Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s that prevent

androgen An androgen (from Greek ''andr-'', the stem of the word meaning ) is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This includes ...

s like

testosterone Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...

and

dihydrotestosterone Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone primarily involved in the growth and repair of the prostate and the penis, as well as the production o ...

(DHT) from mediating their biological effects in the body. They act by blocking 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 th ...

(AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s, for instance androgens and

anabolic steroid Anabolic steroids, also known as anabolic-androgenic steroids (AAS), are a class of drugs that are structurally related to testosterone, the main male sex hormone, and produce effects by binding to the androgen receptor (AR). Anabolism, Anaboli ...

s (AAS) like testosterone, DHT, and

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

and

selective androgen receptor modulator Selective androgen receptor modulators (SARMs) are a class of drugs that tissue selectivity, selectively activate the androgen receptor in specific tissue (biology), tissues, promoting muscle and bone growth while having less effect on male re ...

s (SARMs) like

enobosarm Enobosarm, also formerly known as ostarine and by the developmental code names GTx-024, MK-2866, and S-22, is a selective androgen receptor modulator (SARM) which is under development for the treatment of hormone sensitive cancer, androgen rece ...

. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens. Antiandrogens are used to treat an assortment of androgen-dependent conditions. In men, antiandrogens are used in the treatment of

prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...

enlarged prostate 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 lo ...

, scalp hair loss, overly high sex drive, unusual and problematic sexual urges, and early puberty. In women, antiandrogens are used to treat

acne Acne ( ), also known as ''acne vulgaris'', is a long-term Cutaneous condition, skin condition that occurs when Keratinocyte, dead skin cells and Sebum, oil from the skin clog hair follicles. Typical features of the condition include comedo, ...

, seborrhea, excessive hair growth, scalp hair loss, and high androgen levels, such as those that occur in

polycystic ovary syndrome Polycystic ovary syndrome, or polycystic ovarian syndrome, (PCOS) is the most common endocrine disorder in women of reproductive age. The name is a misnomer, as not all women with this condition develop cysts on their ovaries. The name origin ...

(PCOS). Antiandrogens are also used as a component of

feminizing hormone therapy Feminizing hormone therapy, also known as transfeminine hormone therapy, is a form of Transgender_health_care#Gender-affirming_care , gender-affirming care and a gender-affirming hormone therapy , gender-affirming hormone therapy to change t ...

for transgender women and as puberty blockers in transgender girls.

Side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of antiandrogens depend on the type of antiandrogen and the specific antiandrogen in question. In any case, common side effects of antiandrogens in men include

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 ...

, breast enlargement, feminization,

hot flash 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, and may typically last from t ...

es,

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 ...

infertility In biology, infertility is the inability of a male and female organism to Sexual reproduction, reproduce. It is usually not the natural state of a healthy organism that has reached sexual maturity, so children who have not undergone puberty, whi ...

, and

osteoporosis Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk. It is the most common reason f ...

. In women, antiandrogens are much better tolerated, and antiandrogens that work only by directly blocking androgens are associated with minimal side effects. However, because

estrogen Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...

s are made from androgens in the body, antiandrogens that suppress androgen production can cause low estrogen levels and associated symptoms like hot flashes, menstrual irregularities, and osteoporosis in premenopausal women. There are a few different major types of antiandrogens. These include AR

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain.androgen synthesis inhibitors, and antigonadotropins. AR antagonists work by directly blocking the effects of androgens, while androgen synthesis inhibitors and antigonadotropins work by lowering androgen levels. AR antagonists can be further divided into

steroidal antiandrogen A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically receptor antagonist, antagonists of the androgen receptor (AR) and act both by receptor antagonist, blocking the effects of androgens like ...

s and

nonsteroidal antiandrogen A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens lik ...

s; androgen synthesis inhibitors can be further divided mostly into CYP17A1 inhibitors and 5α-reductase inhibitors; and antigonadotropins can be further divided into gonadotropin-releasing hormone modulators (GnRH modulators),

progestogen Progestogens, also sometimes written progestins, 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 progestoge ...

s, and

Medical uses

Antiandrogens are used in the treatment of an assortment of androgen-dependent conditions in both males and females. They are used to treat men with

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, urinary retention, inability t ...

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 h ...

, hypersexuality,

paraphilia A paraphilia is an experience of recurring or intense sexual arousal to atypical objects, places, situations, fantasies, behaviors, or individuals. It has also been defined as a sexual interest in anything other than a legally consenting human ...

s, and priapism, as well as boys with precocious puberty. In women and girls, antiandrogens are used to treat

, seborrhea,

hidradenitis suppurativa Hidradenitis suppurativa (HS), sometimes known as acne inversa or Verneuil's disease, is a long-term dermatological condition characterized by the occurrence of inflamed and swollen lesions, lumps. These are typically painful and break open, r ...

