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| Trade names | Belara, Lutéran, Prostal, others |
| Other names | CMA; RS-1280; ICI-39575; STG-155; NSC-92338; 17α-Acetoxy-6-chloro-6-dehydroprogesterone; 17α-Acetoxy-6-chloropregna-4,6-diene-3,20-dione |
| Routes of administration | By mouth[1] |
| Drug class | Progestogen;Progestin;Progestogen ester;Antigonadotropin;Steroidal antiandrogen |
| ATC code | |
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| Pharmacokinetic data | |
| Bioavailability | 100%[1][2][3] |
| Protein binding | 96.6–99.4% (toalbumin and not toSHBGTooltip sex hormone-binding globulin orCBGTooltip corticosteroid-binding globulin)[1][2] |
| Metabolism | Liver (reduction,hydroxylation,deacetylation,conjugation)[1][3] |
| Metabolites | •3α-Hydroxy-CMA[4][1] •3β-Hydroxy-CMA[4][1] • Others[1] |
| Eliminationhalf-life | 25–89 hours[5][1][2][6] |
| Excretion | Urine: 33–45%[6][2] Feces: 24–41%[6][2] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.005.563 |
| Chemical and physical data | |
| Formula | C23H29ClO4 |
| Molar mass | 404.93 g·mol−1 |
| 3D model (JSmol) | |
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Chlormadinone acetate (CMA), sold under the brand namesBelara,Gynorelle,Lutéran, andProstal among others, is aprogestin andantiandrogen medication which is used inbirth control pills to preventpregnancy, as a component ofmenopausal hormone therapy, in the treatment ofgynecological disorders, and in the treatment ofandrogen-dependent conditions likeenlarged prostate andprostate cancer in men andacne andhirsutism in women.[1][5][7][2][8][9][10] It is available both at a low dose in combination with anestrogen in birth control pills and, in a few countries likeFrance andJapan, at low, moderate, and high doses alone for various indications.[11] It is takenby mouth.[1]
Side effects of the combination of an estrogen and CMA includemenstrual irregularities,headaches,nausea,breast tenderness,vaginal discharge, and others.[2] At high dosages, CMA can causesexual dysfunction,demasculinization,adrenal insufficiency, and changes incarbohydrate metabolism among other adverse effects.[12][13] The drug is a progestin, or asyntheticprogestogen, and hence is anagonist of theprogesterone receptor, thebiological target of progestogens likeprogesterone.[1] It is also anantiandrogen, and hence is anantagonist of theandrogen receptor, thebiological target of androgens liketestosterone anddihydrotestosterone.[1] Due to its progestogenic activity, CMA hasantigonadotropic effects.[1][14][15] The medication has weakglucocorticoid activity and no other importanthormonal activity.[1]
CMA was discovered in 1959 and was introduced for medical use in 1965.[16][17][18] It may be considered a "first-generation" progestin.[19] The medication was withdrawn in some countries in 1970 due to concerns aboutmammarytoxicity observed in dogs, but this turned out not to apply to humans.[7][20][21][22][23] CMA is available widely throughout the world in birth control pills, but is notably not marketed in any predominantlyEnglish-speaking countries.[24][11] It is available alone in only a few countries, including France,Mexico, Japan, andSouth Korea.[24][11]
CMA is used at a low dose incombination withethinylestradiol (EE), anestrogen, incombined birth control pills.[5][25] It has also been used in the treatment ofgynecological conditions includingvaginal bleeding,oligomenorrhea,polymenorrhea,hypermenorrhea,dysmenorrhea, secondaryamenorrhea, andendometriosis and inFrance (under the brand name Lutéran) inmenopausal hormone therapy in combination with anestrogen.[7][5][25] CMA is used at dosages of 1 to 2 mg/day in combined birth control pills and at dosages of 2 to 10 mg/day in the treatment of gynecological disorders.[24] Combined birth control pills containing EE and CMA have been found to be useful in reducingandrogen-dependent symptoms such asskin and hair conditions.[2][26][27] Dosages of CMA of 15 to 20 mg/day have been found to improvehot flashes.[1] High-dose CMA-only tablets are used as a form ofprogestogen-only birth control, although they are not specifically licensed as such.[28]
