Antiandrogen
Encyclopedia
Antiandrogens, or androgen antagonists, first discovered
in the 1960s, prevent androgen
s 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 androgen production. Antiandrogens can be prescribed to treat an array of diseases and disorders. In men, antiandrogens are most frequently used to treat prostate cancer. In women, antiandrogens are used to decrease levels of male hormones causing symptoms of hyperandrogenism
. Antiandrogens present in the environment have become a topic of concern. Many industrial chemicals, pesticides and insecticides exhibit antiandrogenic effects. Certain plant species have also been found to produce antiandrogens. Environmental antiandrogens can have harmful effects on reproductive organ development in fetuses exposed in utero as well as their offspring.
s. Nonsteroidal antiandrogens, or “pure” antiandrogens, counter androgens and have no steroidal effects. Antiandrogens inhibit circulating androgens by blocking androgen receptors, suppressing androgen synthesis, or acting in both those ways. The most common antiandrogens are androgen receptor (AR) antagonists which act on the target cell level and competitively bind to androgen receptors.
, benign prostatic hyperplasia
, hypersexuality
, male contraception, and for those that have undergone gender reassignment. For women, antiandrogens are often prescribed for severe cases of acne
, amenorrhea, seborrhea, hirsutism
, androgenic alopecia, hidradenitis suppurativa
, and hyperandrogenism
.
), reduced activity or function of the accessory male sex organs, and slowed or halted development or reversal of male secondary sex characteristic
s.
Antiandrogenic drugs are often indicated to treat severe male sexual disorders, such as hypersexuality
(excessive sexual desire) and sexual deviation such as paraphilia
, a disorder involving intense recurrent sexual urges), since lowering male hormone levels decreases libido. As a part of a program for registered sex offenders recently released from prisons, the offender is sometimes administered antiandrogen drugs to reduce the likelihood of repeat offenses by reducing sexual drive. On occasion, antiandrogens are used as a male contraceptive
agent, to purposefully prevent or counteract masculinisation in the case of transsexual women undergoing sex reassignment therapy
, and to prevent the symptoms associated with reduced testosterone
, such as hot flashes, following castration
.
. Prostate cancer is the most commonly diagnosed form of cancer found in men. Some prostate cancer cells require androgens for growth. To counteract cancer cell proliferation, antiandrogenic drugs are used for hormone therapy called androgen deprivation therapy
(ADT). Some antiandrogenic drugs suppress androgen production while others inhibit androgens from binding to the cancer cells’ androgen receptors. These two classes of drugs can be prescribed separately or can be used together for a complete/combined androgen blockade (CAB). When the body is deprived of androgens, the therapy is termed castration-based therapy as the lack of androgens mimics castration. By competing with circulating androgens for binding sites on prostate cell receptors, antiandrogens promote apoptosis and inhibit prostate cancer growth. Hormone therapy antiandrogen drugs can be prescribed as monotherapy or in addition to radical radiotherapy or prostatectomy. Antiandrogen monotherapy generally causes fewer side effects in males although it may block androgen less effectively than combined therapies. Monotherapy is often preferred by men as it is less likely than combined therapies to diminish libido or cause tenderness of the breasts, diarrhea, and nausea.
Androgen-deprivation therapy (ADT) has been shown to cause initial reduction of prostate tumors. However, antiandrogenic drugs can cause prostate cancer tumors to become androgen independent. Androgen independence occurs when cells that are not reliant on androgen proliferate and spread while cells that require androgen for survival undergo apoptosis
. The cells that do not require androgen become the basis of the tumors, causing reoccurring tumors a few years after the initial disappearance of the prostate cancer. Once prostate cancer becomes androgen independent, hormone therapy will most likely no longer benefit the individual and a new treatment approach will be needed.
