Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a

progestin A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a ''synthetic'' progestogen. Pro ...

and

antiandrogen Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the ...

medication which is used in

birth control pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progesti ...

s to prevent

pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ...

, 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 Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that su ...

in men and

acne Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and ...

and

hirsutism Hirsutism is excessive body hair on parts of the body where hair is normally absent or minimal. The word is from early 17th century: from Latin ''hirsutus'' meaning "hairy". It usually refers to a "male" pattern of hair growth in a female that ...

in women. It is available both at a low dose in combination with an

estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal ac ...

in birth control pills and, in a few countries like

France France (), officially the French Republic ( ), is a country primarily located in Western Europe. It also comprises of Overseas France, overseas regions and territories in the Americas and the Atlantic Ocean, Atlantic, Pacific Ocean, Pac ...

and

Japan Japan ( ja, 日本, or , and formally , ''Nihonkoku'') is an island country in East Asia. It is situated in the northwest Pacific Ocean, and is bordered on the west by the Sea of Japan, while extending from the Sea of Okhotsk in the n ...

, at low, moderate, and high doses alone for various indications. It is taken

by mouth Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...

Side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of the combination of an estrogen and CMA include menstrual irregularities,

headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of th ...

breast tenderness Breast pain is the symptom of discomfort in either one or both breasts. Pain in both breasts is often described as ''breast tenderness'', is usually associated with the menstrual period and is not serious. Pain that involves only one part of a br ...

vaginal discharge Vaginal discharge is a mixture of liquid, cells, and bacteria that lubricate and protect the vagina. This mixture is constantly produced by the cells of the vagina and cervix, and it exits the body through the vaginal opening. The composition, amou ...

, and others. At high dosages, CMA can cause

sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...

demasculinization Virilization or masculinization is the biological development of adult male characteristics in young males or females. Most of the changes of virilization are produced by androgens. Virilization is most commonly used in three medical and biology ...

adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal gland normally secretes glucocorticoids (primarily cortisol), mineralocorticoids (primarily aldosterone), and andro ...

, and changes in

carbohydrate metabolism Carbohydrate metabolism is the whole of the biochemistry, biochemical processes responsible for the metabolic anabolism, formation, catabolism, breakdown, and interconversion of carbohydrates in life, living organisms. Carbohydrates are central t ...

among other adverse effects. The drug is a progestin, or a

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic ...

progestogen Progestogens, also sometimes written progestagens or gestagens, are a class of natural or synthetic steroid hormones that bind to and activate the progesterone receptors (PR). Progesterone is the major and most important progestogen in the bod ...

, and hence is an

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ag ...

of the

progesterone receptor The progesterone receptor (PR), also known as NR3C3 or nuclear receptor subfamily 3, group C, member 3, is a protein found inside cells. It is activated by the steroid hormone progesterone. In humans, PR is encoded by a single ''PGR'' gene resid ...

, the

biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...

of progestogens like

progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...

. It is also an

, and hence is an

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, ri ...

of the

androgen receptor The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in ...

, the

of androgens like

testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristi ...

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...

. Due to its progestogenic activity, CMA has

antigonadotropic An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituita ...

effects. The medication has weak glucocorticoid activity and no other important

hormonal A hormone (from the Greek participle , "setting in motion") is a class of signaling molecules in multicellular organisms that are sent to distant organs by complex biological processes to regulate physiology and behavior. Hormones are required f ...

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 Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a subs ...

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 English usually refers to: * English language * English people English may also refer to: Peoples, culture, and language * ''English'', an adjective for something of, from, or related to England ** English national ...

-speaking countries. It is available alone in only a few countries, including France,

Mexico Mexico (Spanish language, Spanish: México), officially the United Mexican States, is a List of sovereign states, country in the southern portion of North America. It is borders of Mexico, bordered to the north by the United States; to the so ...

, Japan, and

South Korea South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korea, Korean Peninsula and sharing a Korean Demilitarized Zone, land border with North Korea. Its western border is formed ...

Medical uses

CMA is used at a low dose in

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are th ...

with

ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological disord ...

