Cyproterone acetate

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Cyproterone acetate
230px
Acetato de ciproterona3D.png
Systematic (IUPAC) name
(1R,3aS,3bR,7aR,8aS,8bS,8cS,10aS)-1-Acetyl-5-chloro-8b,10a-dimethyl-7-oxo-1,2,3,3a,3b,7,7a,8,8a,8b,8c,9,10,10a-tetradecahydrocyclopenta[a]cyclopropa[g]phenanthren-1-yl acetate
Clinical data
Trade names Androcur, Cyprostat, Siterone, others
AHFS/Drugs.com Micromedex Detailed Consumer Information
Pregnancy
category
  • X
Legal status
  • ℞ (Prescription only)
Routes of
administration
Oral, intramuscular
Pharmacokinetic data
Bioavailability 100%
Protein binding 96%
Metabolism liver
Biological half-life 40 hours
Excretion 60% bile, 33% renal
Identifiers
CAS Number 427-51-0 YesY
ATC code G03HA01 (WHO)
PubChem CID: 9880
IUPHAR/BPS 2865
ChemSpider 9496 YesY
UNII 4KM2BN5JHF YesY
ChEBI CHEBI:50743 YesY
ChEMBL CHEMBL139835 YesY
Chemical data
Formula C24H29ClO4
Molecular mass 416.94 g/mol
  • O=C4\C=C3\C(\Cl)=C/[C@@H]1[C@H](CC[C@@]2([C@@](OC(=O)C)(C(=O)C)CC[C@@H]12)C)[C@@]3(C)[C@H]5C[C@@H]45
  • InChI=1S/C24H29ClO4/c1-12(26)24(29-13(2)27)8-6-16-14-10-20(25)19-11-21(28)15-9-18(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 (abbreviated as CPA), also sold under brand names such as Androcur among others, is a synthetic, steroidal antiandrogen, progestin, and antigonadotropin.[1] 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.[2] CPA is also used for its progestogenic effects, for instance, as a component of some combined oral contraceptive pills in combination with ethinyl estradiol, such as in Diane-35 among others.[3]

Medical uses

CPA has been in use as an antiandrogen since 1964, and was the first antiandrogen introduced for clinical use.[4] It is used widely 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 the United States instead.[5] 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.[6] Combination formulations of CPA with ethinyl estradiol, a formulation sometimes referred to as co-cyprindiol, have been available as contraceptives since 1997.[4]

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 it is not available and spironolactone, a diuretic with antiandrogen properties, is generally employed instead, CPA is widely used as a component of hormone replacement therapy (HRT) for trans women.[7]

In the treatment of acne in women, a formulation of daily CPA in combination with ethinyl estradiol has been found to result in overall improvement in 75–90% of people, with responses approaching 100% improvement.[8]

Investigational

CPA may be effective in the treatment of obsessive-compulsive disorder (OCD).[9] In very limited clinical research, it has been reported to be "considerably" effective in the treatment of OCD in women.[10][11]

Side effects

Feminization

Side effects in males resulting directly from the antiandrogen and antigonadotropic properties of CPA include physical demasculinization, gynecomastia (breast enlargement) and general physical feminization, breast pain/tenderness, galactorrhea (milk outflow), sexual dysfunction (including loss of libido and erectile dysfunction), impaired spermatogenesis, and reversible infertility.[4] In the treatment of men with prostate cancer, CPA has been described as causing "severe" suppression of libido and erectile potency, comparable to that seen with surgical castration.[12]

Depression

CPA has been associated with an increased rate of depression in both men and women.[13] It has been reported that as many as 20–30% of women treated with the drug for hirsutism (dosage range 25–100 mg) may show depressive symptoms.[14][15] Also, a study found that around 20% of women treated with Dianette (which contains only 2 mg CPA) for contraceptive purposes developed depression.[16] As the antiandrogen component of transgender HRT, treatment with CPA (as well as with spironolactone to a lesser extent) has also been associated with a significantly higher rate of depressive symptomatology in trans women relative to treatment with GnRH analogues (which are more selective in their action and are considered not to have a significant risk of depression in this patient population (with concomitant supplementation of estrogen)).[17] The depressive effects of CPA may be related to its glucocorticoid, antiandrogen, and/or antigonadotropic effects, as glucocorticoids, antiandrogens (in men), and GnRH analogues have all been associated with depression.[18][19][20][21] Vitamin B12 deficiency induced by CPA might also or alternatively be a critical factor.[16] Because of the side effect of depression, CPA should be used with caution in individuals with a history of the condition, especially if severe.[22]

Vitamin B12 deficiency

High-dose CPA treatment has been found to produce vitamin B12 deficiency.[23][24] Low-dose (2 mg/day) CPA in combination with ethinyl estradiol has also been associated with vitamin B12 deficiency.[8] It is notable that vitamin B12 deficiency is associated with depression, anxiety, irritability, and fatigue via depletion of central monoamine neurotransmitters,[25][26] and it has been suggested that this may be involved in the adverse neuropsychiatric consequences commonly observed with CPA therapy.[16] Serum vitamin B12 monitoring and supplementation as necessary is recommended during CPA treatment.[23][24][8]