CMA has been widely used as a means ofandrogen deprivation therapy in the treatment ofprostate cancer andbenign prostatic hyperplasia (BPH) inJapan andSouth Korea, but has seen little use for these indications elsewhere in the world.[8][9][10][13][11] It is used at dosages of 50 to 100 mg/day in the treatment of prostate diseases.[24] Similarly tocyproterone acetate (CPA), CMA shows a lower risk of hot flashes thangonadotropin-releasing hormone analogues (GnRH analogues).[13] The medication is the only othersteroidal antiandrogen besides CPA that has been approved and used for the treatment of prostate cancer;megestrol acetate has also been researched, but has not been approved.[7][29]
CMA has also been found to be effective in the treatment of otherandrogen-dependent conditions such asacne,seborrhea,hirsutism, andpattern hair loss in women, similarly to CPA.[7][2][30][27] It has been studied at moderate dosages of 4 to 12 mg/day in the treatment ofprecocious puberty in girls.[7] It showed similar benefits as those ofmedroxyprogesterone acetate in these girls and was found to reduce, but not abolish premature development such asbreast growth andmenstruation.[7] Only slight or noaxillary hair growth was observed in the girls.[7] CMA has also been used as a component ofhormone therapy fortransgender women, similarly to CPA andspironolactone, albeit mostly only in Japan.[31]
CMA has been used to prevent thetestosterone flare at the start ofgonadotropin-releasing hormone agonist therapy in men with prostate cancer.[32][33]
CMA is available in the form oforaltablets at low doses (2 mg) in combination with EE in birth control pills (e.g., as Belara inGermany and Brazil),[34] at low to moderate doses (2, 5, 10, 25 mg) alone (e.g., as Lutéran inFrance and Lutoral inMexico),[35][36] and at high doses (50 mg) alone (e.g., as Prostal inJapan and Prostal-L inSouth Korea).[11][37]
Contraindications of combined birth control pills, such as those containing EE and CMA, include known or suspectedpregnancy,lactation andbreastfeeding, a history of or known susceptibility tothromboembolism,cholestasis (but notliver cirrhosis orchronic hepatitis), andbreast cancer among others.[38] CMA is ateratogen in animals and may have the potential to causefetal harm, such asfeminization of male fetuses among other defects.[39][40]
The most commonside effects of birth control pills containing EE and low-dose CMA have been found to includemenstrual abnormalities,headache (37%),nausea (23%),breast tenderness (22%), andvaginal discharge (19%) among others.[2] These formulations do not adversely affectsexual desire orfunction in women and show little or no risk ofdepression,mood swings, orweight gain.[25][5] High-dosage CMA is associated withsexual dysfunction (e.g.,reduced libido,erectile dysfunction), reducedbody hair,adrenal insufficiency, and alterations incarbohydratemetabolism.[12][13] Conversely, it does not share adverse effects of estrogens such asbreast discomfort andgynecomastia.[7] CMA does not increase the risk ofvenous thromboembolism.[25][5] There is acase report ofautoimmune progesterone dermatitis with CMA.[23] Similarly to other progestins but in contrast toprogesterone, CMA has been found to significantly increase the risk ofbreast cancer when used in combination with an estrogen in menopausal hormone therapy.[41] No abnormalities inliver function tests have been observed in women taking combined birth control pills containing CMA or CPA.[2] Unlike CPA, high-dosage CMA does not seem to be associated withhepatotoxicity.[13]
