Cyproterone
Encyclopedia
Cyproterone acetate is an antiandrogen
(i.e., it suppresses the actions of testosterone
(and its metabolite dihydrotestosterone
) on tissues). It acts by blocking androgen receptors
which prevents androgens from binding to them and suppresses luteinizing hormone
(which in turn reduces testosterone levels). Its main indications are prostate cancer
, benign prostatic hyperplasia
, priapism
, hypersexuality
and other conditions in which androgen action maintains the disease process. Due to its anti-androgen
effect, it can also be used to treat hirsutism
, and is a common component in hormone therapy
for male-to-female transsexual people.
Until the development of leuprolide
, cyproterone was one of the few drugs used to treat precocious puberty
. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation
.
In addition, cyproterone acetate has weak progestational
activity (i.e., it acts like progesterone
) and can be used to treat hot flashes. As part of some combined oral contraceptive pills (Dianette in UK and Diane-35 in other countries) it decreases acne
and hirsutism
(male-pattern hair growth).
, and acts as an androgen receptor
antagonist
with weak progestational
and glucocorticoid
activity. Some portion is metabolized by hydrolysis
to cyproterone and acetic acid
.
However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form.
Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone.
Cyproterone acetate inhibits the steroidogenic enzyme
21-hydroxylase and to a lesser extent 3beta-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol
.
The blockade of 21-hydroxylase can also result in reduced production of aldosterone
, the primary mineralcorticoid hormone. Mutations in the gene encoding 21-hydroxylase
are fairly common in the human population, therefore some patients may be affected more than others. Although cyproterone has some glucocorticoid activity,
this is offset by the fact that cyproterone acetate inhibits cortisol production and can act as a competitive inhibitor of cortisol at the glucocorticoid receptor,
thus its adrenosuppressive effects are usually fairly minor.
However, since the glucocorticoid effects appear to be due to metabolites, rather than cyproterone acetate itself, the net effect may vary depending on the rate at which cyproterone acetate is metabolized.
The progestational and glucocorticoid effects reduce production of gonadotropin
s, which usually results in lower testosterone levels, however the blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, reducing the efficacy of the antiandrogen treatment. Due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5-alpha-reductase inhibitor
finasteride
, and studies of hirsutism
treatment show increased efficacy of this combination over cyproterone acetate alone.
Some in vitro studies have suggested that cyproterone or cyproterone acetate may have a slight inhibitory effect on 5-alpha-reductase, however no significant reduction in DHT production has been observed in vivo.
Cyproterone acetate is metabolized by the CYP3A4
enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestational activity.
Therefore, use of cyproterone acetate in combination with substances which inhibit CYP3A4 may increase the progestational effects. Cyproterone acetate increases production of CYP3A4 by activating the pregnane x receptor
.
toxicity, and patients should be monitored for changes in liver enzymes
, especially if taking a high dose (200–300 mg/day). Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.
Suppression of adrenal function and reduced response to ACTH
have been reported. Low cortisol
levels may impair carbohydrate metabolism
, and patients with diabetes mellitus
may require adjustments in insulin
dosage. Low aldosterone
levels may lead to salt loss and hyperkalemia
(excess potassium). Patients taking cyproterone should have their cortisol
levels and electrolyte
s monitored, and if hyperkalemia develops, reduce the consumption of food having a high potassium
content.
Used alone, cyproterone acetate does not appear to have a significant effect on blood clotting factors, but in combination with ethinylestradiol
(as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis
.
Women who take contraceptive pills containing cyproterone acetate have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel
.
Cyproterone acetate is also associated with striae (stretch mark) formation, due to its glucocorticoid activity and drying of the skin.
Cyproterone has been associated with depressive mood changes
in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant
effects. This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone
.
Cyproterone acetate suppresses production of estrogen
due to its antigonadotrophic effect, and long-term use without estrogen replacement may result in osteoporosis
.