(EE), an

, in

combined birth control pill The combined oral contraceptive pill (COCP), often referred to as the birth control pill or colloquially as "the pill", is a type of birth control that is designed to be taken orally by women. The pill contains two important hormones: progesti ...

s. It has also been used in the treatment of

gynecological condition Gynaecology or gynecology (see spelling differences) is the area of medicine that involves the treatment of women's diseases, especially those of the reproductive organs. It is often paired with the field of obstetrics, forming the combined area ...

s including

vaginal bleeding Vaginal bleeding is any expulsion of blood from the vagina. This bleeding may originate from the uterus, vaginal wall, or cervix. Generally, it is either part of a normal menstrual cycle or is caused by hormonal or other problems of the reproductiv ...

, oligomenorrhea,

polymenorrhea Polymenorrhea, also known as frequent periods, frequent menstruation, or frequent menstrual bleeding, is a menstrual disorder in which menstrual cycles are shorter than 21days in length and hence where menstruation occurs more frequently than usu ...

hypermenorrhea Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnorm ...

dysmenorrhea Dysmenorrhea, also known as period pain, painful periods or menstrual cramps, is pain during menstruation. Its usual onset occurs around the time that menstruation begins. Symptoms typically last less than three days. The pain is usually in th ...

, secondary amenorrhea, and

endometriosis Endometriosis is a disease of the female reproductive system in which cells similar to those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. Most often this is on the ovaries, fa ...

and in

(under the brand name Lutéran) in menopausal hormone therapy in combination with an

. 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 flash Hot flashes (also known as hot flushes) are a form of flushing, often caused by the changing hormone levels that are characteristic of menopause. They are typically experienced as a feeling of intense heat with sweating and rapid heartbeat, an ...

es. High-dose CMA-only tablets are used as a form of

progestogen-only birth control Progestogen-only contraception (or progestin-only contraception) relies on progestogens alone to achieve contraception. It is one of the two major types of hormonal contraception, with the other major type being combined hormonal contraceptive me ...

, although they are not specifically licensed as such. CMA has been widely used as a means of

androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen hormones, such as testosterone, to grow. ADT red ...

in the treatment of

and

benign prostatic hyperplasia Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...

(BPH) in

and

, 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 Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent condition ...

(CPA), CMA shows a lower risk of hot flashes than

gonadotropin-releasing hormone analogue A GnRH modulator, or GnRH receptor modulator, also known as an LHRH modulator or LHRH receptor modulator, is a type of medication which modulates the GnRH receptor, the biological target of the hypothalamic hormone gonadotropin-releasing hormone ...

s (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 Megestrol acetate (MGA), sold under the brand name Megace among others, is a progestin medication which is used mainly as an appetite stimulant to treat wasting syndromes such as cachexia.https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/ ...

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

, seborrhea,

, and

pattern hair loss Pattern hair loss (also known as androgenetic alopecia (AGA)) is a hair loss condition that primarily affects the top and front of the scalp. In male-pattern hair loss (MPHL), the hair loss typically presents itself as either a receding front ...

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 medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...

in girls. It showed similar benefits as those of

medroxyprogesterone acetate Medroxyprogesterone acetate (MPA), also known as depot medroxyprogesterone acetate (DMPA) in injectable form and sold under the brand name Depo-Provera among others, is a hormonal medication of the progestin type. It is used as a method of bi ...

in these girls and was found to reduce, but not abolish premature development such as breast growth and

menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...

. Only slight or no axillary hair growth was observed in the girls. CMA has also been used as a component of

hormone therapy Hormone therapy or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also be referred to as hormonal therapy or antihormone therapy. The most general classes of hormone therapy are oncologic ho ...

for

transgender women A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...

, similarly to CPA and

spironolactone Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood press ...

, albeit mostly only in Japan. CMA has been used to prevent the

flare at the start of

gonadotropin-releasing hormone agonist A gonadotropin-releasing hormone agonist (GnRH agonist) is a type of medication which affects gonadotropins and sex hormones. They are used for a variety of indications including in fertility medicine and to lower sex hormone levels in the treatm ...

therapy in men with prostate cancer.

Available forms

CMA is available in the form of

oral The word oral may refer to: Relating to the mouth * Relating to the mouth, the first portion of the alimentary canal that primarily receives food and liquid ** Oral administration of medicines ** Oral examination (also known as an oral exam or or ...

tablet Tablet may refer to: Medicine * Tablet (pharmacy), a mixture of pharmacological substances pressed into a small cake or bar, colloquially called a "pill" Computing * Tablet computer, a mobile computer that is primarily operated by touching the ...

s 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

and Lutoral in

), and at high doses (50 mg) alone (e.g., as Prostal in

and Prostal-L in

Contraindications

Contraindication In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...

s of combined birth control pills, such as those containing EE and CMA, include known or suspected

lactation Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...

and

breastfeeding Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that bre ...

