Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.
Side effects of the combination of an estrogen and CMA include menstrual irregularities, headaches, nausea, breast tenderness, vaginal discharge, and others. At high dosages, CMA can cause sexual dysfunction, demasculinization, adrenal insufficiency, and changes in carbohydrate metabolism among other adverse effects. The drug is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It is also an antiandrogen, and hence is an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone. Due to its progestogenic activity, CMA has antigonadotropic effects. The medication has weak glucocorticoid activity and no other important hormonal activity.
CMA was discovered in 1959 and was introduced for medical use in 1965. It may be considered a "first-generation" progestin. The medication was withdrawn in some countries in 1970 due to concerns about mammary toxicity observed in dogs, but this turned out not to apply to humans. CMA is available widely throughout the world in birth control pills, but is notably not marketed in any predominantly English-speaking countries. It is available alone in only a few countries, including France, Mexico, Japan, and South Korea.
Medical uses CMA is used at a low dose in combination with ethinylestradiol (EE), an estrogen, in combined birth control pills. It has also been used in the treatment of gynecological conditions including vaginal bleeding, oligomenorrhea, polymenorrhea, hypermenorrhea, dysmenorrhea, secondary amenorrhea, and endometriosis and in France (under the brand name Lutéran) in menopausal hormone therapy in combination with an estrogen. 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. Combined birth control pills containing EE and CMA have been found to be useful in reducing androgen-dependent symptoms such as skin and hair conditions. Dosages of CMA of 15 to 20 mg/day have been found to improve hot flashes. High-dose CMA-only tablets are used as a form of progestogen-only birth control, although they are not specifically licensed as such.
CMA has been widely used as a means of androgen deprivation therapy in the treatment of prostate cancer and benign prostatic hyperplasia (BPH) in Japan and South Korea, but has seen little use for these indications elsewhere in the world. It is used at dosages of 50 to 100 mg/day in the treatment of prostate diseases. Similarly to cyproterone acetate (CPA), CMA shows a lower risk of hot flashes than gonadotropin-releasing hormone analogues (GnRH analogues). The medication is the only other steroidal 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.
CMA has also been found to be effective in the treatment of other androgen-dependent conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, similarly to CPA. It has been studied at moderate dosages of 4 to 12 mg/day in the treatment of precocious puberty in girls. It showed similar benefits as those of medroxyprogesterone acetate in these girls and was found to reduce, but not abolish premature development such as breast growth and menstruation. Only slight or no axillary hair growth was observed in the girls. CMA has also been used as a component of hormone therapy for transgender women, similarly to CPA and spironolactone, albeit mostly only in Japan.
CMA has been used to prevent the testosterone flare at the start of gonadotropin-releasing hormone agonist therapy in men with prostate cancer.
Available forms CMA is available in the form of oral tablets at low doses (2 mg) in combination with EE in birth control pills (e.g., as Belara in Germany and Brazil), at low to moderate doses (2, 5, 10, 25 mg) alone (e.g., as Lutéran in France and Lutoral in Mexico), and at high doses (50 mg) alone (e.g., as Prostal in Japan and Prostal-L in South Korea).
Contraindications Contraindications of combined birth control pills, such as those containing EE and CMA, include known or suspected pregnancy, lactation and breastfeeding, a history of or known susceptibility to thromboembolism, cholestasis (but not liver cirrhosis or chronic hepatitis), and breast cancer among others. CMA is a teratogen in animals and may have the potential to cause fetal harm, such as feminization of male fetuses among other defects.
Side effects
The most common side effects of birth control pills containing EE and low-dose CMA have been found to include menstrual abnormalities, headache (37%), nausea (23%), breast tenderness (22%), and vaginal discharge (19%) among others. These formulations do not adversely affect sexual desire or function in women and show little or no risk of depression, mood swings, or weight gain. High-dosage CMA is associated with sexual dysfunction (e.g., reduced libido, erectile dysfunction), reduced body hair, adrenal insufficiency, and alterations in carbohydrate metabolism. Conversely, it does not share adverse effects of estrogens such as breast discomfort and gynecomastia. CMA does not increase the risk of venous thromboembolism. There is a case report of autoimmune progesterone dermatitis with CMA. Similarly to other progestins but in contrast to progesterone, CMA has been found to significantly increase the risk of breast cancer when used in combination with an estrogen in menopausal hormone therapy. No abnormalities in liver function tests have been observed in women taking combined birth control pills containing CMA or CPA. Unlike CPA, high-dosage CMA does not seem to be associated with hepatotoxicity.