In one study, the efficacy of reducing prostate cancer cells by castration was compared to combined androgen blockade (CAB) in which castration is combined with an antiandrogenic drug. Flutamide
(brand name Eulexin), nilutamide
(brand names Anandron and Nilandron) and bicalutamide
(brand name Casodex) are nonsteroidal, “pure” antiandrogens. Flutamide has several side effects that the newer bicalutamide does not. Used in combination with castration, nilutamide
and flutamide
were found to have a minimal effect on prolonging survival while bicalutamide
significantly prolonged life in prostate cancer patients. As a result of these conclusions, since 2007 combined androgen blockade with bicalutamide has been used as an effective, safe, and cost-efficient treatment of prostate cancer.
5-alpha-reductase inhibitor
s such as finasteride
(brand names Proscar and Propecia), dutasteride
(brand name Avodart), bexlosteride
, izonsteride
, turosteride
, and epristeride
are antiandrogenic as they prevent the reduction of testosterone
to dihydrotestosterone
(DHT). DHT is 3-5 times more potent than testosterone or other androgens (except in skeletal muscle tissue, where testosterone is the main androgen). They are unique because they do not counteract the effects or production of other androgens other than DHT. Dihydrotestosterone is necessary for development of both external male sex organs and the prostate. 5α-reductase inhibitors are most often used to treat benign prostatic hyperplasia
since the resulting decrease in dihydrotestosterone inhibits proliferation of prostate cells.
, seborrhea, amenorrhea (absence of menstrual periods), hirsutism
(excessive facial and bodily hair in women), and hidradenitis suppurativa
can all be caused by an excess of male hormones.
Hormonal antiandrogen treatment is given to female patients that suffer from multiple symptoms of hyperandrogenism. Acne is the most common of all the skin disorders that result from male hormones overproduction. Fewer androgens present in a female’s tissues results in a reduction of oil (sebum) production and bumps (comedone). Also, antiandrogenic drugs are often combined with topical and oral pharmaceuticals to treat acne. In women that suffer from overproduction of hair due to high testosterone levels (hirsutism), antiandrogenic drugs are used to slow hair growth, lighten hair color, and thin the hair. For females with pattern hair loss (androgenic alopecia), antiandrogens can assist in reducing hair shedding and thinning.
The most common antiandrogenic drugs used to treat women with hyperandrogenism are spironolactone
and cyproterone acetate. Spironolactone
(brand names Aldactone and Spirotone), a synthetic 17-spirolactone corticosteroid
is used primarily to treat low-renin
hypertension
, hypokalemia
, and Conn's syndrome
. Cyproterone acetate (brand names Androcur, Climen, Diane 35, and Ginette 35) is a synthetic
steroid
, a potent antiandrogen that also possesses progestational
properties. Oral contraceptives that mediate progesterone have no effect on androgens but may be combined with spironolactone and cyprone acetate for the purpose of correcting menstrual irregularities.
s, that antagonistically affect androgen receptors and androgen production can negatively affect individuals that come in contact with the compounds as well as their future generations. Certain pesticides and insecticides as well as in industrial chemicals contain antiandrogenic chemicals. Some species of plants produce phytochemicals with antiandrogenic effects. Exposure to these environmental antiandrogens has resulted in adverse effects on animals that allude to human health risks.
Animal studies with vinclozolin
, procymidone
, linuron, and the DDT
metabolite dichlorodiphenyldichloroethylene
(p.p’-DDE) show irregular reproductive development due to their function as androgen receptor antagonists that inhibit androgen-activated gene expression. Even with low doses of antiandrogenic pesticides, developmental effects such as reduced anogenital distance and induction of areolas were seen in male rats.
Animal studies show that deformities result in offspring exposed to antiandrogens. Male mice can display malformations that resemble the reproductive organs of females as in the case of exposure to vinclozolin
or proymidone. Exposure to vinclozolin or procymidone in utero feminized male offspring, as seen in abnormalities of anogenital distance, small or absent sex accessory glands, hypospadias
, undescended testes, retained nipples, cleft phallus
, and presence of a vaginal pouch. Male mice exposed before puberty to vinclozolin experienced delayed pubertal development visualized by delayed onset of androgen-dependent preputial
separation.
Ketoconazole
's imidazole
derivative is used as a broad-spectrum antifungal agent effective against a variety of fungal infections. Although ketoconazole is a relatively weak antiandrogen, side-effects seen as a result of exposure include serious liver
damage and reduced levels of androgens from both the testicle
s and adrenal gland
s.