, a history of or known susceptibility to

thromboembolism Thrombosis (from Ancient Greek "clotting") is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets ...

, cholestasis (but not

liver cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue repai ...

or chronic hepatitis), and

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or ...

among others. CMA is a teratogen in animals and may have the potential to cause

fetal A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...

harm, such as feminization of male fetuses among other defects.

Side effects

The most common

side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

s of birth control pills containing EE and low-dose CMA have been found to include menstrual abnormalities,

(37%),

(23%),

(22%), and

(19%) among others. These formulations do not adversely affect

sexual desire Sexual desire is an emotion and motivational state characterized by an interest in sexual objects or activities, or by a drive to seek out sexual objects or to engage in sexual activities. It is an aspect of sexuality, which varies significantly f ...

or function in women and show little or no risk of depression,

mood swing A mood swing is an extreme or sudden change of mood. Such changes can play a positive part in promoting problem solving and in producing flexible forward planning, or be disruptive. When mood swings are severe, they may be categorized as par ...

s, or

weight gain Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs w ...

. High-dosage CMA is associated with

(e.g., reduced libido,

erectile dysfunction Erectile dysfunction (ED), also called impotence, is the type of sexual dysfunction in which the penis fails to become or stay erect during sexual activity. It is the most common sexual problem in men.Cunningham GR, Rosen RC. Overview of ma ...

), reduced

body hair Body hair, or androgenic hair, is the terminal hair that develops on the human body during and after puberty. It is differentiated from the head hair and less visible vellus hair, which is much finer and lighter in color. The growth of androge ...

, and alterations in

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may o ...

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...

. Conversely, it does not share adverse effects of estrogens such as breast discomfort and

gynecomastia Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...

. CMA does not increase the risk of

venous thromboembolism Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...

. There is a

case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occur ...

autoimmune progesterone dermatitis Autoimmune progesterone dermatitis may appear as urticarial papules, deep gyrate lesions, papulovesicular lesions, an eczematous eruption, or as targetoid lesions. Autoimmune progesterone dermatitis initially manifests with eye symptoms, e.g. burni ...

with CMA. Similarly to other progestins but in contrast to

, CMA has been found to significantly increase the risk of

when used in combination with an estrogen in menopausal hormone therapy. No abnormalities in

liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...

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 Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...

. Similarly to

and

, CMA appears to show less potential for

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...

genotoxicity Genotoxicity is the property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer. While genotoxicity is often confused with mutagenicity, all mutagens are genotoxic, but some genotoxic ...

and carcinogenicity than CPA in

bioassay A bioassay is an analytical method to determine the concentration or potency of a substance by its effect on living animals or plants (''in vivo''), or on living cells or tissues(''in vitro''). A bioassay can be either quantal or quantitative, dir ...

s. This seems to be related to the lack of the C1α,2α

methylene group In organic chemistry, a methylene group is any part of a molecule that consists of two hydrogen atoms bound to a carbon atom, which is connected to the remainder of the molecule by two single bonds. The group may be represented as , where th ...

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 Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide. It occurs in t ...

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 Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles hav ...

, without serious

adverse effect An adverse effect is an undesired harmful effect resulting from a medication or other intervention, such as surgery. An adverse effect may be termed a " side effect", when judged to be secondary to a main or therapeutic effect. The term compl ...

s or

described.

Interactions

As CMA does not inhibit

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

s, it may have a lower risk of

drug interaction Drug interactions occur when a drug's mechanism of action is disturbed by the concomitant administration of substances such as foods, beverages, or other drugs. The cause is often the inhibition of the specific receptors available to the drug, ...

s than

19-nortestosterone Nandrolone, also known as 19-nortestosterone, is an androgen and anabolic steroid (AAS) which is used in the form of esters such as nandrolone decanoate (brand name Deca-Durabolin) and nandrolone phenylpropionate (brand name Durabolin). Nandrolon ...

progestins.

Pharmacology

Pharmacodynamics

CMA has

ic activity,

effects,

ic activity, and weak glucocorticoid activity.