Side-effects in men which directly result from its antiandrogenic action include gynecomastia
(breast growth), galactorrhea
(milk outflow), and erectile dysfunction
.
of cyproterone acetate can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg, at intervals of several weeks. The primary concern is the manner in which cyproterone acetate affects the adrenal gland
. Due to its glucocorticoid activity, high levels of cyproterone acetate may reduce ACTH, resulting in adrenal insufficiency
if discontinued suddenly. In addition, although cyproterone acetate reduces androgen production in the gonads, it can increase adrenal androgen production, in some cases resulting in an overall rise in testosterone levels.
Thus the sudden withdrawal of cyproterone acetate may result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT
, suppress adrenal function, further reducing cortisol production.
In theory, 5-alpha-reductase inhibitor
s such as finasteride
and dutasteride
may be able to mitigate this effect somewhat by preventing the conversion of testosterone to the more potent DHT.
A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptor
s. These altered androgen receptors can be stimulated, rather than inhibited, by cyproterone. In such cases, withdrawal of cyproterone results in a reduction in cancer growth, rather than the opposite.
of cyproterone are complicated due to its lipophilic
nature. Although the mean elimination half-life is usually estimated at around 40 hours, this primarily reflects its accumulation in fat cells. Elimination from the bloodstream is considerably faster, and the amount stored in fat may be affected by food intake. Therefore it is recommended that this medication be given in divided doses 2-3 times per day, or in the form of a long-acting injection.
ethinylestradiol and taken once daily for 21 days, followed by 7-day interval with placebo
pills (Co-cyprindiol BAN
sold as Dianette in UK, and Diane in US).
For the treatment of hypersexuality
, severe hirsutism
, or for the treatment of male-to-female transsexuals, 25 mg twice daily is usually sufficient, although up to 100 mg/day is permitted. As side effects are dose-dependent, treatment with the lowest effective dose is advisable.
Use during pregnancy is contraindicated, and for women of childbearing age, cyproterone should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional cyproterone should be taken only on days 1-10 of a 28-day package of birth control pills.
Doses up to 300 mg/day are used for the treatment of metastatic prostate cancer
, but at high doses the risk of serious hepatic toxicity or adrenal suppression requires careful monitoring. In treatment of prostate cancer, cyproterone is often co-administered with a GnRH agonist and a 5-alpha-reductase inhibitor
.
Antiandrogen
Antiandrogens, or androgen antagonists, first discovered in the 1960s, prevent androgens from expressing their biological effects on responsive tissues. Antiandrogens alter the androgen pathway by blocking the appropriate receptors, competing for binding sites on the cell's surface, or affecting...
(i.e., it suppresses the actions of testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
(and its metabolite dihydrotestosterone
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
) on tissues). It acts by blocking androgen receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
which prevents androgens from binding to them and suppresses luteinizing hormone
Luteinizing hormone
Luteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
(which in turn reduces testosterone levels). Its main indications are prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, benign prostatic hyperplasia
Benign prostatic hyperplasia
Benign prostatic hyperplasia also known as benign prostatic hypertrophy , benign enlargement of the prostate , and adenofibromyomatous hyperplasia, refers to the increase in size of the prostate....
, priapism
Priapism
Priapism is a potentially harmful and painful medical condition in which the erect penis or clitoris does not return to its flaccid state, despite the absence of both physical and psychological stimulation, within four hours. There are two types of priapism: low-flow and high-flow. Low-flow...
, hypersexuality
Hypersexuality
Hypersexuality is extremely frequent or suddenly increased sexual urges or sexual activity. Hypersexuality is typically associated with lowered sexual inhibitions. Although hypersexuality can be caused by some medical conditions or medications, in most cases the cause is unknown...
and other conditions in which androgen action maintains the disease process. Due to its anti-androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
effect, it can also be used to treat hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, and is a common component in hormone therapy
Hormone therapy
Hormone therapy, or hormonal therapy is the use of hormones in medical treatment. Treatment with hormone antagonists may also referred to as hormonal therapy...
for male-to-female transsexual people.