Organophostphate insecticides such as fenitrothion can also behave as androgen receptor antagonists. Fenitrothion was found to completely inhibit dihydrotestosterone-dependent human androgen receptor activation, resulting in reduced weights of seminal vesicles and the ventral prostate. Structural similarity of fenitrothion with linuron further supports the findings of antiandrogenic activity.
Phthalates are mainly found in plastics. Fetuses that are exposed to a mixture of pthalates in utero may show signs of disrupted reproductive development. When Di-n-butyl phthalate (DBP), diisobutyl phthalate
(DiBP), benzyl butyl phthalate
(BBP), Bis(2-ethylhexyl) phthalate
(DEHP) and di-n-pentyl phthalate (DPP) were combined, reductions in both testosterone synthesis and gene expression of steroidogenic pathway proteins were seen. The result in male rats was undescended testes and abnormal development of reproductive tissues.
Parabens are commonly found in cosmetics and pharmaceuticals. Paraben esters have been found to mimic androgen antagonist activity. Antiandrogenic endocrine disruption has been shown in aquatic species but the mechanism is unknown. Researchers believe parabens have the ability to bind to human androgen receptors but it still remains unclear.
The best known plant-derived anti-androgen is 3,3'-Diindolylmethane
(DIM)
Spearmint tea has antiandrogenic properties in females with hirsutism
.,
Scutellaria baicalensis
may also have antiandrogenic properties.
The compound N-butylbenzene-sulfonamide (NBBS) isolated from Pygeum africanum is a specific androgen antagonist.,
Glycyrrhiza glabra has shown antiandrogenic activity in male rats
A herbal formula (termed KMKKT) containing Korean Angelica gigas
Nakai (AGN) root and nine other oriental herbs has shown in vitro anti-androgen activity.
Pygeum africanum contains an antiandrogenic compound atraric acid.
Duke's database lists several more herbs that have antiandrogenic properties.
The future of antiandrogenic drugs is believed to be peptide antagonists. Current androgen receptor antagonist drugs bind to the ligand binding domain on the receptors and inhibit receptor function. Androgen receptor peptide antagonists act in an alternative manner. A peptide antagonist interrupts androgen receptor protein interactions from the surface of the receptor. This approach is “mechanism-based” and has greater potential for blocking receptor activity than the traditional ligand-receptor binding approach. Researchers are trying to target the ligand-binding domain and N-terminal domain of androgen receptors.
Discovery and development of antiandrogens
In the 1960s, the first antiandrogen, or androgen antagonist, was discovered. Antiandrogens antagonise the androgen receptor and thereby block the biological effects of testosterone and dihydrotestosterone . Antiandrogens are important for men with hormonally responsive diseases like prostate...
in the 1960s, prevent 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...
s 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 androgen production. Antiandrogens can be prescribed to treat an array of diseases and disorders. In men, antiandrogens are most frequently used to treat prostate cancer. In women, antiandrogens are used to decrease levels of male hormones causing symptoms of hyperandrogenism
Hyperandrogenism
Hyperandrogenism is a medical condition characterized by excessive production and/or secretion of androgens.It is one of the primary symptoms of polycystic ovary syndrome. In such cases, it presents with symptoms such as acne or hyperseborrhea, is frequent in adolescent girls and is often...
. Antiandrogens present in the environment have become a topic of concern. Many industrial chemicals, pesticides and insecticides exhibit antiandrogenic effects. Certain plant species have also been found to produce antiandrogens. Environmental antiandrogens can have harmful effects on reproductive organ development in fetuses exposed in utero as well as their offspring.
Mechanism of action
Antiandrogens are classified as steroidal or nonsteroidal. Steroidal antiandrogens not only counter androgens, but also affect secondary sex characteristicSecondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
s. Nonsteroidal antiandrogens, or “pure” antiandrogens, counter androgens and have no steroidal effects. Antiandrogens inhibit circulating androgens by blocking androgen receptors, suppressing androgen synthesis, or acting in both those ways. The most common antiandrogens are androgen receptor (AR) antagonists which act on the target cell level and competitively bind to androgen receptors.