Similarly tomegestrol acetate andmedroxyprogesterone acetate, CMA appears to show less potential forlivergenotoxicity andcarcinogenicity than CPA inbioassays.[42][43][44][45][46] This seems to be related to the lack of the C1α,2αmethylene group of CPA in these steroids.[43][47][44] A case ofhepatocellular carcinoma has been reported in a woman taking a birth control pill containing CMA.[45][42] However, the incidence ofliver tumors in women in association with CMA-containing birth control pills appears to be similar to that for birth control pills containing other progestins.[45]
CMA has been studied in men withadvanced prostate cancer at massive dosages of 1,000 to 2,000 mg/dayorally and 100 to 500 mg/day viaintramuscular injection, without seriousadverse effects ortoxicity described.[7][48]
As CMA does not inhibitcytochrome P450enzymes, it may have a lower risk ofdrug interactions than19-nortestosterone progestins.[5][2]
CMA hasprogestogenic activity,antigonadotropic effects,antiandrogenic activity, and weakglucocorticoid activity.[1][2]
| Compound | PRTooltip Progesterone receptor | ARTooltip Androgen receptor | ERTooltip Estrogen receptor | GRTooltip Glucocorticoid receptor | MRTooltip Mineralocorticoid receptor | SHBGTooltip Sex hormone-binding globulin | CBGTooltip Corticosteroid binding globulin | |
|---|---|---|---|---|---|---|---|---|
| CMA | 67–172 | 3–76 | 0 | 8 | 0 | 0 | 0 | |
| 3α-Hydroxy-CMA | 33 | 4 | ? | 2 | ? | ? | ? | |
| 3β-Hydroxy-CMA | 72 | 15 | ? | 6 | ? | ? | ? | |
| Notes: Values are percentages (%). Referenceligands (100%) werepromegestone for thePRTooltip progesterone receptor,metribolone for theARTooltip androgen receptor,E2 for theERTooltip estrogen receptor,DEXATooltip dexamethasone for theGRTooltip glucocorticoid receptor,aldosterone for theMRTooltip mineralocorticoid receptor,DHTTooltip dihydrotestosterone forSHBGTooltip sex hormone-binding globulin, andcortisol forCBGTooltip Corticosteroid-binding globulin.Sources:[1][2][4] | ||||||||
CMA is aprogestogen, or anagonist of theprogesterone receptor.[1][2] It is highlypotent in its progestogenic activity, with about 330 times the potency ofprogesterone in theClauberg test and about 2,000 to 10,000 times the oral potency of progesterone in the McPhail assay.[7][2] For comparison, the potencies ofmedroxyprogesterone acetate and CPA in the Clauberg assay were about 330- and 1,000-fold that of progesterone, respectively.[7] The progestogenic activity of CMA is responsible for its functionalantigonadotropic andantiestrogenic effects and for itscontraceptive effects.[1][25][7] The oralovulation-inhibiting dosage of CMA in women is 1.5 to 4 mg/day and itsendometrial transformation dosage is 25 mg/cycle.[1][49] In one study of ovulation inhibition, CMA was 68% effective at 1 mg/day, 85% effective at 2 mg/day, and 100% effective at 4 mg/day.[50] The effective dosage of CMA as aprogestogen-only pill for contraception is 0.5 mg/day.[51][52][49] Inhibition of ovulation is incomplete at this dosage and contraceptive effects are instead mainly achieved via progestogenic changes in theendometrium andcervix.[52][49]
In rabbitbioassays, PR activation was similar for CMA and its majoractive metabolites 3α-hydroxychlormadinone acetate (3α-OH-CMA) and 3β-hydroxychlormadinone acetate (3β-OH-CMA).[4]
Due to its progestogenic activity, CMA hasantigonadotropic effects, and hence can inhibit thesecretion of thegonadotropinsluteinizing hormone (LH) andfollicle-stimulating hormone (FSH) from thepituitary gland.[2][53][12] As a result, CMA suppressesovulation andgonadalsex hormoneproduction and can strongly decrease circulating testosterone and estradiol levels at sufficiently high dosages.[2][53][12] The medication at a dosage of 50 mg/day has been found to suppress testosterone levels by about 76 to 85% (to approximately 50–100 ng/dL) and estradiol levels by about 55 to 59% (to approximately 7–8 pg/mL) in men with BPH.[12] As such, CMA has powerful functionalantiandrogenic andantiestrogenic effects via its antigonadotropic effects.[2][14][15]
