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. [1] [2] Cyproterone and CPA were among the first antiandrogens to be developed. [4]

Contents

The term cyproterone is often used as a synonym and shorthand for cyproterone acetate, and when the term occurs, what is almost always being referred to is, confusingly, CPA and not actually cyproterone. Cyproterone itself, unlike CPA, was never introduced for medical use and hence is not available as a medication.

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Cyproterone is a potent antiandrogen, similarly to CPA. [5] [6] However, it has approximately three-fold lower potency as an antagonist of the androgen receptor (AR) relative to CPA. [6] Like CPA, cyproterone is actually a weak partial agonist of the AR, and hence has the potential for both antiandrogenic and androgenic activity in some contexts. [7] Unlike CPA (which is a highly potent progestogen), cyproterone is a pure antiandrogen [3] and is virtually devoid of progestogenic activity. [8] [9] [10] [11] As such, it is not an antigonadotropin, and is actually progonadotropic in males, increasing gonadotropin and testosterone levels due to inhibition of AR-mediated negative feedback on the hypothalamic–pituitary–gonadal axis. [5] [11] [12]

Due to its progonadotropic effects in males, unlike CPA, cyproterone has been found, in male rodents, to increase testicular weight, increase the total number of type A spermatogonia, increase the total number of Sertoli cells, [13] hyperstimulate the Leydig cells, and to have almost no effect on spermatogenesis. Conversely, it has also been reported for male rodents that spermiogenesis is inhibited and that accessory sexual gland weights (e.g., prostate gland, seminal vesicles) and fertility were markedly reduced, although with rapid recovery from the changes upon cessation of treatment. [12] In any case, the medication is said to not be an effective antispermatogenic agent, whereas CPA is effective. [14] Also unlike CPA, due to its lack of progestogenic and antigonadotropic activity, cyproterone does not suppress ovulation in women. [3] [15]

Other activities

Both CPA and, to a smaller extent, cyproterone possess some weak glucocorticoid activity and suppress adrenal gland and spleen weight in animals, with CPA having about one-fifth the potency of prednisone in mice. [8] [16] Unlike CPA, cyproterone seems to show some inhibition of 17β-hydroxysteroid dehydrogenase and 5α-reductase in vitro . [6] In contrast to CPA, cyproterone shows no affinity for opioid receptors. [17]

Chemistry

Cyproterone, also known as 1α,2α-methylene-6-chloro-17α-hydroxy-δ6-progesterone or as 1α,2α-methylene-6-chloro-17α-hydroxypregna-4,6-diene-3,20-dione, is a synthetic pregnane steroid and a derivative of progesterone. [1] [2] It is the free alcohol or 17α-deacetylated analogue of CPA. [1] [2]

History

Cyproterone, along with CPA, was first patented in 1962, [18] with subsequent patents in 1963 and 1965. [1] It was studied clinically between 1967 and 1972. [19] [20] Unlike CPA, the medication was never marketed for medical use. [1] [2] Cyproterone was the first pure antiandrogen to be developed, [21] with other closely following examples of this class including the steroidal antiandrogens benorterone and BOMT and the nonsteroidal antiandrogen flutamide. [4]

Society and culture

Generic names

Cyproterone is the generic name of the drug and its INN Tooltip International Nonproprietary Name. [1] [2] It is also known by the developmental code names SH-80881 and SH-881. [1] [2]

Research

In clinical studies, cyproterone was found to be far less potent and effective as an antiandrogen than CPA, likely in significant part due to its lack of concomitant antigonadotropic action. [3] Cyproterone was studied as a treatment for precocious puberty by Bierich (1970, 1971), but no significant improvement was observed. [22] In men, 100 mg/day cyproterone proved to be rather ineffective in treating acne, which was hypothesized to be related to its progonadotropic effects in males and counteraction of its antiandrogen activity. [3] [23] In women however, who have much lower levels of testosterone and in whom the medication has no progonadotropic activity, 100 to 200 mg/day oral cyproterone was effective in reducing sebum production in all patients as early as 2 to 4 weeks following the start of treatment. [3] In contrast, topical cyproterone was far less effective and barely outperformed placebo. [3]

Another study showed disappointing results with 100 mg/day cyproterone for reducing sebum production in women with hyperandrogenism. [3] Similarly, the medication showed disappointing results in the treatment of hirsutism in women, with a distinct hair reduction occurring in only a limited percentage of cases. [3] In the same study, the reduction of acne was better, but was clearly inferior to that produced by CPA, and only the improvement in seborrhea was regarded as satisfactory. [3] The addition of an oral contraceptive to cyproterone resulted in a somewhat better improvement in acne and seborrhea relative to cyproterone alone. [3] According to Jacobs (1979), "[cyproterone] proved to be without clinical value for reasons that cannot be discussed here." [24] In any case, cyproterone has been well tolerated by patients in dosages of up to 300 mg/day. [3]

Related Research Articles

<span class="mw-page-title-main">Antiandrogen</span> Class of pharmaceutical drugs

Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.

