Chlormadinone acetate

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Chlormadinone acetate
Chlormadinone acetate.svg
Systematic (IUPAC) name
(8ξ,10ξ,13ξ,17α)-6-chloro-3,20-dioxopregn-4-en-17-yl acetate
Clinical data
Legal status
  • ℞ (Prescription only)
Routes of
administration		 Oral
Pharmacokinetic data
Biological half-life 34-38 hours
Identifiers
CAS Number 302-22-7
ATC code G03DB06 (WHO)
PubChem CID: 9324
ChemSpider 8963
ChEMBL CHEMBL110691
Chemical data
Formula C23H29ClO4
Molecular mass 404.92696 g/mol
  • CC(=O)[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2C=C(C4=CC(=O)CC[C@]34C)Cl)C)OC(=O)C
  • InChI=1S/C23H29ClO4/c1-13(25)23(28-14(2)26)10-7-18-16-12-20(24)19-11-15(27)5-8-21(19,3)17(16)6-9-22(18,23)4/h11-12,16-18H,5-10H2,1-4H3/t16-,17+,18+,21-,22+,23+/m1/s1
  • Key:QMBJSIBWORFWQT-DFXBJWIESA-N

Chlormadinone acetate (INN, USAN, BAN, JAN) (sold under brand names including Clordion, Gestafortin, Lormin, Non-Ovlon, Normenon, Verton, and many others), sometimes abbreviated as CMA, and also known as 17α-acetoxy-6-chloro-6-dehydroprogesterone, is a steroidal progestin with additional antiandrogen and antigonadotropic (and by extension antiestrogenic) effects.[1][2][3][4] CMA has been used in the treatment of vaginal bleeding, oligomenorrhea, polymenorrhea, hypermenorrhea, secondary amenorrhea, and endometriosis.[5] It has also been used clinically as a hormonal contraceptive, and in part due to its capacity to lower estrogen levels, but also for improved effectiveness in contraception, chlormadinone has frequently been combined with ethinyl estradiol for this purpose.[6]

CMA is the acetate ester of chlormadinone, which, in contrast to CMA, was never marketed.[1][2]

Pharmacology

CMA acts predominantly as a potent progestogen, but also as an antiandrogen. Due to its potent actions as a progestogen, CMA also has strong antigonadotropic properties, and thus additional antiandrogen as well as antiestrogen properties.[7]

Like other steroidal progestins with antiandrogen properties such as cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate, as well as spironolactone (a steroidal antimineralocorticoid with antiandrogen and progestogen properties), but unlike non-steroidal antiandrogens such as flutamide and bicalutamide, CMA is not a silent antagonist of the androgen receptor (AR) but rather a weak partial agonist of the AR with the capacity to activate the receptor in the absence of more efficacious agonists such as testosterone.[8]

Similarly to other 17α-hydroxyprogesterone derivatives such as cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate, CMA is a weak glucocorticoid, and has the potential to cause adrenal insufficiency upon abrupt discontinuation of the drug at sufficient dosages.[9][10]

CMA is a competitive inhibitor of 5α-reductase.[11]

Withdrawal as a hormonal contraceptive

In the 1960s, CMA was introduced as a component of oral contraceptives. However, around 1970, all such formulations were withdrawn from the market due to the finding that CMA induced mammary gland tumors in Beagle dogs.[5][12][13][14] 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.[5][12][13] In addition to CMA, mammary tumors were found in dogs with various other 17α-hydroxyprogesterone derivatives, including medroxyprogesterone acetate, megestrol acetate, and anagestone acetate, and they were also discontinued for the indication of hormonal contraception (although medroxyprogesterone acetate has since been reintroduced).[12][13] Tumors were also observed with progesterone, as well as with ethynerone and chloroethynyl norgestrel, but notably not with the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, or etynodiol diacetate, which remained on the market.[12] 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."[5] Subsequent research revealed species differences between dogs and humans and established that there is no similar risk in humans.[15]

See also

References

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  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'strict' not found.
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  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ 5.0 5.1 5.2 5.3 Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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  12. ↑ 12.0 12.1 12.2 12.3 Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ 13.0 13.1 13.2 Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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