Until the development of leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
, cyproterone was one of the few drugs used to treat precocious puberty
Precocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
. It was also used in animal experimentation to investigate the actions of androgens in fetal sexual differentiation
Sexual differentiation
Sexual differentiation is the process of development of the differences between males and females from an undifferentiated zygote...
.
In addition, cyproterone acetate has weak progestational
Progestagen
Progestogens are a group of hormones including progesterone.The progestogens are one of the five major classes of steroid hormones, in addition to the estrogens, androgens, mineralocorticoids, and glucocorticoids. All progestogens are characterized by their basic 21-carbon skeleton, called a...
activity (i.e., it acts like progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
) and can be used to treat hot flashes. As part of some combined oral contraceptive pills (Dianette in UK and Diane-35 in other countries) it decreases acne
Acne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
and hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
(male-pattern hair growth).
Pharmacology
Cyproterone acetate is a synthetic derivative of 17-hydroxyprogesterone17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
, and acts as an androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
with weak progestational
Progestagen
Progestogens are a group of hormones including progesterone.The progestogens are one of the five major classes of steroid hormones, in addition to the estrogens, androgens, mineralocorticoids, and glucocorticoids. All progestogens are characterized by their basic 21-carbon skeleton, called a...
and glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
activity. Some portion is metabolized by hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
to cyproterone and acetic acid
Acetic acid
Acetic acid is an organic compound with the chemical formula CH3CO2H . It is a colourless liquid that when undiluted is also called glacial acetic acid. Acetic acid is the main component of vinegar , and has a distinctive sour taste and pungent smell...
.
However, unlike many other steroid esters, cyproterone acetate is not extensively hydrolyzed, and much of its pharmacological activity is attributed to its acetate form.
Cyproterone acetate has approximately three times the anti-androgenic activity of cyproterone.
Cyproterone acetate inhibits the steroidogenic enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
21-hydroxylase and to a lesser extent 3beta-hydroxysteroid dehydrogenase, both of which are needed to synthesize cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
.
The blockade of 21-hydroxylase can also result in reduced production of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, the primary mineralcorticoid hormone. Mutations in the gene encoding 21-hydroxylase
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency , in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia, and "CAH" in most contexts refers to 21-hydroxylase deficiency...
are fairly common in the human population, therefore some patients may be affected more than others. Although cyproterone has some glucocorticoid activity,
this is offset by the fact that cyproterone acetate inhibits cortisol production and can act as a competitive inhibitor of cortisol at the glucocorticoid receptor,
thus its adrenosuppressive effects are usually fairly minor.
However, since the glucocorticoid effects appear to be due to metabolites, rather than cyproterone acetate itself, the net effect may vary depending on the rate at which cyproterone acetate is metabolized.
The progestational and glucocorticoid effects reduce production of gonadotropin
Gonadotropin
Gonadotropins are protein hormones secreted by gonadotrope cells of the pituitary gland of vertebrates. This is a family of proteins, which include the mammalian hormones follitropin , lutropin , placental chorionic gonadotropins hCG and eCG and chorionic gonadotropin , as well as at least two...
s, which usually results in lower testosterone levels, however the blockade of adrenal 21-hydroxylase results in the accumulation of androgen precursors which may be converted to testosterone, reducing the efficacy of the antiandrogen treatment. Due to the possibility of increased adrenal androgens, cyproterone acetate is sometimes combined with the 5-alpha-reductase inhibitor
5-alpha-reductase inhibitor
5α-Reductase inhibitors are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic alopecia...
finasteride
Finasteride
Finasteride is a synthetic antiandrogen that inhibits type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone...
, and studies of hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
treatment show increased efficacy of this combination over cyproterone acetate alone.
Some in vitro studies have suggested that cyproterone or cyproterone acetate may have a slight inhibitory effect on 5-alpha-reductase, however no significant reduction in DHT production has been observed in vivo.