Blood clots

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.[27] 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.[28]

Hepatotoxicity

The most serious potential side effect of CPA is hepatotoxicity, and patients should be monitored for changes in liver enzymes, especially if taking a high dose (e.g., above 50–100 mg/day, and even more especially at the range of 200–300 mg/day).[29] Toxicity is dose-dependent, and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.[30]

Meningiomas

Very rarely, high-dose (but not low-dose (i.e., contraceptive-dose)) CPA treatment has been associated with the incidence and aggravation of meningiomas (a type of usually-benign brain tumor).[31][32] For this reason, high-dose CPA is contraindicated in people with meningioma or a history of meningoma.[22][33]

Miscellaneous

High-dose CPA in combination with estrogen has been associated with a dramatically (400-fold) increased incidence of hyperprolactinemia in trans women.[34] Estrogen alone has been associated only with single case reports of prolactinoma in this population.[34]

Due to suppression of the production of estrogens, long-term use of high-dose CPA without concomitant estrogen therapy can result in the development of osteoporosis in both sexes.[35]

CPA has been associated with the formation of stretch marks, due potentially to glucocorticoid activity and/or causing dry skin.[36]

Withdrawal

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.[37] Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects.[citation needed] This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production.[38]

Adrenal insufficiency

Suppression of adrenal function and reduced response to adrenocorticotropic hormone (ACTH) have been reported with CPA treatment. As a result, adrenal insufficiency and hence low cortisol and aldosterone levels and ACTH responsiveness can occur upon discontinuation of CPA. 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 or discontinue the medication.

Antiandrogen withdrawal syndrome

A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptors. These altered androgen receptors 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.[39]

Pharmacology

Activity profile

CPA is known to possess the following pharmacological activity:

CPA is equally potent as a progestogen and antiandrogen.[45] It is the most potent progestin of the 17α-hydroxyprogesterone group, being 1200-fold more potent than hydroxyprogesterone acetate, 12-fold more potent than medroxyprogesterone acetate, and 3-fold more potent than chlormadinone acetate.[45] The progestins of the 17α-hydroxyprogesterone group are extremely potent; in fact, CPA is the strongest progestogen known, with about 1000-fold the potency of progesterone in an animal assay.[46] CPA is also reported to be the most powerful antiandrogen known.[46]

CPA may also have a slight direct inhibitory effect on 5α-reductase, though the evidence for this is sparse and conflicting.[47][48][49] 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.[50][51]

CPA does not have significant affinity for the estrogen receptor (ER) or for the mineralocorticoid receptor (MR).[citation needed]

CPA has been found to bind non-selectively to the opioid receptors, including the μ-, δ-, and κ-opioid receptor subtypes, albeit very weakly relative to its other actions (IC50 for inhibition of [3H]diprenorphine binding = 1.62 ± 0.33 µM).[52] It has been suggested that activation of opioid receptors could have the potential to explain the side effect of sedation sometimes seen at high doses with CPA treatment and/or its effectiveness in the treatment of cluster headaches.[52]

Antiandrogenic

CPA is a potent androgen receptor (AR) competitive antagonist.[40] 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.[40][53][54][55] 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 inherently 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.[53][54] 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.[40][56]

Progestogenic

CPA is an extremely potent progestin;[57] as mentioned previously, it is the most potent progestin known.[46] It is effective as a hormonal contraceptive (combined with low-dose ethinyl estradiol) at a dosage of 2 mg/day.[57][58]

Through its action as a progestogen, CPA has been found to significantly increase prolactin secretion and to induce extensive lobuloalveolar development of the mammary glands of female rhesus macaques.[59] In accordance, a study found that CPA, in all cases, induced full lobuloalveolar development in trans women treated with the drug in combination with estrogen for a prolonged period of time.[60][61][62] Pregnancy-like breast hyperplasia was observed in two of the subjects.[62] In contrast, the same study found that men with prostate cancer treated with a non-progestogenic antiandrogen such as flutamide or bicalutamide and no estrogen showed only moderate and incomplete lobuloalveolar development of the breasts.[60] Based on the above research, it was concluded by the study authors that combined estrogenic and progestogenic action is required in trans women for full, female-like histologic breast development including lobuloalveolar maturation.[60][61] Also, it was noted that lobuloalveolar maturation reverses upon discontinuation of CPA after surgical castration, indicating that continued progestogen treatment is necessary to maintain the histology.[60]

The action of CPA as a progestogen is responsible for its antigonadotropic effects.[40][57]

Antigonadotropic

CPA has powerful antigonadotropic effects.[40] In humans, it blunts the gonadotropin releasing hormone (GnRH)-induced secretion of gonadotropins,[63] 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.[64][65][66][67][68] The antigonadotropic effects of CPA are mediated by hyperactivation of the PR.[12][40][57] However, its inhibition of steroidogenic enzymes may also contribute to its ability to suppress sex hormone levels.[69]