Medical applications
Antiandrogenic pharmaceuticals are used to treat an array of medical conditions that are dependent on the androgen pathway. Antiandrogens are often prescribed for men with prostate cancerProstate 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....
, 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...
, male contraception, and for those that have undergone gender reassignment. For women, antiandrogens are often prescribed for severe cases of 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...
, amenorrhea, seborrhea, 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...
, androgenic alopecia, hidradenitis suppurativa
Hidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
, and hyperandrogenism
Hyperandrogenism
Hyperandrogenism is a medical condition characterized by excessive production and/or secretion of androgens.It is one of the primary symptoms of polycystic ovary syndrome. In such cases, it presents with symptoms such as acne or hyperseborrhea, is frequent in adolescent girls and is often...
.
Pharmaceuticals for men
Antiandrogens in males can result in hyposexuality (diminished sexual desire or libidoLibido
Libido refers to a person's sex drive or desire for sexual activity. The desire for sex is an aspect of a person's sexuality, but varies enormously from one person to another, and it also varies depending on circumstances at a particular time. A person who has extremely frequent or a suddenly...
), reduced activity or function of the accessory male sex organs, and slowed or halted development or reversal of male secondary sex characteristic
Secondary sex characteristic
Secondary sex characteristics are features that distinguish the two sexes of a species, but that are not directly part of the reproductive system. They are believed to be the product of sexual selection for traits which give an individual an advantage over its rivals in courtship and aggressive...
s.
Antiandrogenic drugs are often indicated to treat severe male sexual disorders, such as 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...
(excessive sexual desire) and sexual deviation such as paraphilia
Paraphilia
Paraphilia is a biomedical term used to describe sexual arousal to objects, situations, or individuals that are not part of normative stimulation and that may cause distress or serious problems for the paraphiliac or persons associated with him or her...
, a disorder involving intense recurrent sexual urges), since lowering male hormone levels decreases libido. As a part of a program for registered sex offenders recently released from prisons, the offender is sometimes administered antiandrogen drugs to reduce the likelihood of repeat offenses by reducing sexual drive. On occasion, antiandrogens are used as a male contraceptive
Male contraceptive
Male contraceptives include condoms, withdrawal , and vasectomy. In other animals, castration is commonly used for contraception...
agent, to purposefully prevent or counteract masculinisation in the case of transsexual women undergoing sex reassignment therapy
Sex reassignment therapy
Sex reassignment therapy is an umbrella term for all medical procedures regarding sex reassignment of both transgender and intersexual people...
, and to prevent the symptoms associated with reduced 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...
, such as hot flashes, following castration
Castration
Castration is any action, surgical, chemical, or otherwise, by which a male loses the functions of the testicles or a female loses the functions of the ovaries.-Humans:...
.
Prostate Cancer
Decreasing the body’s response to androgen can have beneficial effects in treating prostate cancerProstate 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...
. Prostate cancer is the most commonly diagnosed form of cancer found in men. Some prostate cancer cells require androgens for growth. To counteract cancer cell proliferation, antiandrogenic drugs are used for hormone therapy called androgen deprivation therapy
Androgen deprivation therapy
Androgen deprivation therapy , a treatment for prostate cancer that reduces the production or effect of androgen hormones, eg. testosterone, which many prostate cancers depend on. The side-effects make it controversial in some cases. There is an increased risk of osteoporosis, and possibly...
(ADT). Some antiandrogenic drugs suppress androgen production while others inhibit androgens from binding to the cancer cells’ androgen receptors. These two classes of drugs can be prescribed separately or can be used together for a complete/combined androgen blockade (CAB). When the body is deprived of androgens, the therapy is termed castration-based therapy as the lack of androgens mimics castration. By competing with circulating androgens for binding sites on prostate cell receptors, antiandrogens promote apoptosis and inhibit prostate cancer growth. Hormone therapy antiandrogen drugs can be prescribed as monotherapy or in addition to radical radiotherapy or prostatectomy. Antiandrogen monotherapy generally causes fewer side effects in males although it may block androgen less effectively than combined therapies. Monotherapy is often preferred by men as it is less likely than combined therapies to diminish libido or cause tenderness of the breasts, diarrhea, and nausea.