Cyproterone acetate is metabolized by the CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
enzyme, forming the active metabolite 15β-hydroxycyproterone acetate, which retains its antiandrogen activity, but has reduced progestational activity.
Therefore, use of cyproterone acetate in combination with substances which inhibit CYP3A4 may increase the progestational effects. Cyproterone acetate increases production of CYP3A4 by activating the pregnane x receptor
Pregnane X receptor
In the field of molecular biology, the pregnane X receptor , also known as the steroid and xenobiotic sensing nuclear receptor or nuclear receptor subfamily 1, group I, member 2 is a protein that in humans is encoded by the NR1I2 gene.PXR is a nuclear receptor whose primary function is to sense...
.
Side effects
The most serious potential side effect is liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
toxicity, and patients should be monitored for changes in liver enzymes
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
, especially if taking a high dose (200–300 mg/day). Toxicity is dose-dependent and the low doses used in birth control pills (2 mg) do not appear to represent a significant risk.
Suppression of adrenal function and reduced response to ACTH
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
have been reported. Low cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
levels may impair carbohydrate metabolism
Carbohydrate metabolism
Carbohydrate metabolism denotes the various biochemical processes responsible for the formation, breakdown and interconversion of carbohydrates in living organisms....
, and patients with diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
may require adjustments in insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
dosage. Low aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
levels may lead to salt loss and hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
(excess potassium). Patients taking cyproterone should have their cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
levels and electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s monitored, and if hyperkalemia develops, reduce the consumption of food having a high potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
content.
Used alone, cyproterone acetate does not appear to have a significant effect on blood clotting factors, but in combination with ethinylestradiol
Ethinylestradiol
Ethynylestradiol , also ethynyl estradiol , is a derivative of estradiol. Ethynyl estradiol is an orally bio-active estrogen used in almost all modern formulations of combined oral contraceptive pills...
(as in combined oral contraceptive pills) presents an increased risk of deep vein thrombosis
Deep vein thrombosis
Deep vein thrombosis is the formation of a blood clot in a deep vein. Deep vein thrombosis commonly affects the leg veins or the deep veins of the pelvis. Occasionally the veins of the arm are affected...
.
Women who take contraceptive pills containing cyproterone acetate have a six- to sevenfold risk of developing thromboembolism compared to women who do not take any contraceptive pill, and twice the risk of women who take a contraceptive pill containing levonorgestrel
Levonorgestrel
Levonorgestrel is a second generation synthetic progestogen used as an active ingredient in some hormonal contraceptives.-Chemistry:...
.
Cyproterone acetate is also associated with striae (stretch mark) formation, due to its glucocorticoid activity and drying of the skin.
Cyproterone has been associated with depressive mood changes
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
in some patients, presumably due to androgen deprivation. However, others have reported significant antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
effects. This may be due to its effect on adrenal hormones, as similar antidepressant effects have been observed with other adrenal suppressants, such as metyrapone
Metyrapone
Metyrapone is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome .-Mechanism:...
.
Cyproterone acetate suppresses production of estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
due to its antigonadotrophic effect, and long-term use without estrogen replacement may result in osteoporosis
Osteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
.
Side-effects in men which directly result from its antiandrogenic action include gynecomastia
Gynecomastia
Gynecomastia or Gynaecomastia, , is the abnormal development of large mammary glands in males resulting in breast enlargement. The term comes from the Greek γυνή gyné meaning "woman" and μαστός mastós meaning "breast"...
(breast growth), galactorrhea
Galactorrhea
Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.Contemporary Maternal-Newborn Nursing Care defines galactorrhea as "nipple discharge." -Causes:...
(milk outflow), and erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
.
