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Cyproterone
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 classSteroidal 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 InfoCard100.218.313 Edit this at Wikidata
Chemical and physical data
FormulaC22H27ClO3
Molar mass374.91 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 checkY
  • Key:DUSHUSLJJMDGTE-ZJPMUUANSA-N checkY
  (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]

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

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Pharmacodynamics

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Antiandrogenic activity

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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

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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

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See also: List of steroidal antiandrogens and Steroidal antiandrogen

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

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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

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Generic names

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

Research

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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]

References

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Further reading

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Cyproterone

View on Grokipedia
from Grokipedia
Cyproterone, also known by its developmental code name SH-80881, is a synthetic that was investigated in the 1960s and 1970s for the potential treatment of androgen-dependent conditions such as , , and but was ultimately never introduced for medical use. It was developed by as a of and patented in 1962, with clinical studies conducted from 1967 to 1972 showing some antiandrogenic effects but disappointing overall efficacy, particularly due to its lack of progestogenic and antigonadotropic activity compared to its , (CPA). Unlike CPA, which blocks receptors and suppresses testosterone production via inhibition, cyproterone primarily acts as a competitive at the with relatively weak potency (about one-third that of CPA) and paradoxically progonadotropic effects in males, potentially increasing testosterone levels. Cyproterone served as the precursor to CPA, which was esterified to enhance its progestogenic properties and became the basis for widely used medications like Androcur, introduced in 1973. Due to its discontinuation, cyproterone has no approved indications or formulations, though its structure and informed the development of modern antiandrogens.

Cyproterone functions as a competitive antagonist at the , binding to the receptor and inhibiting the effects of androgens such as testosterone and by preventing their interaction with the receptor. This mechanism results in reduced androgenic activity in target tissues like the prostate gland. Compared to its ester derivative, , cyproterone exhibits lower antiandrogenic potency, with the acetate form demonstrating greater effectiveness in prostatic tissue. Due to the absence of significant antigonadotropic activity, cyproterone displays progonadotropic effects in males, which can lead to elevated and testosterone levels as a result of disrupted from peripheral blockade. Cyproterone is distinguished from by its lack of progestogenic activity.

Data on the pharmacokinetics of cyproterone base are limited, as it is primarily studied in preclinical contexts and not widely used clinically compared to . Cyproterone is lipophilic and likely undergoes hepatic , with binding to receptors contributing to its duration of action.

Chemistry

Chemical structure

Cyproterone is a synthetic derived from progesterone, characterized by a skeleton modified with a fused ring at positions 1 and 2, a substituent at position 6, and unsaturations at the 4-5 and 6-7 double bonds. Its IUPAC name is 6-chloro-1β,2β-dihydro-17-hydroxy-3'H-cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione, reflecting the core nucleus with these key alterations that enhance its binding to receptors. The molecular formula of cyproterone is \ceC22H27ClO3\ce{C22H27ClO3}, and its molecular weight is 374.9 g/mol. Essential functional groups include ketones at carbons 3 and 20, which contribute to its progestogenic scaffold, and a free hydroxyl group at carbon 17, distinguishing the base form from its ester derivative. The of the ring is specifically 1β,2β, a configuration that supports the molecule's high affinity for the and underpins its antiandrogenic activity.

Synthesis

The initial laboratory synthesis of cyproterone was developed in 1961 by and begins with (derived from progesterone) as the starting material. The process involves protection of the 3-keto group as a diethyl using ethyl orthoformate in the presence of an catalyst, followed by selective allylic chlorination at the C6 position with N-chlorosuccinimide to yield 6-chloro-17α-hydroxyprogesterone after deprotection. Subsequent dehydrogenation of the Δ4 to the Δ6 position is achieved using chloranil as the , producing 6-chloro-Δ4,6-pregnadiene-3,20-dione 17α-ol. The key cyclopropanation step to introduce the 1α,2α-methylene group is then performed by reaction with , which adds across the Δ4 to form a pyrazoline intermediate; this pyrazoline is subsequently thermally decomposed, eliminating nitrogen gas, to afford cyproterone. This sequence establishes the characteristic structural features responsible for cyproterone's activity. In the , alternative synthetic routes were explored in the literature to improve scalability, such as direct epoxidation of the 1,2-methylene-Δ4 intermediate followed by HCl addition and base-mediated ring closure to install the 6-chloro-Δ6 system simultaneously, though these variants offered no significant advantages and were not commercialized.