Androgen-deprivation therapy (ADT) has been shown to cause initial reduction of prostate tumors. However, antiandrogenic drugs can cause prostate cancer tumors to become androgen independent. Androgen independence occurs when cells that are not reliant on androgen proliferate and spread while cells that require androgen for survival undergo apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. The cells that do not require androgen become the basis of the tumors, causing reoccurring tumors a few years after the initial disappearance of the prostate cancer. Once prostate cancer becomes androgen independent, hormone therapy will most likely no longer benefit the individual and a new treatment approach will be needed.
In one study, the efficacy of reducing prostate cancer cells by castration was compared to combined androgen blockade (CAB) in which castration is combined with an antiandrogenic drug. Flutamide
Flutamide
Flutamide is an oral nonsteroidal antiandrogen drug primarily used to treat prostate cancer. It competes with testosterone and its powerful metabolite, dihydrotestosterone for binding to androgen receptors in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer...
(brand name Eulexin), nilutamide
Nilutamide
Nilutamide is an antiandrogen medication used in the treatment of advanced stage prostate cancer. Nilutamide blocks the androgen receptor, preventing its interaction with testosterone. Because most prostate cancer cells rely on the stimulation of the androgen receptor for growth and survival,...
(brand names Anandron and Nilandron) and bicalutamide
Bicalutamide
Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer and hirsutism...
(brand name Casodex) are nonsteroidal, “pure” antiandrogens. Flutamide has several side effects that the newer bicalutamide does not. Used in combination with castration, nilutamide
Nilutamide
Nilutamide is an antiandrogen medication used in the treatment of advanced stage prostate cancer. Nilutamide blocks the androgen receptor, preventing its interaction with testosterone. Because most prostate cancer cells rely on the stimulation of the androgen receptor for growth and survival,...
and flutamide
Flutamide
Flutamide is an oral nonsteroidal antiandrogen drug primarily used to treat prostate cancer. It competes with testosterone and its powerful metabolite, dihydrotestosterone for binding to androgen receptors in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer...
were found to have a minimal effect on prolonging survival while bicalutamide
Bicalutamide
Bicalutamide is an oral non-steroidal anti-androgen used in the treatment of prostate cancer and hirsutism...
significantly prolonged life in prostate cancer patients. As a result of these conclusions, since 2007 combined androgen blockade with bicalutamide has been used as an effective, safe, and cost-efficient treatment of prostate cancer.
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...
(brand names Proscar and Propecia), dutasteride
Dutasteride
Dutasteride is a dual 5-a reductase inhibitor that inhibits conversion of testosterone to dihydrotestosterone ....
(brand name Avodart), bexlosteride
Bexlosteride
Bexlosteride is a potent and noncompetitive inhibitor of the enzyme 5α-reductase related to finasteride and dutasteride. It is selective for the type I isoform of the enzyme. It was never marketed.- References :...
, izonsteride
Izonsteride
Izonsteride is a selective inhibitor of the 5α-redcutase, with dual effects on both the type I and type II isoforms of the enzyme. It was under development by Eli Lilly and Company and Fujisawa for the treatment of benign prostatic hyperplasia but was never marketed...
, turosteride
Turosteride
Turosteride is a selective inhibitor of the enzyme 5α-redcutase which was under investigation by GlaxoSmithKline for the treatment of benign prostatic hyperplasia , but was never marketed. Similarly to finasteride, turosteride is selective for the type II isoform of 5α-redcutase, with about...
, and epristeride
Epristeride
Epristeride is a selective, transition state, non-competitive inhibitor of the type II isoform of the enzyme 5α-reductase, similarly to finasteride and turosteride...
are antiandrogenic as they prevent the reduction 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...
to 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...
