Chlormadinone acetate

Chlormadinone acetate
Clinical data
Routes of
By mouth
ATC code G03DB06 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Biological half-life 34–38 hours
CAS Number 302-22-7
PubChem (CID) 9324
ChemSpider 8963
KEGG D01299
Chemical and physical data
Formula C23H29ClO4
Molar mass 404.92696 g/mol
3D model (Jmol) Interactive image

Chlormadinone acetate (abbreviated as CMA) (INN, USAN, BAN, JAN) (sold under brand names including Clordion, Gestafortin, Lormin, Non-Ovlon, Normenon, Verton, and many others), 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]



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]

Activity profile

The human receptor binding and profiles of CMA and active metabolites have been found to be as follows:[12]

Receptor CMA 3α-Hydroxy-CMA 3β-Hydroxy-CMA
PR 2.5 nM 13 nM 6.0 nM
AR 3.8 nM 83 nM 20 nM
GR 16 nM 69 nM 21 nM

In rabbit bioassays, PR activation was similar for CMA, 3α-OH-CMA, and 3β-OH-CMA, AR antagonism was similar for CMA and 3α-OH-CMA but lower for 3β-OH-CMA, and 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 lower efficacy partial agonist or antagonist of the GR).[12]


CMA was marketed in combination with mestranol by Eli Lilly under the brand name C-Quens from 1965 to 1971 in the United States.[13][14] It was the first sequential contraceptive pill to be introduced in the U.S.[14] CMA has also been marketed in combination with mestranol under the brand names Ovosiston, Aconcen, and Sequens.[15][16] Due to findings of mammary gland nodules in beagle dogs (see below), C-Quens was voluntarily withdrawn from the U.S. market by Eli Lilly in 1971 and all oral contraceptives of CMA were discontinued in the U.S. by 1972.[17]

Mammary toxicity in dogs

Mammary tumors in beagle dogs treated by (left) MK-665 (ethynerone with mestranol) and (right) chloroethynyl norgestrel with mestranol for 4 years at a dosage of 1.05 mg/kg/day cyclically.

In the 1960s, CMA was introduced as a component of oral contraceptives. However, around 1970, such formulations were withdrawn from many markets due to the finding that CMA induced mammary gland tumors in Beagle dogs.[5][18][19][20] (CMA has continued to be widely used as a contraceptive in some countries, such as Germany and China, however.)[21] 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][18][19] 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).[18][19] 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.[18] 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.[22]

See also


  1. 1 2 F.. Macdonald (1997). Dictionary of Pharmacological Agents. CRC Press. p. 419. ISBN 978-0-412-46630-4. Retrieved 29 May 2012.
  2. 1 2 Index Nominum 2000: International Drug Directory. Taylor & Francis US. 2000. p. 215. ISBN 978-3-88763-075-1. Retrieved 29 May 2012.
  3. Raudrant D, Rabe T (2003). "Progestogens with antiandrogenic properties". Drugs. 63 (5): 463–92. doi:10.2165/00003495-200363050-00003. PMID 12600226.
  4. Chassard D, Schatz B (2005). "[The antigonadrotropic activity of chlormadinone acetate in reproductive women]". Gynécologie, Obstétrique & Fertilité (in French). 33 (1-2): 29–34. doi:10.1016/j.gyobfe.2004.12.002. PMID 15752663.
  5. 1 2 3 4 A. Hughes; S. H. Hasan; G. W. Oertel; H. E. Voss; F. Bahner; F. Neumann; H. Steinbeck; K.-J. Gräf; J. Brotherton; H. J. Horn; R. K. Wagner (27 November 2013). Androgens II and Antiandrogens / Androgene II und Antiandrogene. Springer Science & Business Media. pp. 531–. ISBN 978-3-642-80859-3.
  6. Bouchard P (2005). "Chlormadinone acetate (CMA) in oral contraception--a new opportunity". The European Journal of Contraception & Reproductive Health Care. 10 Suppl 1: 7–11. doi:10.1080/13625180500434889. PMID 16356876.
  7. H.J.T. Coelingh Benni; H.M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 151–. ISBN 978-1-85070-322-8.
  8. Luthy IA, Begin DJ, Labrie F (1988). "Androgenic activity of synthetic progestins and spironolactone in androgen-sensitive mouse mammary carcinoma (Shionogi) cells in culture". J. Steroid Biochem. 31 (5): 845–52. doi:10.1016/0022-4731(88)90295-6. PMID 2462135.
  9. John A. Thomas (12 March 1997). Endocrine Toxicology, Second Edition. CRC Press. pp. 152–. ISBN 978-1-4398-1048-4.
  10. Nick Panay (31 August 2015). Managing the Menopause. Cambridge University Press. pp. 126–. ISBN 978-1-107-45182-7.
  11. Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1404–. ISBN 978-1-60913-345-0.
  12. 1 2 Schneider, J.; Kneip, C.; Jahnel, U. (2009). "Comparative Effects of Chlormadinone Acetate and Its 3α- and 3β-Hydroxy Metabolites on Progesterone, Androgen and Glucocorticoid Receptors". Pharmacology. 84 (2): 74–81. doi:10.1159/000226601. ISSN 1423-0313.
  13. Richard Patterson (21 December 2012). Drugs in Litigation: Damage Awards Involving Prescription and Nonprescription Drugs. LexisNexis. pp. 184–. ISBN 978-0-327-18698-4.
  14. 1 2 Robert Bud; Bernard S. Finn; Helmuth Trischler (1999). Manifesting Medicine: Bodies and Machines. Taylor & Francis. pp. 113–. ISBN 978-90-5702-408-5.
  15. Helmuth Vorherr (2 December 2012). The Breast: Morphology, Physiology, and Lactation. Elsevier Science. pp. 123–. ISBN 978-0-323-15726-1.
  17. Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments. United Nations Publications. 1983. pp. 52–53,260. ISBN 978-92-1-130230-1.
  18. 1 2 3 4 C.H. Lingeman (6 December 2012). Carcinogenic Hormones. Springer Science & Business Media. pp. 149–. ISBN 978-3-642-81267-5.
  19. 1 2 3 Christian Streffer; H. Bolt; D. Follesdal; P. Hall; J.G. Hengstler; P. Jacob; D. Oughton; K. Prieß; E. Rehbinder; E. Swaton (11 November 2013). Low Dose Exposures in the Environment: Dose-Effect Relations and Risk Evaluation. Springer Science & Business Media. pp. 135–. ISBN 978-3-662-08422-9.
  20. Gisela Dallenbach-Hellweg (9 March 2013). Histopathology of the Endometrium. Springer Science & Business Media. pp. 183–. ISBN 978-3-662-07788-7.
  21. A. T. Gregoire (13 March 2013). Contraceptive Steroids: Pharmacology and Safety. Springer Science & Business Media. pp. 381–. ISBN 978-1-4613-2241-2.
  22. Benno Clemens Runnebaum; Thomas Rabe; Ludwig Kiesel (6 December 2012). Female Contraception: Update and Trends. Springer Science & Business Media. pp. 134–135. ISBN 978-3-642-73790-9.
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