Glucocorticoidic

Due to negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis, administration of exogenous glucocorticoids such as prednisone and dexamethasone suppress the secretion of adrenocorticotropic hormone (ACTH) from the pituitary gland and the production of cortisol from the adrenal glands, resulting in adrenal suppression and atrophy and, upon discontinuation of the glucocorticoid, temporary adrenal insufficiency. Similarly, albeit relatively weakly, CPA has the ability to reduce ACTH and cortisol levels and produce adrenal gland shrinkage, as well as, upon discontinuation, adrenal insufficiency, in both animals and humans, indicating that it possesses glucocorticoid properties.[70][71][72][73][74][75] Paradoxically however, in vitro, CPA is an antagonist of the glucocorticoid receptor (GR)[41][76][77] and a suppressor of adrenal cortisol and corticosterone production by inhibiting the enzymes 3β-hydroxysteroid dehydrogenase and 21-hydroxylase,[71][78][79][80] which are antiglucocorticoid actions. This paradox may be explained by the fact that certain active metabolites of CPA, such as its major metabolite 15β-hydroxycyproterone acetate (which is present at serum levels approximately twice those of CPA in humans[81]),[82] are, contrarily, agonists of the GR,[83] and it can be assumed that their glucocorticoid actions overall significantly outweigh the simultaneous antiglucocorticoid actions of CPA. Both cyproterone and CPA, via their metabolites, have been found to possess glucocorticoid effects, and based on studies in mice, it has been suggested that CPA has approximately 1/5th the potency of prednisone as a glucocorticoid.[84]

While various studies have clearly shown reduced cortisol and ACTH levels and ACTH responsiveness in humans with CPA treatment, some studies contradict their findings and report no such effects even with high dosages.[83][85][86][87][88]

Megestrol acetate, medroxyprogesterone acetate, and chlormadinone acetate, steroidal progestins and close analogues of CPA, all similarly possess glucocorticoid properties and the potential for producing adrenal insufficiency upon their discontinuation.[89][90]

Estrogenic

Because CPA does not bind to the ER, and because it suppresses estrogen production via its action as an antigonadotropin, the drug produces no general estrogenic effects (direct or indirect), and is potently antiestrogenic at sufficient dosages. However, androgens potently antagonize the action of estrogen in the breasts, so CPA can produce a sole indirect estrogenic effect of slight gynecomastia in males via its action as an antiandrogen. In any case, the incidence and severity of this side effect is less than that observed with non-steroidal antiandrogens such as flutamide, which, in contrast, do not lower estrogen levels (and actually can increase them).[91][92]

Pharmacokinetics

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.[93] However, unlike many other steroid esters, CPA is not extensively hydrolyzed, and much of its pharmacological activity is attributable to its unchanged form.[29] CPA has approximately three times the potency as an antiandrogen of cyproterone;[94] in addition, cyproterone is completely devoid of progestogenic activity.[46]

CPA is metabolized by CYP3A4, forming the major active metabolite 15β-hydroxycyproterone acetate. This metabolite retains antiandrogen activity, but has reduced activity as a progestogen.[81][95][96] As a result, the co-administration of CPA with drugs which inhibit CYP3A4 may increase its potency as a progestogen.

Dosage and administration

As an oral contraceptive, CPA is combined with ethinyl estradiol and taken once daily for 21 days, followed by a 7-day free interval.[citation needed]

For the treatment of hypersexuality, severe hirsutism, or for the treatment of trans women, 50–100 mg daily is usually sufficient, although higher doses per day is permitted.[citation needed] 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.[citation needed]

High doses may be 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.[citation needed]

History

CPA was discovered in the early 1960s, and Rudolf Wiechert, a Schering employee, together with F. Neumann in Berlin filed for a patent as "progestational agent" in 1962.U.S. Patent 3,234,093 Only one year after patent approval in 1965, Neumann published evidence of CPA's antiandrogenic effect in rats; he reported an "organizational effect of CPA on the brain".[97]

During the same year, in 1966, prenatal administration of CPA in male rats was shown to cause urogenital malformations by a group in Lund, Sweden.[98] CPA started being used in animal experiments around the world to investigate how antiandrogens affected fetal sexual differentiation.

In 1970, the first human experiments with CPA began by measuring serum levels after oral administration,[99] rates of spermatogenesis, and hair growth in women. Starting in 1972, psychiatrists trialed "sexually deviant" persons with CPA.[100] In 1973, CPA was first approved in Europe, under the brand name Androcur.[101][102] In the mid-1970s, non- or weakly-progestogenic antiandrogens like spironolactone became available. Until the development of leuprolide, CPA was one of the few drugs used to treat precocious puberty.

Society and culture

Names

Cyproterone acetate is the INN, USAN, BAN, JAN. It is also known as 1,2α-methylene-6-chloro-δ6-17α-acetoxyprogesterone.

Brand names for when it is used in combination with ethinyl estradiol include Diane-35 throughout most of the world, Dianette in the United Kingdom, Bella Hexal in Germany, Diane in Sweden, and Dixi-35 in Chile.[3]

See also

References

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