(DHT). DHT is 3-5 times more potent than testosterone or other androgens (except in skeletal muscle tissue, where testosterone is the main androgen). They are unique because they do not counteract the effects or production of other androgens other than DHT. Dihydrotestosterone is necessary for development of both external male sex organs and the prostate. 5α-reductase inhibitors are most often used to treat 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....
since the resulting decrease in dihydrotestosterone inhibits proliferation of prostate cells.
Pharmaceuticals for women
Hyperandrogenism is a condition found in women where ovaries overproduce androgens, which are typically considered male hormones as they are important for the development of male reproductive organs and secondary male characteristics. Antiandrogenic drugs can help to counteract male hormones that cause skin and hair problems in women. Gonadotrophin, a pituitary hormone, is involved in ovarial androgen production. Antiandrogens are able to suppress the release of gonadotrophin, which in turn lowers the quantity of androgens present in the body. Androgenic alopecia (a type of hair loss and pattern baldness), acne vulgarisAcne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
, seborrhea, amenorrhea (absence of menstrual periods), 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...
(excessive facial and bodily hair in women), and hidradenitis suppurativa
Hidradenitis suppurativa
Hidradenitis suppurativa is a skin disease that most commonly affects areas bearing apocrine sweat glands or sebaceous glands, such as the underarms, breasts, inner thighs, groin and buttocks.-Overview:...
can all be caused by an excess of male hormones.
Hormonal antiandrogen treatment is given to female patients that suffer from multiple symptoms of hyperandrogenism. Acne is the most common of all the skin disorders that result from male hormones overproduction. Fewer androgens present in a female’s tissues results in a reduction of oil (sebum) production and bumps (comedone). Also, antiandrogenic drugs are often combined with topical and oral pharmaceuticals to treat acne. In women that suffer from overproduction of hair due to high testosterone levels (hirsutism), antiandrogenic drugs are used to slow hair growth, lighten hair color, and thin the hair. For females with pattern hair loss (androgenic alopecia), antiandrogens can assist in reducing hair shedding and thinning.
The most common antiandrogenic drugs used to treat women with hyperandrogenism are spironolactone
Spironolactone
Spironolactone , commonly referred to as simply spiro, is a diuretic and is used as an antiandrogen.It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called...
and cyproterone acetate. Spironolactone
Spironolactone
Spironolactone , commonly referred to as simply spiro, is a diuretic and is used as an antiandrogen.It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called...
(brand names Aldactone and Spirotone), a synthetic 17-spirolactone corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
is used primarily to treat low-renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
, and Conn's syndrome
Conn's syndrome
Primary aldosteronism, also known as primary hyperaldosteronism, is characterized by the overproduction of the mineralocorticoid hormone aldosterone by the adrenal glands., when not a result of excessive renin secretion. Aldosterone causes increase in sodium and water retention and potassium...
. Cyproterone acetate (brand names Androcur, Climen, Diane 35, and Ginette 35) is a synthetic
Chemical synthesis
In chemistry, chemical synthesis is purposeful execution of chemical reactions to get a product, or several products. This happens by physical and chemical manipulations usually involving one or more reactions...
steroid
Steroid
A steroid is a type of organic compound that contains a characteristic arrangement of four cycloalkane rings that are joined to each other. Examples of steroids include the dietary fat cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.The core...
, a potent antiandrogen that also possesses 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...
properties. Oral contraceptives that mediate progesterone have no effect on androgens but may be combined with spironolactone and cyprone acetate for the purpose of correcting menstrual irregularities.
Environmental exposure
Exposure to antiandrogens can occur unintentionally due to natural or anthropogenic compounds in the environment. Environmental compounds affecting the endocrine system, termed endocrine disruptorEndocrine disruptor
Endocrine disruptors are chemicals that interfere with endocrine in animals, including humans. These disruptions can cause cancerous tumors, birth defects, and other developmental disorders...
s, that antagonistically affect androgen receptors and androgen production can negatively affect individuals that come in contact with the compounds as well as their future generations. Certain pesticides and insecticides as well as in industrial chemicals contain antiandrogenic chemicals. Some species of plants produce phytochemicals with antiandrogenic effects. Exposure to these environmental antiandrogens has resulted in adverse effects on animals that allude to human health risks.