CMA is a potentantiandrogen, orantagonist of theandrogen receptor (AR), with about 30 to 40% of theaffinity of CPA for the receptor and about 20% of the antiandrogenic potency of CPA in animals.[1][54] Like other progestins with antiandrogenic activity such as CPA,megestrol acetate, andspironolactone, but unlikenonsteroidal antiandrogens such asflutamide andbicalutamide, CMA is not asilent antagonist of the AR but rather a weakpartial agonist with the capacity to activate the receptor in the absence of moreefficaciousagonists such astestosterone.[25][55] In rabbit bioassays, AR antagonism was similar for CMA and 3α-OH-CMA but lower for 3β-OH-CMA.[4] Both the antigonadotropic and antiandrogenic actions of CMA are thought to be involved in its effectiveness in the treatment of prostate cancer.[13]
When low-dose CMA is combined with EE, as in combined birth control pills, the antiandrogenic activity of CMA is reinforced, due to a large increase insex hormone-binding globulin (SHBG) levels and consequent fall in freetestosterone levels induced by EE.[25][56] Unlike19-nortestosterone progestins likelevonorgestrel, CMA does not antagonize the EE-induced increase in SHBG levels.[25][56]
Similarly to other17α-hydroxyprogesteronederivatives such as CPA, medroxyprogesterone acetate, and megestrol acetate, CMA has weak affinity for theglucocorticoid receptor (comparable to that ofprogesterone) and weakglucocorticoid activity, and has the potential to causeadrenal insufficiency upon abrupt discontinuation at sufficient dosages.[57][58][25] However, the medication shows significant glucocorticoid activity only at dosages much higher than those present in birth control pills.[2] In rabbit bioassays, GR activation was highest for CMA but less for 3α-OH-CMA and not observed with 3β-OH-CMA (suggesting that it may, in contrast, be a lowerefficacy partial agonist or antagonist of the GR).[4] CMA has no affinity for theestrogen ormineralocorticoid receptors and has noestrogenic orantimineralocorticoid activity.[1][2][5] Unlikeprogesterone but similarly to other progestins, CMA has no knownneurosteroid activity (e.g.,GABAA receptormodulation) orsedative effects.[1]
CMA has been reported to be acompetitive inhibitor of5α-reductase.[25][59] However, it seems to shows very lowpotency in this action, with 0.0% inhibition of theenzyme at a concentration of 1 μM, and in relation to this, has been said not to have an important influence on the enzyme.[1][5] CMA may also act weakly as atestosterone biosynthesis inhibitor at high dosages.[2] Unlike19-nortestosterone progestins, CMA does notinhibit enzymes in thecytochrome P450 system, which may give it a lower risk ofdrug interactions.[5][2]
Certain progestins have been found to stimulate theproliferation ofMCF-7breast cancercellsin vitro, an action that is independent of the classical PRs and is instead mediated via theprogesterone receptor membrane component-1 (PGRMC1).[60]Progesterone and CMA, in contrast, act neutrally in this assay.[60] It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins inclinical studies.[61]
Theoralbioavailability of CMA is 100%, which is due to lowfirst-pass metabolism.[1][2][3] In combination with 30 μg EE, a single 2 mg oral dose of CMA producedmaximal serum levels of 1.6 ng/mL after about 1 to 2 hours and chronic administration producedsteady-state levels of 2.0 ng/mL.[1][5][2] Steady-state concentrations of CMA are achieved after 7 to 15 days.[2][5] Thedistribution half-life of CMA is about 2.5 hours.[1][3][6] The medication is highlylipophilic and is taken up into and accumulated infat and somefemale reproductivetissues, although this may only occur at high dosages (e.g., ≥10 mg/day).[2][1] Thevolume of distribution of CMA is unknown, but that of the closely related steroid CPA is very large at 1,300 L.[2] Theplasma protein binding of CMA is 96.6 to 99.4%, with about 1 to 3% free.[1][2] It is bound toalbumin, with noaffinity for SHBG orcorticosteroid-binding globulin.[1]