Progestogenic activity

CMA is a

, or an

of the

. It is highly potent in its progestogenic activity, with about 330 times the potency of

in the

Clauberg test Carl Clauberg (28 September 1898 – 9 August 1957) was a German gynecologist who conducted medical experiments on human subjects (mainly Jewish) at Auschwitz concentration camp. He worked with Horst Schumann in X-ray sterilization experime ...

and about 2,000 to 10,000 times the oral potency of progesterone in the McPhail assay. For comparison, the potencies of

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

and

antiestrogen Antiestrogens, also known as estrogen antagonists or estrogen blockers, are a class of drugs which prevent estrogens like estradiol from mediating their biological effects in the body. They act by blocking the estrogen receptor (ER) and/or ...

ic effects and for its

contraceptive Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...

effects. The oral

ovulation Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilize ...

-inhibiting dosage of CMA in women is 1.5 to 4 mg/day and its

endometrial transformation Decidualization is a process that results in significant changes to cells of the endometrium in preparation for, and during, pregnancy. This includes morphological and functional changes (the decidual reaction) to endometrial stromal cells (ESCs), ...

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 Progestogen-only pills or progestin-only pills (POP) are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills. Although such pills are sometimes called " ...

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 The endometrium is the inner epithelial layer, along with its mucous membrane, of the mammalian uterus. It has a basal layer and a functional layer: the basal layer contains stem cells which regenerate the functional layer. The functional layer ...

and

cervix The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus (womb) in the human female reproductive system. The cervix is usually 2 to 3 cm long (~1 inch) and roughly cylindrical in shape, which changes during ...

. In rabbit

s, PR activation was similar for CMA and its major

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

s 3α-hydroxychlormadinone acetate (3α-OH-CMA) and 3β-hydroxychlormadinone acetate (3β-OH-CMA).

Antigonadotropic effects

Due to its progestogenic activity, CMA has

effects, and hence can inhibit the

secretion 440px Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...

of the

gonadotropin Gonadotropins are glycoprotein hormones secreted by gonadotropic cells of the anterior pituitary of vertebrates. This family includes the mammalian hormones follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the placental/ chorioni ...

luteinizing hormone Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...

(LH) and

follicle-stimulating hormone Follicle-stimulating hormone (FSH) is a gonadotropin, a glycoprotein polypeptide hormone. FSH is synthesized and secreted by the gonadotropic cells of the anterior pituitary gland and regulates the development, growth, pubertal maturation, ...

(FSH) from the

pituitary gland In vertebrate anatomy, the pituitary gland, or hypophysis, is an endocrine gland, about the size of a chickpea and weighing, on average, in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain. The h ...

. As a result, CMA suppresses

and

gonad A gonad, sex gland, or reproductive gland is a mixed gland that produces the gametes and sex hormones of an organism. Female reproductive cells are egg cells, and male reproductive cells are sperm. The male gonad, the testicle, produces sp ...

sex hormone Sex hormones, also known as sex steroids, gonadocorticoids and gonadal steroids, are steroid hormones that interact with vertebrate steroid hormone receptors. The sex hormones include the androgens, estrogens, and progestogens. Their effect ...

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

ic and

ic effects via its antigonadotropic effects.

Antiandrogenic activity

CMA is a potent

, or

of the

(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,

, and

, but unlike nonsteroidal antiandrogens such as flutamide and

bicalutamide Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...

, CMA is not a silent antagonist of the AR but rather a weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

with the capacity to activate the receptor in the absence of more

efficacious Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

s such as

. 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 Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...

(SHBG) levels and consequent fall in free

levels induced by EE. Unlike

progestins like

levonorgestrel Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B One-Step amon ...

, CMA does not antagonize the EE-induced increase in SHBG levels.

Other activity

Similarly to other

17α-hydroxyprogesterone 17α-Hydroxyprogesterone (17α-OHP), also known as 17-OH progesterone (17-OHP), or hydroxyprogesterone (OHP), is an endogenous progestogen steroid hormone related to progesterone. It is also a chemical intermediate in the biosynthesis of many o ...

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

s such as CPA, medroxyprogesterone acetate, and megestrol acetate, CMA has weak affinity for the

glucocorticoid receptor The glucocorticoid receptor (GR, or GCR) also known as NR3C1 (nuclear receptor subfamily 3, group C, member 1) is the receptor to which cortisol and other glucocorticoids bind. The GR is expressed in almost every cell in the body and regulates ...