Pesticides and Insecticides
Exposure to pesticides and insecticides with antiandrogenic properties has been found to negatively affect humans and laboratory animals. Androgens are important in fetal development as well as in pubertal development. Exposure during critical periods of development can cause reproductive malformations in males while exposure after birth and before puberty can delay pubertal development.Animal studies with vinclozolin
Vinclozolin
- Introduction :Vinclozolin is a common dicarboximide fungicide used to control various diseases in vineyards, and on fruits and vegetables such as raspberries, lettuce, kiwi, beans and onions. It is also used on turf on golf courses...
, procymidone
Procymidone
Procymidone is a pesticide. It is often used for killing unwanted ferns and nettles, and as a dicarboximide fungicide for killing fungi. It is a known endocrine disruptor ....
, linuron, and the DDT
DDT
DDT is one of the most well-known synthetic insecticides. It is a chemical with a long, unique, and controversial history....
metabolite dichlorodiphenyldichloroethylene
Dichlorodiphenyldichloroethylene
Dichlorodiphenyldichloroethylene is a chemical compound formed by the loss of hydrogen chloride from DDT, of which it is one of the more common breakdown products. DDE is fat soluble which tends to build up in the fat of animals. Due to its stability in fat, DDE is rarely excreted from the body,...
(p.p’-DDE) show irregular reproductive development due to their function as androgen receptor antagonists that inhibit androgen-activated gene expression. Even with low doses of antiandrogenic pesticides, developmental effects such as reduced anogenital distance and induction of areolas were seen in male rats.
Animal studies show that deformities result in offspring exposed to antiandrogens. Male mice can display malformations that resemble the reproductive organs of females as in the case of exposure to vinclozolin
Vinclozolin
- Introduction :Vinclozolin is a common dicarboximide fungicide used to control various diseases in vineyards, and on fruits and vegetables such as raspberries, lettuce, kiwi, beans and onions. It is also used on turf on golf courses...
or proymidone. Exposure to vinclozolin or procymidone in utero feminized male offspring, as seen in abnormalities of anogenital distance, small or absent sex accessory glands, hypospadias
Hypospadias
Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
, undescended testes, retained nipples, cleft phallus
Phallus
A phallus is an erect penis, a penis-shaped object such as a dildo, or a mimetic image of an erect penis. Any object that symbolically resembles a penis may also be referred to as a phallus; however, such objects are more often referred to as being phallic...
, and presence of a vaginal pouch. Male mice exposed before puberty to vinclozolin experienced delayed pubertal development visualized by delayed onset of androgen-dependent preputial
Foreskin
In male human anatomy, the foreskin is a generally retractable double-layered fold of skin and mucous membrane that covers the glans penis and protects the urinary meatus when the penis is not erect...
separation.
Ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
's imidazole
Imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is a diazole and is classified as an alkaloid. Imidazole refers to the parent compound, whereas imidazoles are a class of heterocycles with similar ring structure, but varying substituents...
derivative is used as a broad-spectrum antifungal agent effective against a variety of fungal infections. Although ketoconazole is a relatively weak antiandrogen, side-effects seen as a result of exposure include serious liver
Liver
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...
damage and reduced levels of androgens from both the testicle
Testicle
The testicle is the male gonad in animals. Like the ovaries to which they are homologous, testes are components of both the reproductive system and the endocrine system...
s and 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...
s.
Organophostphate insecticides such as fenitrothion can also behave as androgen receptor antagonists. Fenitrothion was found to completely inhibit dihydrotestosterone-dependent human androgen receptor activation, resulting in reduced weights of seminal vesicles and the ventral prostate. Structural similarity of fenitrothion with linuron further supports the findings of antiandrogenic activity.