<span class="mw-page-title-main">Progestogen (medication)</span> Medication producing effects similar to progesterone

A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.

<span class="mw-page-title-main">Chlormadinone acetate</span> Chemical compound

Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.

<span class="mw-page-title-main">Medrogestone</span> Chemical compound

Medrogestone, sold under the brand name Colprone among others, is a progestin medication which has been used in menopausal hormone therapy and in the treatment of gynecological disorders. It is available both alone and in combination with an estrogen. It is taken by mouth.

<span class="mw-page-title-main">Cyproterone acetate</span> Chemical compound

Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.

<span class="mw-page-title-main">Delmadinone acetate</span> Chemical compound

Delmadinone acetate (DMA), sold under the brand name Tardak among others, is a progestin and antiandrogen which is used in veterinary medicine to treat androgen-dependent conditions such as benign prostatic hyperplasia. It must be used with care as it has the potential to cause adrenal insufficiency via inhibition of adrenocorticotropic hormone (ACTH) secretion from the pituitary gland. DMA is the C17α acetate ester of delmadinone, which, in contrast to DMA, was never marketed for medical use.

<span class="mw-page-title-main">Benorterone</span> Chemical compound

Benorterone, also known by its developmental code name SKF-7690 and as 17α-methyl-B-nortestosterone, is a steroidal antiandrogen which was studied for potential medical use but was never marketed. It was the first known antiandrogen to be studied in humans. It is taken by mouth or by application to skin.

<span class="mw-page-title-main">Osaterone acetate</span> Chemical compound

Osaterone acetate, sold under the brand name Ypozane, is a medication which is used in veterinary medicine for the treatment of enlarged prostate in dogs. It is given by mouth.

<span class="mw-page-title-main">Hydroxyprogesterone acetate</span> Chemical compound

Hydroxyprogesterone acetate (OHPA), sold under the brand name Prodox, is an orally active progestin related to hydroxyprogesterone caproate (OHPC) which has been used in clinical and veterinary medicine. It has reportedly also been used in birth control pills.

<span class="mw-page-title-main">Anagestone acetate</span> Chemical compound

Anagestone acetate, sold under the brand names Anatropin and Neo-Novum, is a progestin medication which was withdrawn from medical use due to carcinogenicity observed in animal studies.

<span class="mw-page-title-main">Inocoterone acetate</span> Chemical compound

Inocoterone acetate is a steroid-like nonsteroidal antiandrogen (NSAA) that was developed for topical administration to treat acne but was never marketed. It is the acetate ester of inocoterone, which is less potent in comparison. Inocoterone acetate is actually not a silent antagonist of the androgen receptor but rather a weak partial agonist, similarly to steroidal antiandrogens like cyproterone acetate.

<span class="mw-page-title-main">Clomegestone acetate</span> Chemical compound

Clomegestone acetate, or clomagestone acetate, also known as 6-chloro-17α-acetoxy-16α-methylpregna-4,6-diene-3,20-dione, is a steroidal progestin of the 17α-hydroxyprogesterone group which was developed as an oral contraceptive but was never marketed. It is the acetate ester of clomegestone, which, similarly to clomegestone acetate, was never marketed. Clomegestone acetate is also the 17-desoxy cogener of clometherone, and is somewhat more potent in comparison. Similarly to cyproterone acetate, clomegestone acetate has been found to alter insulin receptor concentrations in adipose tissue, and this may indicate the presence of glucocorticoid activity.