Similarly to megestrol acetate and medroxyprogesterone acetate, CMA appears to show less potential for liver genotoxicity and carcinogenicity than CPA in bioassays. This seems to be related to the lack of the C1α,2α methylene group of CPA in these steroids.Siddique, Y.H., T. Beg and M. Afzal, 2008. Structural Relationships of Some Synthetic Progestins and their Genotoxic Effects. In: Recent Trends in Toxicology, Siddique, Y.H. (Ed.). Transworld Research Network, Trivandrum, Kerala, India, pp: 75-84. 978-81-7895-384-7 A case of hepatocellular carcinoma has been reported in a woman taking a birth control pill containing CMA. However, the incidence of liver tumors in women in association with CMA-containing birth control pills appears to be similar to that for birth control pills containing other progestins.
Overdose CMA has been studied in men with advanced prostate cancer at massive dosages of 1,000 to 2,000 mg/day orally and 100 to 500 mg/day via intramuscular injection, without serious adverse effects or toxicity described.
Interactions As CMA does not inhibit cytochrome P450 enzymes, it may have a lower risk of drug interactions than 19-nortestosterone progestins.
Pharmacology
Pharmacodynamics CMA has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and weak glucocorticoid activity.
Relative affinities (%) of and metabolites Compound 67–172 3–76 0 8 0 0 0 33 4 ? 2 ? ? ? 72 15 ? 6 ? ? ? Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , for the , for the , aldosterone for the , for , and cortisol for . Sources:
Progestogenic activity CMA is a progestogen, or an agonist of the progesterone receptor. It is highly potent in its progestogenic activity, with about 330 times the potency of progesterone in the Clauberg test and about 2,000 to 10,000 times the oral potency of progesterone in the McPhail assay. For comparison, the potencies of medroxyprogesterone acetate and CPA in the Clauberg assay were about 330- and 1,000-fold that of progesterone, respectively. The progestogenic activity of CMA is responsible for its functional antigonadotropic and antiestrogenic effects and for its contraceptive effects. The oral ovulation-inhibiting dosage of CMA in women is 1.5 to 4 mg/day and its endometrial transformation dosage is 25 mg/cycle. 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. The effective dosage of CMA as a progestogen-only pill for contraception is 0.5 mg/day. Inhibition of ovulation is incomplete at this dosage and contraceptive effects are instead mainly achieved via progestogenic changes in the endometrium and cervix.
In rabbit bioassays, PR activation was similar for CMA and its major active metabolites 3α-hydroxychlormadinone acetate (3α-OH-CMA) and 3β-hydroxychlormadinone acetate (3β-OH-CMA).
Antigonadotropic effects
Due to its progestogenic activity, CMA has antigonadotropic effects, and hence can inhibit the secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. As a result, CMA suppresses ovulation and gonadal sex hormone production and can strongly decrease circulating testosterone and estradiol levels at sufficiently high dosages. 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. As such, CMA has powerful functional antiandrogenic and antiestrogenic effects via its antigonadotropic effects.
Antiandrogenic activity CMA is a potent antiandrogen, or antagonist of the androgen receptor (AR), with about 30 to 40% of the affinity of CPA for the receptor and about 20% of the antiandrogenic potency of CPA in animals. Like other progestins with antiandrogenic activity such as CPA, megestrol acetate, and spironolactone, but unlike nonsteroidal antiandrogens such as flutamide and bicalutamide, CMA is not a silent antagonist of the AR but rather a weak partial agonist with the capacity to activate the receptor in the absence of more efficacious agonists such as testosterone. In rabbit bioassays, AR antagonism was similar for CMA and 3α-OH-CMA but lower for 3β-OH-CMA. Both the antigonadotropic and antiandrogenic actions of CMA are thought to be involved in its effectiveness in the treatment of prostate cancer.
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 in sex hormone-binding globulin (SHBG) levels and consequent fall in free testosterone levels induced by EE. Unlike 19-nortestosterone progestins like levonorgestrel, CMA does not antagonize the EE-induced increase in SHBG levels.
Other activity