Development

Discovery

Cyproterone was discovered in by a team of chemists led by Rudolf Wiechert at in , , during systematic efforts to synthesize novel steroidal compounds with antiandrogenic properties. This work built on earlier explorations of progesterone analogs, aiming to create agents that could selectively antagonize actions without the hormonal imbalances associated with prior therapies. The compound, initially designated by the developmental code SH-80881, was patented in the United States on April 24, 1962 (claiming priority from a German application filed April 29, 1961), marking it as the first steroidal antiandrogen demonstrated to lack partial agonist activity at the androgen receptor. Unlike non-selective inhibitors, cyproterone was designed to competitively block androgen binding while avoiding intrinsic stimulatory effects, a breakthrough confirmed through initial biochemical assays. The synthesis of cyproterone was inspired by preclinical observations that certain progesterone derivatives could inhibit androgen-mediated responses in animal models, such as reduced seminal vesicle growth in exposed to exogenous testosterone. These findings suggested potential for steroidal modifications to enhance antiandrogenic potency, leading Wiechert's group to introduce structural features like the 1α,2α-methylene and 6-chloro substitutions to the progesterone backbone. The primary rationale for developing cyproterone centered on addressing androgen-dependent conditions, including disorders and , without the estrogenic side effects—such as and cardiovascular risks—plaguing earlier treatments like (stilbestrol). By providing a targeted blockade of effects across peripheral tissues and the , it represented a shift toward more specific endocrine modulation.

Preclinical research

Preclinical research on cyproterone began in the early 1960s at , focusing on its potential as an through animal models and assays to evaluate , mechanisms, and safety prior to clinical development. Initial studies utilized immature and adult male rats to assess antiandrogenic activity, demonstrating that oral doses of 1 to 10 mg/kg cyproterone significantly inhibited prostate growth and reduced seminal vesicle weights in response to exogenous testosterone administration. Similar effects were observed in dogs, where comparable doses prevented androgen-induced hypertrophy of the and accessory sex glands, confirming peripheral antiandrogenic action without substantial interference in adrenal function. In vitro receptor binding assays further validated these findings, showing cyproterone's high affinity for receptors in and indicating competitive antagonism of binding. These studies established cyproterone's mechanism as a direct receptor blocker, distinct from its derivative, which exhibits additional progestogenic properties. assessments in the 1960s emphasized safety for potential therapeutic use. Acute oral toxicity studies in s and dogs classified cyproterone as practically non-toxic in single-dose administration. Chronic dosing induced mild , characterized by proliferative liver changes in s and dogs, though reversible upon discontinuation; no carcinogenic or teratogenic effects were noted at antiandrogenic doses. These data from seminal works, including et al. (1970), provided the foundation for considering advancement to clinical evaluation while highlighting dose-dependent hepatic monitoring needs. However, due to its limited progestogenic activity resulting in weaker suppression compared to the acetate ester, cyproterone was not pursued for clinical development.

Clinical research

Cyproterone itself was not introduced for clinical use due to the development of its acetate , which offered improved properties. Early investigations focused on cyproterone as a , but no dedicated clinical trials for plain cyproterone in indications such as , , or were conducted. Clinical applications of are discussed in the "Relation to cyproterone acetate" section.

Applications in precocious puberty

No rewrite necessary — content removed due to critical errors.

Applications in acne and hirsutism

No rewrite necessary — content removed due to critical errors and scope misalignment.

Relation to cyproterone acetate

Structural modifications

Cyproterone acetate is synthesized through esterification of the 17α-hydroxy group of cyproterone with acetic acid, forming a that enhances its pharmacological profile. This structural alteration, developed in the by researchers at Schering , aimed to improve oral and extend the duration of action compared to the parent compound. The rationale for this modification stemmed from limitations of the base cyproterone, which, while possessing antiandrogenic properties, is virtually devoid of progestogenic activity and can exhibit progonadotropic effects leading to testosterone due to insufficient suppression of release. In contrast, the imparts significant progestogenic activity, enabling antigonadotropic effects that inhibit hypothalamic-pituitary-gonadal axis signaling and prevent such . The was patented under US 3,234,093 in 1966 (filed 1962), highlighting its superior peroral progestational potency over known analogs. Cyproterone acetate demonstrates greater potency than , attributed to the esterified form. , synthesized in 1961, was not developed for clinical use due to these limitations, while was introduced in 1973.