<span class="mw-page-title-main">BOMT</span> Chemical compound

BOMT, also known by its developmental code name Ro 7-2340 and as 6α-bromo-4-oxa-17α-methyl-5α-dihydrotestosterone, is a synthetic steroidal antiandrogen which was first produced in 1970 and was never marketed for medical use. It is the 6α-brominated, 4-oxygenated, and 17α-methylated derivative of the androgen dihydrotestosterone (DHT). Along with benorterone, cyproterone, and flutamide, BOMT was among the earliest antiandrogens to be developed and extensively studied, although it is less well-documented in comparison to the others. BOMT has been investigated clinically in the treatment of benign prostatic hyperplasia, though development for this use did not continue. There was also interest in BOMT for the potential applications of acne, pattern hair loss, and possibly prostate cancer, but it was not developed for these indications either.

<span class="mw-page-title-main">Trimethyltrienolone</span> Chemical compound

Trimethyltrienolone (TMT), also known by its developmental code name R-2956 or RU-2956, is an antiandrogen medication which was never introduced for medical use but has been used in scientific research.

<span class="mw-page-title-main">Steroidal antiandrogen</span> Class of compounds

A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.

<span class="mw-page-title-main">15β-Hydroxycyproterone acetate</span> Chemical compound

15β-Hydroxycyproterone acetate (15β-OH-CPA) is a steroidal antiandrogen and the major metabolite of cyproterone acetate (CPA). It is formed from CPA in the liver by hydroxylation via the cytochrome P450 enzyme CYP3A4. During therapy with CPA, 15β-OH-CPA circulates at concentrations that are approximately twice those of CPA. 15β-OH-CPA has similar or even greater antiandrogen activity compared to CPA. However, it has only about one-tenth of the activity of CPA as a progestogen. 15β-OH-CPA also shows some glucocorticoid activity, similarly to CPA and unesterified cyproterone.

The pharmacology of progesterone, a progestogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.

<span class="mw-page-title-main">Pharmacodynamics of spironolactone</span> Mechanisms of action

The pharmacodynamics of spironolactone, an antimineralocorticoid and antiandrogen medication, concern its mechanisms of action, including its biological targets and activities, as well as its physiological effects. The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition. In addition, spironolactone has sometimes been found to increase estradiol and cortisol levels and hence could have slight indirect estrogenic and glucocorticoid effects. The medication has also been found to interact very weakly with the estrogen and progesterone receptors, and to act as an agonist of the pregnane X receptor. Likely due to increased activation of the estrogen and/or progesterone receptors, spironolactone has very weak but significant antigonadotropic effects.

<span class="mw-page-title-main">Pharmacology of cyproterone acetate</span>

The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.

<span class="mw-page-title-main">Ethinylestradiol/cyproterone acetate</span> Combination drug

Ethinylestradiol/cyproterone acetate (EE/CPA), also known as co-cyprindiol and sold under the brand names Diane and Diane-35 among others, is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also used to treat androgen-dependent conditions in women such as acne, seborrhea, excessive facial/body hair growth, scalp hair loss, and high androgen levels associated with ovaries with cysts. The medication is taken by mouth once daily for 21 days, followed by a 7-day free interval.