(comparable to that of

) and weak glucocorticoid activity, and has the potential to cause

upon abrupt discontinuation at sufficient dosages. However, the medication shows significant glucocorticoid activity only at dosages much higher than those present in birth control pills. 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 lower

efficacy Efficacy is the ability to perform a task to a satisfactory or expected degree. The word comes from the same roots as ''effectiveness'', and it has often been used synonymously, although in pharmacology a distinction is now often made between ...

partial agonist or antagonist of the GR). CMA has no affinity for the

mineralocorticoid receptor The mineralocorticoid receptor (or MR, MLR, MCR), also known as the aldosterone receptor or nuclear receptor subfamily 3, group C, member 2, (NR3C2) is a protein that in humans is encoded by the ''NR3C2'' gene that is located on chromosome 4q31 ...

s and has no

ic or

antimineralocorticoid An antimineralocorticoid, also known as a mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is ofte ...

activity. Unlike

but similarly to other progestins, CMA has no known

neurosteroid Neurosteroids, also known as neuroactive steroids, are endogenous or exogenous steroids that rapidly alter neuronal excitability through interaction with ligand-gated ion channels and other cell surface receptors. The term ''neurosteroid'' was co ...

activity (e.g., GABA_A receptor

modulation In electronics and telecommunications, modulation is the process of varying one or more properties of a periodic waveform, called the '' carrier signal'', with a separate signal called the ''modulation signal'' that typically contains informat ...

) or

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but ...

effects. CMA has been reported to be a

competitive inhibitor Competitive inhibition is interruption of a chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for binding or bonding. Any metabolic or chemical messenger system can potentially be affected b ...

5α-reductase 5α-Reductases, also known as 3-oxo-5α-steroid 4-dehydrogenases, are enzymes involved in steroid metabolism. They participate in three metabolic pathways: bile acid biosynthesis, androgen and estrogen metabolism. There are three isozymes o ...

. However, it seems to shows very low

potency Potency may refer to: * Potency (pharmacology), a measure of the activity of a drug in a biological system * Virility * Cell potency, a measure of the differentiation potential of stem cells * In homeopathic dilutions, potency is a measure of how ...

in this action, with 0.0% inhibition of the

at a concentration of 1 μM, and in relation to this, has been said not to have an important influence on the enzyme. CMA may also act weakly as a testosterone biosynthesis inhibitor at high dosages. Unlike

progestins, CMA does not

inhibit Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotr ...

enzymes in the

system, which may give it a lower risk of

s. Certain progestins have been found to stimulate the proliferation of

MCF-7 MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old White woman. MCF-7 is the acronym of Michigan Cancer Foundation-7, referring to the institute in Detroit where the cell line was established in 1973 by Herbert Soule and co-wor ...

cell Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery ...

s ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...

'', an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1).

Progesterone Progesterone (P4) is an endogenous steroid and progestogen sex hormone involved in the menstrual cycle, pregnancy, and embryogenesis of humans and other species. It belongs to a group of steroid hormones called the progestogens and is the majo ...

and CMA, in contrast, act neutrally in this assay. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in

clinical studies Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

Pharmacokinetics

The

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of CMA is 100%, which is due to low

first-pass metabolism The first pass effect (also known as first-pass metabolism or presystemic metabolism) is a phenomenon of drug metabolism whereby the concentration of a drug, specifically when administered orally, is greatly reduced before it reaches the system ...

. In combination with 30 μg EE, a single 2 mg oral dose of CMA produced maximal serum levels of 1.6 ng/mL after about 1 to 2 hours and chronic administration produced

steady-state In systems theory, a system or a process is in a steady state if the variables (called state variables) which define the behavior of the system or the process are unchanging in time. In continuous time, this means that for those properties '' ...

levels of 2.0 ng/mL. Steady-state concentrations of CMA are achieved after 7 to 15 days. The distribution half-life of CMA is about 2.5 hours. The medication is highly

lipophilic Lipophilicity (from Greek λίπος "fat" and φίλος "friendly"), refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. Such non-polar solvents are themselves lipo ...

and is taken up into and accumulated in fat and some female reproductive tissues, although this may only occur at high dosages (e.g., ≥10 mg/day). The

volume of distribution In pharmacology, the volume of distribution (VD, also known as apparent volume of distribution, literally, ''volume of dilution'') is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same c ...

of CMA is unknown, but that of the closely related steroid CPA is very large at 1,300 L. The plasma protein binding of CMA is 96.6 to 99.4%, with about 1 to 3% free. It is bound to

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Album ...