CMA is extensivelymetabolized in theliver byreduction,hydroxylation,deacetylation, andconjugation.[1][2] Reduction occurs at the C3ketone with preservation of the δ4(5)double bond, hydroxylation is at the C2α, C3α, C3β, and C15β positions, and conjugation includesglucuronidation andsulfation.[1] The mainmetabolites of CMA are 2α-OH-CMA, 3α-OH-CMA, and 3β-OH-CMA, with the latter two being importantactive metabolites.[2][4] Other metabolites of CMA are inactive.[2] Theelimination half-life of CMA has been reported to be 25 to 34 hours after a single dose and 34 to 39 hours after multiple doses, although some publications have reported its half-life to be as long as 80 to 89 hours.[1][2][25][5][6]Enterohepatic reabsorption of CMA occurs.[2] The medication has been found to beexcreted 33 to 45% inurine and 24 to 41% infeces, as well as inbile.[6][2][1] Only 74% of a dose is excreted 7 days after administration, which is due to accumulation of CMA in tissues and lowclearance.[1]
CMA, also known as 17α-acetoxy-6-chloro-6-dehydroprogesterone or as 17α-acetoxy-6-chloropregna-4,6-diene-3,20-dione, is asyntheticpregnanesteroid andderivative ofprogesterone.[62][63] It is specifically a derivative of17α-hydroxyprogesterone with achlorine atom at the C6 position, adouble bond between the C6 and C7 positions, and anacetateester at the C17α position.[62][63] CMA is the C17α acetate ester ofchlormadinone, which, in contrast to CMA, was never marketed.[62][63]Analogues of CMA include other 17α-hydroxyprogesterone derivatives such asCPATooltip cyproterone acetate,delmadinone acetate,hydroxyprogesterone caproate,medroxyprogesterone acetate,megestrol acetate, andosaterone acetate.[62][63] CMA is identical inchemical structure to CPA except that it lacks the 1α,2α-methylenesubstitution of CPA.[62][63] The structure of CMA is also nearly the same as those of delmadinone acetate and osaterone acetate, which similarly have A-ring modifications.[62][63]
Chemical syntheses of CMA have been published.[64][37][65][66]
CMA was discovered and first described in 1959.[16][65] It was marketed in combination withmestranol byEli Lilly under the brand nameC-Quens from 1965 to 1971 in theUnited States.[17][18] It was the first sequential contraceptive pill to be introduced in theU.S.[18] CMA has also been marketed in combination with mestranol under the brand namesOvosiston,Aconcen, andSequens.[67][68] Due to findings ofmammary glandnodules inbeagledogs (seebelow), C-Quens was voluntarily withdrawn from theU.S. market by Eli Lilly in 1971 and all oral contraceptives of CMA were discontinued in theU.S. by 1972.[69] However, subsequent research found that there is no such risk in humans,[70] and CMA has continued to be widely used in oral contraceptives in many other countries, such asGermany andChina.[71] The antiandrogenic activity of CMA was first described in 1966,[5][72] and the medication was subsequently developed for use alone at high dosages in the treatment ofandrogen-dependent conditions likeprostate cancer.[8][9][10][13]
In the 1960s, CMA was introduced as a component oforal contraceptives.[17][18] However, around 1970, such formulations werewithdrawn from many markets such as theUnited States andUnited Kingdom due to the finding that CMA induced alarmingmammary glandtumors inBeagle dogs.[7][20][21][22][23] The doses administered that caused the nodules were 10 or 25 times the recommended human dosage for an extended period of time (2–4 years), while no tumors were found in dogs treated with 1–2 times the human dosage.