Withdrawal effects
Abrupt withdrawalWithdrawal
Withdrawal can refer to any sort of separation, but is most commonly used to describe the group of symptoms that occurs upon the abrupt discontinuation/separation or a decrease in dosage of the intake of medications, recreational drugs, and alcohol...
of cyproterone acetate can be harmful, and the package insert from Schering AG recommends that the daily dose be reduced by no more than 50 mg, at intervals of several weeks. The primary concern is the manner in which cyproterone acetate affects the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
. Due to its glucocorticoid activity, high levels of cyproterone acetate may reduce ACTH, resulting in adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
if discontinued suddenly. In addition, although cyproterone acetate reduces androgen production in the gonads, it can increase adrenal androgen production, in some cases resulting in an overall rise in testosterone levels.
Thus the sudden withdrawal of cyproterone acetate may result in undesirable androgenic effects. This is a particular concern because androgens, especially DHT
Dihydrotestosterone
Dihydrotestosterone is an androgen or male sex hormone. The enzyme 5α-reductase synthesises DHT in the prostate, testes, hair follicles, and adrenal glands...
, suppress adrenal function, further reducing cortisol production.
In theory, 5-alpha-reductase inhibitor
5-alpha-reductase inhibitor
5α-Reductase inhibitors are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic alopecia...
s such as finasteride
Finasteride
Finasteride is a synthetic antiandrogen that inhibits type II 5-alpha reductase, the enzyme that converts testosterone to dihydrotestosterone...
and dutasteride
Dutasteride
Dutasteride is a dual 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone ....
may be able to mitigate this effect somewhat by preventing the conversion of testosterone to the more potent DHT.
A paradoxical effect occurs with certain prostate cancer cells which have genetic mutations in their androgen receptor
Androgen receptor
The androgen receptor , also known as NR3C4 , is a type of nuclear receptor that is activated by binding of either of the androgenic hormones testosterone or dihydrotestosterone in the cytoplasm and then translocating into the nucleus...
s. These altered androgen receptors can be stimulated, rather than inhibited, by cyproterone. In such cases, withdrawal of cyproterone results in a reduction in cancer growth, rather than the opposite.
Pharmacokinetics
The pharmacokineticsPharmacokinetics
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism...
of cyproterone are complicated due to its lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...
nature. Although the mean elimination half-life is usually estimated at around 40 hours, this primarily reflects its accumulation in fat cells. Elimination from the bloodstream is considerably faster, and the amount stored in fat may be affected by food intake. Therefore it is recommended that this medication be given in divided doses 2-3 times per day, or in the form of a long-acting injection.
Dosage and administration
As an oral contraceptive, 2 mg cyproterone acetate is combined with 35 or 50 mcgMicrogram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
ethinylestradiol and taken once daily for 21 days, followed by 7-day interval with placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
pills (Co-cyprindiol BAN
British Approved Name
A British Approved Name is the official non-proprietary or generic name given to a pharmaceutical substance, as defined in the British Pharmacopoeia...
sold as Dianette in UK, and Diane in US).
For the treatment of hypersexuality
Hypersexuality
Hypersexuality is extremely frequent or suddenly increased sexual urges or sexual activity. Hypersexuality is typically associated with lowered sexual inhibitions. Although hypersexuality can be caused by some medical conditions or medications, in most cases the cause is unknown...
, severe hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, or for the treatment of male-to-female transsexuals, 25 mg twice daily is usually sufficient, although up to 100 mg/day is permitted. As side effects are dose-dependent, treatment with the lowest effective dose is advisable.
Use during pregnancy is contraindicated, and for women of childbearing age, cyproterone should be administered with a combined oral contraceptive. To ensure that it does not interfere with regular withdrawal bleeding, additional cyproterone should be taken only on days 1-10 of a 28-day package of birth control pills.
Doses up to 300 mg/day are used for the treatment of metastatic prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, but at high doses the risk of serious hepatic toxicity or adrenal suppression requires careful monitoring. In treatment of prostate cancer, cyproterone is often co-administered with a GnRH agonist and a 5-alpha-reductase inhibitor
5-alpha-reductase inhibitor
5α-Reductase inhibitors are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic alopecia...
.