, with no affinity for SHBG or corticosteroid-binding globulin. CMA is extensively

metabolized Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

in the

by reduction,

hydroxylation In chemistry, hydroxylation can refer to: *(i) most commonly, hydroxylation describes a chemical process that introduces a hydroxyl group () into an organic compound. *(ii) the ''degree of hydroxylation'' refers to the number of OH groups in a ...

deacetylation : In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...

, and

conjugation Conjugation or conjugate may refer to: Linguistics *Grammatical conjugation, the modification of a verb from its basic form * Emotive conjugation or Russell's conjugation, the use of loaded language Mathematics *Complex conjugation, the change ...

. Reduction occurs at the C3

ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double b ...

with preservation of the δ⁴⁽⁵⁾

double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betwee ...

, hydroxylation is at the C2α, C3α, C3β, and C15β positions, and conjugation includes

glucuronidation Glucuronidation is often involved in drug metabolism of substances such as drugs, pollutants, bilirubin, androgens, estrogens, mineralocorticoids, glucocorticoids, fatty acid derivatives, retinoids, and bile acids. These linkages involve gl ...

and

sulfation Sulfation is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected less directly. Regardless of the mechanism, the ...

. The main

metabolite In biochemistry, a metabolite is an intermediate or end product of metabolism. The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, ...

s of CMA are 2α-OH-CMA, 3α-OH-CMA, and 3β-OH-CMA, with the latter two being important

s. Other metabolites of CMA are inactive. The

elimination half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...

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. Enterohepatic reabsorption of CMA occurs. The medication has been found to be excreted 33 to 45% in

urine Urine is a liquid by-product of metabolism in humans and in many other animals. Urine flows from the kidneys through the ureters to the urinary bladder. Urination results in urine being excreted from the body through the urethra. Cellul ...

and 24 to 41% in

feces Feces ( or faeces), known colloquially and in slang as poo and poop, are the solid or semi-solid remains of food that was not digested in the small intestine, and has been broken down by bacteria in the large intestine. Feces contain a rela ...

, as well as in

bile Bile (from Latin ''bilis''), or gall, is a dark-green-to-yellowish-brown fluid produced by the liver of most vertebrates that aids the digestion of lipids in the small intestine. In humans, bile is produced continuously by the liver (liver bi ...

. Only 74% of a dose is excreted 7 days after administration, which is due to accumulation of CMA in tissues and low clearance.

Chemistry

CMA, also known as 17α-acetoxy-6-chloro-6-dehydroprogesterone or as 17α-acetoxy-6-chloropregna-4,6-diene-3,20-dione, is a

pregnane Pregnane, also known as 17β-ethylandrostane or as 10β,13β-dimethyl-17β-ethylgonane, is a C21 steroid and, indirectly, a parent of progesterone. It is a parent hydrocarbon for two series of steroids stemming from 5α-pregnane (originally allop ...

steroid A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and ...

and

. It is specifically a derivative of

with a

chlorine Chlorine is a chemical element with the symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between them. Chlorine i ...

atom at the C6 position, a

between the C6 and C7 positions, and an

acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

at the C17α position. CMA is the C17α acetate ester of chlormadinone, which, in contrast to CMA, was never marketed. Analogues of CMA include other 17α-hydroxyprogesterone derivatives such as , delmadinone acetate,

hydroxyprogesterone caproate Hydroxyprogesterone caproate (OHPC), sold under the brand names Proluton and Makena among others, is a progestin medication which is used to prevent preterm birth in pregnant women with a history of the condition and to treat gynecological diso ...

, and osaterone acetate. CMA is identical in

chemical structure A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of ...

to CPA except that it lacks the 1α,2α- methylene

substitution Substitution may refer to: Arts and media *Chord substitution, in music, swapping one chord for a related one within a chord progression *Substitution (poetry), a variation in poetic scansion * "Substitution" (song), a 2009 song by Silversun Pic ...

of CPA. The structure of CMA is also nearly the same as those of delmadinone acetate and osaterone acetate, which similarly have A-ring modifications.