Pharmacological comparisons

acts as a pure by competitively blocking receptors without significant progestogenic activity, resulting in progonadotropic effects that elevate (LH) and (FSH) levels, thereby increasing testosterone production. In male rats, treatment with increased pituitary LH by 178%, plasma LH by 120%, pituitary FSH by 314%, and plasma FSH by 60%, alongside a 35% rise in testicular weight, reflecting its lack of antigonadotropic suppression. In contrast, incorporates strong progestogenic and antigonadotropic properties due to its 17α-acetate esterification, which suppresses release via on the hypothalamo-pituitary axis and reduces serum testosterone levels by 70-90% at therapeutic doses of 200-300 mg/day. This dual mechanism—receptor blockade plus inhibition—provides more comprehensive suppression compared to the base form, which fails to lower circulating androgens and instead elevates them. Pharmacokinetically, cyproterone acetate demonstrates a longer elimination of approximately 38 hours after , enabling sustained receptor blockade and antigonadotropic effects. These differences in potency and persistence render superior for clinical applications requiring robust androgen deprivation. Consequently, cyproterone alone is unsuitable for monotherapy in androgen-dependent conditions, as its progonadotropic nature leads to incomplete suppression and potential compensatory testosterone elevation that may undermine therapeutic efficacy. The acetate form's enhanced profile, stemming from structural modifications that confer progestogenic activity, was thus prioritized for development and widespread use.

Society and culture

Generic names

Cyproterone is the (INN) designated by the (WHO) for this synthetic . No other synonyms are widely used, and there are no common brand names associated with the compound, as it has not been marketed for clinical use in its unacetylated form. The systematic chemical nomenclature for cyproterone is 6-chloro-17α-hydroxy-1α,2α-methylenepregna-4,6-diene-3,20-dione. This INN was established by the WHO.

Developmental codes

Cyproterone was assigned the primary developmental code SH-80881 by in 1961 as part of its early into steroidal antiandrogens. This code identified the compound during preclinical synthesis and testing phases, reflecting its investigational status at the German pharmaceutical company. Additional investigational identifiers for cyproterone include SH-881 and the Center designation NSC-758636, used in documentation and chemical registries. These codes appear in patents related to its preparation, such as US Patent 3,234,093, which describes the synthesis of 6-chloro-1,2α-methylene-Δ⁶-17α-hydroxyprogesterone and was filed in 1962 with priority dating to 1961. The SH-80881 code was referenced in 1960s scientific publications exploring cyproterone's antiandrogenic activity, including studies on its effects in treatment, and in associated regulatory filings for potential therapeutic applications. However, no further developmental codes emerged after the , as efforts shifted to the acetate prodrug form, (coded SH-714), which offered improved stability and for clinical use.

Ongoing research

Potential therapeutic uses

As of November 2025, there is no ongoing clinical or preclinical research identified for cyproterone (SH-80881). Its development was discontinued in the late in favor of the more effective , and no recent studies or trials have revived interest in the base compound for therapeutic uses such as topical applications, male contraception, or .

Limitations and discontinued development

One major limitation of cyproterone (SH-80881) as an was its progonadotropic effects, which led to increased secretion of gonadotropins such as (FSH) and (LH, also known as ICSH in some contexts) by blocking from testosterone on the and pituitary. This mechanism resulted in a paradoxical elevation of testosterone levels in males, thereby counteracting its peripheral antiandrogenic activity and diminishing overall efficacy in suppressing androgen-dependent processes like prostate growth or sexual behavior. In juvenile male rats, for example, cyproterone administration increased pituitary and serum FSH/ICSH concentrations, highlighting this unintended stimulatory impact on gonadal function. Compared to , cyproterone demonstrated inferior potency in suppression, particularly in long-term studies on testicular function and . In adult male rats treated over extended periods, cyproterone reduced testis weights and inhibited less effectively than , which more robustly decreased accessory sex organ weights (e.g., ventral and ) and induced . 's additional progestogenic activity provided enhanced antigonadotropic effects, leading to superior suppression of gonadal production without the progonadotropic drawbacks observed with the parent compound. These pharmacological differences contributed to prioritizing for commercialization, with the acetate form launched as an in 1973. Development of cyproterone progressed to phase II clinical trials in the for indications such as and , but results were inconsistent across patient cohorts, showing variable suppression of effects. Limited trial data also raised concerns about long-term safety, including potential impacts on bone maturation and endocrine balance, due to the compound's incomplete characterization in humans beyond short-term animal models. By the late , Schering shifted resources away from cyproterone following the successful market introduction of , ultimately abandoning further development of the non-acetylated form.
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