[7][20][21] In addition to CMA, mammary tumors were found in dogs with various other 17α-hydroxyprogesterone derivatives, includingmedroxyprogesterone acetate,megestrol acetate, andanagestone acetate, and they were also discontinued for the indication of hormonal contraception (although medroxyprogesterone acetate has since been reintroduced).[20][21] Tumors were also observed withprogesterone, as well as withethynerone andchloroethynylnorgestrel, but notably not with the non-halogenated19-nortestosterone derivativesnorgestrel,norethisterone,noretynodrel, oretynodiol diacetate, which remained on the market.[20] In any case, according to Hughes et al., "It is still doubtful how much relevance these findings have for humans as the dog mammary gland seems to be the only one which can be directly maintained by progestogens."[7] Subsequent research revealed species differences between dogs and humans and established that there is no similar risk in humans.[70]
CMA was the first progestogen to be studied as aprogestogen-only pill ("minipill").[73] It was discontinued and replaced by other progestins such asnorethisterone andnorgestrel after the findings of toxicity in beagle dogs.[73]
Chlormadinone acetate is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Approved Name.[62][63][11] It is also known by its developmental code nameRS-1280.[11]
CMA has been marketed under a variety of brand names throughout the world including Clordion, Gestafortin, Gestogan, Lormin, Lutéran, Lutoral, Menstridyl, Non-Ovlon, Normenon, Prococyd, Progestormon, Prostal, Synchrogest, Verton, and many others.[62][63][11][37] It is most commonly marketed in combination with EE as acombined birth control pill under the brand names Belara and to a lesser extent Belarina among others.[11] The medication has been marketed for use inveterinary medicine under the brand names Anifertil, Chronosyn, Cyclonorm, Fertiletten, Synchrosyn, and others.[63][11]
CMA is available alone at low, moderate, and/or high doses inFrance (brand name Lutéran),Germany (generics, and formerly Gestafortin),Japan (brand name Prostal),Mexico (brand name Lutoral), andSouth Korea (brand name Prostal-L).[24][74][11][63] It is available in many countries in combination with EE, including throughout most ofEurope andLatin America, and inJapan,Thailand,Israel,Lebanon,Tunisia, andOman (but notably not South Korea).[24][74][11][63] CMA is not available inEnglish-speaking countries including theUnited States,Canada, theUnited Kingdom,Ireland,South Africa,Australia, orNew Zealand, nor is it marketed in any of theNordic countries.[24][74][11][63] CMA was previously marketed in the United States and the United Kingdom in the 1960s, but it was withdrawn in these countries in 1970 due to intermittent concerns about mammary toxicity in dogs.[7][23]
Progestins in birth control pills are sometimes grouped by generation.[75][34] While the19-nortestosterone progestins are consistently grouped into generations, thepregnane progestins used in birth control pills are typically omitted from such classifications or are grouped as "miscellaneous" or "pregnanes".[75][34] In any case, based on its date of introduction in such formulations of 1965, CMA could be considered a "first-generation" progestin.[19]
In addition to its use in humans, CMA has been used inveterinary medicine.[63][11]
The first progesterone derivative 17-acetoxyprogesterone was developed by Schering in 1954 followed by medroxyprogesterone acetate in 1957. This was followed by [megestrol] acetate and chlormadinone acetate in 1959.
In principle, DNA adduct formation is not unique for CPA. DNA adducts in the rat liver were also found after in vitro incubation with megestrol and chlormadinone, as well as after in vivo exposure with both these compounds and with ethinylestradiol. [8-11] However, the adduct level generated by chlormadinone and megestrol is about 30 to 50 times lower than that after CPA.[12] [...] with chlormadinone [acetate] we found 5 liver cell adenomas, 5 focal nodular hyperplasias and 1 liver cell carcinoma.