Synthesis

Chemical syntheses of CMA have been published.Langbein, G., Menzer, E., Meyer, M., & Wesemann, R. (1973). New Synthesis of 17alpha Acetoxy-6-Chloro-6-Dehydroprogesterone (Chlormadinone) on 3, 5, 6, 7-Tetrasubstituted Intermediates. ''Journal Fur Praktische Chemie'', 315(1), 8-22.

History

CMA was discovered and first described in 1959. It was marketed in combination with

mestranol Mestranol, sold under the brand names Enovid, Norinyl, and Ortho-Novum among others, is an estrogen medication which has been used in birth control pills, menopausal hormone therapy, and the treatment of menstrual disorders. It is formulated i ...

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and ...

under the brand name ''C-Quens'' from 1965 to 1971 in the

United States The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country Continental United States, primarily located in North America. It consists of 50 U.S. state, states, a Washington, D.C., ...

. It was the first sequential contraceptive pill to be introduced in the CMA has also been marketed in combination with mestranol under the brand names ''Ovosiston'', ''Aconcen'', and ''Sequens''. Due to findings of

mammary gland A mammary gland is an exocrine gland in humans and other mammals that produces milk to feed young offspring. Mammals get their name from the Latin word ''mamma'', "breast". The mammary glands are arranged in organs such as the breasts in ...

nodules in

beagle The beagle is a breed of small scent hound, similar in appearance to the much larger foxhound. The beagle was developed primarily for hunting hare, known as beagling. Possessing a great sense of smell and superior tracking instincts, th ...

dogs (see

below Below may refer to: *Earth * Ground (disambiguation) *Soil *Floor * Bottom (disambiguation) *Less than *Temperatures below freezing *Hell or underworld People with the surname *Ernst von Below (1863–1955), German World War I general *Fred Below ...

), C-Quens was voluntarily withdrawn from the market by Eli Lilly in 1971 and all oral contraceptives of CMA were discontinued in the by 1972. However, subsequent research found that there is no such risk in humans, and CMA has continued to be widely used in oral contraceptives in many other countries, such as

Germany Germany,, officially the Federal Republic of Germany, is a country in Central Europe. It is the second most populous country in Europe after Russia, and the most populous member state of the European Union. Germany is situated betwee ...

and

China China, officially the People's Republic of China (PRC), is a country in East Asia. It is the world's List of countries and dependencies by population, most populous country, with a Population of China, population exceeding 1.4 billion, slig ...

. The antiandrogenic activity of CMA was first described in 1966,Kraft, H. G., & Kiesler, H. (1966). Anti-estrogeneic and anti-androgenic activities of chlormadinone acetate and related compounds. In Hormonal Steroids. Proceedings of the Second International Congress on Hormonal Steroids, Milano. Excerpta Medica, Amsterdam. and the medication was subsequently developed for use alone at high dosages in the treatment of androgen-dependent conditions like

. In the 1960s, CMA was introduced as a component of oral contraceptives. However, around 1970, such formulations were withdrawn from many markets such as the

and

United Kingdom The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Europe, off the north-western coast of the continental mainland. It comprises England, Scotland, Wales and ...

due to the finding that CMA induced alarming

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

s in Beagle dogs. 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

, and

anagestone acetate Anagestone acetate, sold under the brand names Anatropin and Neo-Novum, is a progestin medication which was withdrawn from medical use due to carcinogenicity observed in animal studies. Medical uses Anagestone acetate was used in combination wit ...

, and they were also discontinued for the indication of hormonal contraception (although medroxyprogesterone acetate has since been reintroduced). Tumors were also observed with

, as well as with ethynerone and chloroethynylnorgestrel, but notably not with the non-halogenated

derivatives

norgestrel Norgestrel, sold under the brand name Ovral among others, is a progestin medication which is used in birth control pills and in menopausal hormone therapy. It is available both in combination with an estrogen and alone. It is taken by mouth. ...

norethisterone Norethisterone, also known as norethindrone and sold under many brand names, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication is available in b ...

, 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. CMA was the first progestogen to be studied as a

("minipill"). It was discontinued and replaced by other progestins such as

and

after the findings of toxicity in beagle dogs.

Society and culture

Generic names

''Chlormadinone acetate'' is the generic name of the drug and its , , , and . It is also known by its developmental code name ''RS-1280''.

