Chlormadinone acetate

Progestogen

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.

Antiandrogen

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.

Glucocorticoid

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.

5α-Reductase

CMA is a competitive inhibitor of 5α-reductase.

Activity profile

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

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).

History

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 Due to findings of mammary gland nodules in beagle dogs (see below), C-Quens was voluntarily withdrawn from the U.S. market by Eli Lilly in 1971 and all oral contraceptives of CMA were discontinued in the U.S. by 1972.

Mammary toxicity in dogs

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 However, around 1970, such formulations were withdrawn from many markets due to the finding that CMA induced mammary gland tumors in Beagle dogs. (CMA has continued to be widely used as a contraceptive in some countries, such as Germany and China, however.) 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. 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). Tumors were also observed with progesterone, as well as with ethynerone and chloroethynylnorgestrel, but notably not with the non-halogenated 19-nortestosterone derivatives norgestrel, norethisterone, noretynodrel, or etynodiol diacetate, which remained on the market. 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." Subsequent research revealed species differences between dogs and humans and established that there is no similar risk in humans.