Industrial Chemicals
Industrial chemicals with antiandrogenic effects are ubiquitous in the environment. Consumer products such as toys and cosmetics may contain phthalates or parabens, which disrupt androgen synthesis.Phthalates are mainly found in plastics. Fetuses that are exposed to a mixture of pthalates in utero may show signs of disrupted reproductive development. When Di-n-butyl phthalate (DBP), diisobutyl phthalate
Diisobutyl phthalate
Diisobutyl Phthalate is prepared by esterification process of isobutanol and phthalic anhydride. Its structural formula is C6H42. Refractive index is 1.488 - 1.492 ....
(DiBP), benzyl butyl phthalate
Benzyl butyl phthalate
Benzylbutylphthalate , also called n-butyl benzyl phthalate or benzyl butyl phthalate, is a phthalate, an ester of phthalic acid, benzyl alcohol and n-butanol. It comes under trade names e.g. Palatinol BB, Unimoll BB, Sicol 160, or Santicizer 160. It is mostly used as a plasticizer for PVC...
(BBP), Bis(2-ethylhexyl) phthalate
Bis(2-ethylhexyl) phthalate
Bisphthalate, commonly abbreviated DEHP, is an organic compound with the formula C6H42. It is sometimes called dioctyl phthalate and abbreviated DOP. It is the most important "phthalate," being the diester of phthalic acid and the branched-chain 2-ethylhexanol. This colourless viscous liquid is...
(DEHP) and di-n-pentyl phthalate (DPP) were combined, reductions in both testosterone synthesis and gene expression of steroidogenic pathway proteins were seen. The result in male rats was undescended testes and abnormal development of reproductive tissues.
Parabens are commonly found in cosmetics and pharmaceuticals. Paraben esters have been found to mimic androgen antagonist activity. Antiandrogenic endocrine disruption has been shown in aquatic species but the mechanism is unknown. Researchers believe parabens have the ability to bind to human androgen receptors but it still remains unclear.
Phytochemicals
Antiandrogenic chemicals can also occur naturally in plants.The best known plant-derived anti-androgen is 3,3'-Diindolylmethane
3,3'-Diindolylmethane
3,3′-Diindolylmethane or DIM is a compound derived from the digestion of indole-3-carbinol, found in cruciferous vegetables such as broccoli, Brussels sprouts, cabbage and kale. The reputation of Brassica vegetables as healthy foods rests in part on the activities of...
(DIM)
Spearmint tea has antiandrogenic properties in females with 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...
.,
Scutellaria baicalensis
Scutellaria baicalensis
Scutellaria baicalensis is a species of flowering plant in the Lamiaceae family.-Medicinal uses:...
may also have antiandrogenic properties.
The compound N-butylbenzene-sulfonamide (NBBS) isolated from Pygeum africanum is a specific androgen antagonist.,
Glycyrrhiza glabra has shown antiandrogenic activity in male rats
A herbal formula (termed KMKKT) containing Korean Angelica gigas
Angelica gigas
Angelica gigas is a monocarpic biennial or short lived perennial plant from China, Japan and Korea. It inhabits forests, grasslands and banks of streams. The roots are used in traditional Chinese medicine...
Nakai (AGN) root and nine other oriental herbs has shown in vitro anti-androgen activity.
Pygeum africanum contains an antiandrogenic compound atraric acid.
Duke's database lists several more herbs that have antiandrogenic properties.
Future Research
Currently, further research is being conducted on the effects of antiandrogens. In the pharmaceutical industry, researchers continue to experiment with antiandrogenic drugs and other treatments in the hope of finding cures to diseases such as prostate cancer. Greater insight into the mechanisms and pathways of antiandrogens would provide more effective treatment that might decrease the likelihood of recurrent prostatic tumors.The future of antiandrogenic drugs is believed to be peptide antagonists. Current androgen receptor antagonist drugs bind to the ligand binding domain on the receptors and inhibit receptor function. Androgen receptor peptide antagonists act in an alternative manner. A peptide antagonist interrupts androgen receptor protein interactions from the surface of the receptor. This approach is “mechanism-based” and has greater potential for blocking receptor activity than the traditional ligand-receptor binding approach. Researchers are trying to target the ligand-binding domain and N-terminal domain of androgen receptors.