Brand names

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. It is most commonly marketed in combination with EE as a

under the brand names Belara and to a lesser extent Belarina among others. The medication has been marketed for use in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, diagnosis, and treatment of disease, disorder, and injury in animals. Along with this, it deals with animal rearing, husbandry, breeding, research on nutri ...

under the brand names Anifertil, Chronosyn, Cyclonorm, Fertiletten, Synchrosyn, and others.

Availability

CMA is available alone at low, moderate, and/or high doses in

(brand name Lutéran),

(generics, and formerly Gestafortin),

(brand name Prostal),

(brand name Lutoral), and

(brand name Prostal-L). It is available in many countries in combination with EE, including throughout most of

Europe Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...

and

Latin America Latin America or * french: Amérique Latine, link=no * ht, Amerik Latin, link=no * pt, América Latina, link=no, name=a, sometimes referred to as LatAm is a large cultural region in the Americas where Romance languages — languages derived ...

, and in

Thailand Thailand ( ), historically known as Siam () and officially the Kingdom of Thailand, is a country in Southeast Asia, located at the centre of the Indochinese Peninsula, spanning , with a population of almost 70 million. The country is b ...

Israel Israel (; he, יִשְׂרָאֵל, ; ar, إِسْرَائِيل, ), officially the State of Israel ( he, מְדִינַת יִשְׂרָאֵל, label=none, translit=Medīnat Yīsrāʾēl; ), is a country in Western Asia. It is situated ...

Lebanon Lebanon ( , ar, لُبْنَان, translit=lubnān, ), officially the Republic of Lebanon () or the Lebanese Republic, is a country in Western Asia. It is located between Syria to the north and east and Israel to the south, while Cyprus lie ...

Tunisia ) , image_map = Tunisia location (orthographic projection).svg , map_caption = Location of Tunisia in northern Africa , image_map2 = , capital = Tunis , largest_city = capital , ...

, and

Oman Oman ( ; ar, عُمَان ' ), officially the Sultanate of Oman ( ar, سلْطنةُ عُمان ), is an Arabian country located in southwestern Asia. It is situated on the southeastern coast of the Arabian Peninsula, and spans the mouth of ...

(but notably not South Korea). CMA is not available in

-speaking countries including the

Canada Canada is a country in North America. Its ten provinces and three territories extend from the Atlantic Ocean to the Pacific Ocean and northward into the Arctic Ocean, covering over , making it the world's second-largest country by to ...

, the

Ireland Ireland ( ; ga, Éire ; Ulster-Scots: ) is an island in the North Atlantic Ocean, in north-western Europe. It is separated from Great Britain to its east by the North Channel, the Irish Sea, and St George's Channel. Ireland is the s ...

South Africa South Africa, officially the Republic of South Africa (RSA), is the southernmost country in Africa. It is bounded to the south by of coastline that stretch along the South Atlantic and Indian Oceans; to the north by the neighbouring coun ...

Australia Australia, officially the Commonwealth of Australia, is a sovereign country comprising the mainland of the Australian continent, the island of Tasmania, and numerous smaller islands. With an area of , Australia is the largest country by ...

, or

New Zealand New Zealand ( mi, Aotearoa ) is an island country in the southwestern Pacific Ocean. It consists of two main landmasses—the North Island () and the South Island ()—and over 700 smaller islands. It is the sixth-largest island coun ...

, nor is it marketed in any of the

Nordic countries The Nordic countries (also known as the Nordics or ''Norden''; lit. 'the North') are a geographical and cultural region in Northern Europe and the North Atlantic. It includes the sovereign states of Denmark, Finland, Iceland, Norway and Sw ...

. 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.

Generation

Progestins in birth control pills are sometimes grouped by generation. While the

progestins are consistently grouped into generations, the

progestins used in birth control pills are typically omitted from such classifications or are grouped as "miscellaneous" or "pregnanes". In any case, based on its date of introduction in such formulations of 1965, CMA could be considered a "first-generation" progestin.

Veterinary use

In addition to its use in humans, CMA has been used in

Medical uses

Available forms

Contraindications

Side effects

Overdose

Interactions

Pharmacology

Pharmacodynamics

Progestogenic activity

Antigonadotropic effects

Antiandrogenic activity

Other activity

Pharmacokinetics

Chemistry

Synthesis

History

Society and culture

Generic names

Brand names

Availability

Generation

Veterinary use

References

Further reading