References

  1. 1 2 3 4 5 6 7 8 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 339–. ISBN   978-1-4757-2085-3.
  2. 1 2 3 4 5 6 7 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 289. ISBN   978-3-88763-075-1 . Retrieved 29 May 2012.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 Orfanos CE, Happle R (1990). Hair and Hair Diseases. Springer Science & Business Media. pp. 1197–. ISBN   978-3-642-74612-3.
  4. 1 2 Schröder FH, Radlmaier A (2009). "Steroidal Antiandrogens". In Jordan VC, Furr BJ (eds.). Hormone Therapy in Breast and Prostate Cancer . Cancer Drug Discovery and Development. Humana Press. pp.  325–346. doi:10.1007/978-1-59259-152-7_15. ISBN   978-1-60761-471-5. The progestational effect [of CPA] is linked to the presence of the acetyl group at position C17 of the steroid. Consequently, the free alcohol of CPA, cyproterone, which lacks the acetyl group, is devoid of progestational properties. However, it still exerts antiandrogenic activity, although less pronounced than CPA. Consequently, cyproterone was the first compound falling into the nowadays well-known class of pure antiandrogens.
  5. 1 2 Moltz L, Römmler A, Schwartz U, Hammerstein J (1978). "Effects of Cyproterone Acetate (CPA) on Pituitary Gonadotrophin Release and on Androgen Secretion Before and After LH-RH Double Stimulation Tests in Men". International Journal of Andrology. 1 (s2b): 713–719. doi: 10.1111/j.1365-2605.1978.tb00518.x . ISSN   0105-6263. [...] Hammerstein 1977). This consideration is based on the fact that free cyproterone is a potent anti- androgen without antigonadotrophic activity and causes, therefore, an increase in gonadotrophins and in androgens (Graf et al. 1974). In [...]
  6. 1 2 3 Giorgi EP, Shirley IM, Grant JK, Stewart JC (March 1973). "Androgen dynamics in vitro in the human prostate gland. Effect of cyproterone and cyproterone acetate". The Biochemical Journal. 132 (3): 465–474. doi:10.1042/bj1320465. PMC   1177610 . PMID   4125095. Cyproterone (6-chloro-17-hydroxy-1,2α-methylenepregna-4,6-diene-3,20-dione) and cyproterone acetate (17-acetoxy-6-chloro-1,2α-methylene-pregna-4,6-diene-3,20-dione) are powerful anti-androgens, which exert multiple actions in many species. Cyproterone acetate has three times the anti-androgenic potency of cyproterone, and also has some progestational properties (for review, see Neumann et al., 1970). [...] Cyproterone seemed to decrease the activity of 17α-hydroxysteroid dehydrogenase and of 5α-steroid reductase in human prostate in vitro, as it does in testes and liver of rats (Breuer & Hoffmann, 1967; Hoffmann & Breuer, 1968; Denef et al., 1968). Cyproterone acetate did not seem to have any direct effect on the activity of these two enzymes.
  7. Sawyer CH, Gorski RA (1971). Steroid Hormones and Brain Function. University of California Press. pp. 366–. ISBN   978-0-520-01887-7.
  8. 1 2 Hughes A, Hasan SH, Oertel GW, Voss HE, Bahner F, Neumann F, et al. (27 November 2013). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 279–. ISBN   978-3-642-80859-3. The only chemical difference between cyproterone and cyproterone acetate consists of a free or esterified hydroxyl group at C17 but this difference accounts for profound differences in the mechanism of action and possibilities for use in the intact organism. Both steroids are highly active antiandrogens at any route of administration, the acetate has a greater antiandrogenic potency than the free alcohol. With the exception of a slight depressive effect on the adrenals, cyproterone does not have other side-activities unrelated to antiandrogenicity. It has, therefore, been termed "pure antiandrogen". Cyproterone acetate has one major additional activity: it is one of the strongest gestagens that have ever been synthesized [23, 70, 32, 77], [...]
  9. Hammerstein J (1981). "Antiandrogens — Basic Concepts for Treatment". Hair Research. pp. 330–335. doi:10.1007/978-3-642-81650-5_49. ISBN   978-3-642-81652-9. Contrary to benorterone, free cyproterone, and flutamide, CPA is not a pure anti- androgen. In fact, it is one of the most potent progestogens known and, in comparison to that potency, it is a relatively weak antiandrogen and a still weaker anti- gonadotropin.
  10. Spona J, Schneider WH, Bieglmayer C, Schroeder R, Pirker R (1979). "Ovulation inhibition with different doses of levonorgestrel and other progestogens: clinical and experimental investigations". Acta Obstetricia et Gynecologica Scandinavica Supplement. 88 (s88): 7–15. doi:10.3109/00016347909157223. PMID   393050. S2CID   30486799. Cyproterone which has a very weak biological progestogen potency exhibited low affinity for the progestogen-receptor (Table I).
  11. 1 2 Labhart A (6 December 2012). Clinical Endocrinology: Theory and Practice. Springer Science & Business Media. pp. 473–. ISBN   978-3-642-96158-8. Cyproterone acetate is 250 and 3330 times as potent a progestational agent as progesterone and cyproterone alcohol (10< respectively (Clauberg assay). [...] The pure anti-androgens, such as cyproteron, block the receptors of the negative feedback system. An uninhibited secretion of the releasing factors and an increased production of gonadotropins results, so that the inhibitory effect on the endorgans may finally be overcome by overpoduction of testosterone (Neumann, 1971). Cyproterone acetate, however, with its marked progestational effect, inhibits the release of LH and FSH at the same time and thus has a lasting anti-androgenic effect (Neumann, 1970). Thus, cyproteron leads to an increase in LH, whereas cyproteron acetate inhibits both LH and FSH.
  12. 1 2 Steinbeck H, Mehring M, Neumann F (July 1971). "Comparison of the effects of cyproterone, cyproterone acetate and oestradiol on testicular function, accessory sexual glands and fertility in a long-term study on rats". Journal of Reproduction and Fertility. 26 (1): 65–76. doi: 10.1530/jrf.0.0260065 . PMID   5091295.
  13. Viguier-Martinez MC, Hochereau De Reviers MT (1977). "Comparative action of cyproterone and cyproterone acetate on pituitary and plasma gonadotropin levels, the male genital tract and spermatogenesis in the growing rat" (PDF). Annales de Biologie Animale, Biochimie, et Biophysique. 17 (6): 1069–1076. doi: 10.1051/rnd:19770814 .
  14. Ewing LL, Robaire B (1978). "Endogenous antispermatogenic agents: prospects for male contraception". Annual Review of Pharmacology and Toxicology. 18 (1): 167–187. doi:10.1146/annurev.pa.18.040178.001123. PMID   206192. Cyproterone (6-chloro-17a-hydroxy-1a,2a-methylene-pregna-4,6-diene-3,20-dione) and cyproterone acetate have received considerable attention as antispermatogenic substances. Cyproterone, which has·only weak antigonadotropic properties, was found to be a poor antispermatogenic agent (42). In contrast, cyproterone acetate, which inhibits gonadotropin secretion, was found to be an antispermatogenic agent (142).
  15. Stewart ME, Pochi PE (April 1978). "Antiandrogens and the skin". International Journal of Dermatology. 17 (3): 167–179. doi:10.1111/j.1365-4362.1978.tb06057.x. PMID   148431. S2CID   43649686. While CPA alone probably suppresses ovulation, cyproterone, which possesses no progestational activity, does not!8,72
  16. Broulik PD, Starka L (November 1975). "Corticosteroid-like effect of cyproterone and cyproterone acetate in mice". Experientia. 31 (11): 1364–1365. doi:10.1007/bf01945829. PMID   1204803. S2CID   11452300.
  17. Gutiérrez M, Menéndez L, Brieva R, Hidalgo A, Baamonde A (November 1998). "Different types of steroids inhibit [3H]diprenorphine binding in mouse brain membranes". General Pharmacology. 31 (5): 747–751. doi:10.1016/s0306-3623(98)00110-4. PMID   9809473.
  18. U.S. patent 3,234,093
  19. Apostolakis M, Tamm J, Voigt KD (1967). "Biochemical and Clinical Studies with Cyproterone". European Journal of Endocrinology. 56 (1 Suppl): S56. doi:10.1530/acta.0.056S056. ISSN   0804-4643.
  20. Walsh PC, Swerdloff RS, Odell WD (June 1972). "Cyproterone: effect on serum gonadotropins in the male". Endocrinology. 90 (6): 1655–1659. doi:10.1210/endo-90-6-1655. PMID   5020316.
  21. Craig JV, Furr BJ (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 326–. ISBN   978-1-59259-152-7.
  22. Rager K, Huenges R, Gupta D, Bierich JR (October 1973). "The treatment of precocious puberty with cyproterone acetate". Acta Endocrinologica. 74 (2): 399–408. doi:10.1530/acta.0.0740399. PMID   4270254. Free cyproterone was first tried as a therapy for precocious puberty by Bierich (1970, 1971). The results, however, did not show any significant improvement.
  23. Raspé G (1969). Schering Workshop on Steroid Metabolism: "in vitro versus in vivo.". Pergamon Press. ISBN   9780080175447. [...] In this investigation a number of normal male volunteers were treated for three weeks with 100 mg free cyproterone per day. Sebum production was measured by the Straufi-Pochi method before treatment and on the 7th, 10th, 11th, 15th, 18th, [...]
  24. Jacobs HS (1979). Advances in gynaecological endocrinology: proceedings of the Sixth Study Group of the Royal College of Obstetricians and Gynaecologists, 18th and 19th October, 1978. Great Britain \): Royal College of Obstetricians and Gynaecologists. p. 367. ISBN   978-0-87489-225-3. Limited clinical experience also exists with benorterone, the first anti-androgen tried in man, and with free cyproterone. In the late sixties benorterone was reported to give promising results in 93 androgenized women but was soon withdrawn from clinical trial, mainly because of the development of gynaecomastia in the male. As a big advantage compared with CPA, it was found to be effective not only orally but also topically. Free cyproterone, on the other hand, proved to be without clinical value for reasons that cannot be discussed here. Thus we are left with CPA as the only anti-androgen that is already on the market in several countries.

Further reading