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 ma ...

, and hyperandrogenism. Antiandrogens are also used in transgender women as a component of

and as puberty blockers in transgender girls.

Men and boys

Prostate cancer

Androgens like testosterone and particularly DHT are importantly involved in the development and progression of prostate cancer. They act as

growth factor A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for ...

s in the

prostate gland The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...

, stimulating

cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...

and tissue growth. In accordance, therapeutic modalities that reduce androgen signaling in the prostate gland, referred to collectively as

androgen deprivation therapy Androgen deprivation therapy (ADT), also called androgen ablation therapy or androgen suppression therapy, is an antihormone therapy whose main use is in treating prostate cancer. Prostate cancer cells usually require androgen, androgen hormones, ...

, are able to significantly slow the course of prostate cancer and extend life in men with the disease. Although antiandrogens are effective in slowing the progression of prostate cancer, they are not generally curative, and with time, the disease adapts and androgen deprivation therapy eventually becomes ineffective. When this occurs, other treatment approaches, such as

chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...

, may be considered. The most common methods of androgen deprivation therapy currently employed to treat prostate cancer are

castration Castration is any action, surgery, surgical, chemical substance, chemical, or otherwise, by which a male loses use of the testicles: the male gonad. Surgical castration is bilateral orchiectomy (excision of both testicles), while chemical cas ...

(with a GnRH modulator or

orchiectomy Orchiectomy (also named orchidectomy) is a surgery, surgical procedure in which one or both testicles are removed. The surgery can be performed for various reasons: *treatment for testicular cancer *as part of gender-affirming surgery for trans ...

), nonsteroidal antiandrogens, and the androgen synthesis inhibitor

abiraterone acetate Abiraterone acetate, sold under the brand name Zytiga among others, is a medication used to treat prostate cancer. Specifically it is used together with a corticosteroid for metastatic castration-resistant prostate cancer (mCRPC) and metasta ...

. Castration may be used alone or in combination with one of the other two treatments. When castration is combined with a nonsteroidal antiandrogen like bicalutamide, this strategy is referred to as combined androgen blockade (also known as complete or maximal androgen blockade). Enzalutamide, apalutamide, and abiraterone acetate are specifically approved for use in combination with castration to treat castration-resistant prostate cancer. Monotherapy with the nonsteroidal antiandrogen bicalutamide is also used in the treatment of prostate cancer as an alternative to castration with comparable effectiveness but with a different and potentially advantageous side effect profile. High-dose estrogen was the first functional antiandrogen used to treat prostate cancer. It was widely used, but has largely been abandoned for this indication in favor of newer agents with improved safety profiles and fewer feminizing side effects.

Cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...

was developed subsequently to high-dose estrogen and is the only steroidal antiandrogen that has been widely used in the treatment of prostate cancer, but it has largely been replaced by nonsteroidal antiandrogens, which are newer and have greater effectiveness, tolerability, and safety. Bicalutamide, as well as enzalutamide, have largely replaced the earlier nonsteroidal antiandrogens flutamide and nilutamide, which are now little used. The earlier androgen synthesis inhibitors

aminoglutethimide Aminoglutethimide (AG), sold under the brand names Elipten, Cytadren, and Orimeten among others, is a medication which has been used in the treatment of seizures, Cushing's syndrome, breast cancer, and prostate cancer, among other indications. ...

and

ketoconazole Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal drug, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin inf ...

have only limitedly been used in the treatment of prostate cancer due to

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, bacteria, bacterium, or plant, as well as the effect o ...

concerns and have been replaced by abiraterone acetate. In addition to active treatment of prostate cancer, antiandrogens are effective as

prophylaxis Preventive healthcare, or prophylaxis, is the application of healthcare measures to prevent diseases.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental health a ...

(preventatives) in reducing the risk of ever developing prostate cancer. Antiandrogens have only limitedly been assessed for this purpose, but the 5α-reductase inhibitors

finasteride Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat pattern hair loss and benign prostatic hyperplasia (BPH) in men. It can also be used to treat hirsutism, excessive hair growth in women. It ...

and

dutasteride Dutasteride, sold under the brand name Avodart among others, is a medication primarily used to treat the symptoms of a benign prostatic hyperplasia (BPH), an enlarged prostate not associated with cancer. A few months may be required before bene ...

and the steroidal AR antagonist

spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

have been associated with significantly reduced risk of prostate cancer. In addition, it is notable that prostate cancer is extremely rare in transgender women who have been on feminizing hormone therapy for an extended period of time.

Enlarged prostate

The 5α-reductase inhibitors

and

are used to treat benign prostatic hyperplasia, a condition in which the prostate becomes enlarged and this results in urinary obstruction and discomfort. They are effective because androgens act as growth factors in the prostate gland. The antiandrogens chlormadinone acetate and oxendolone and the functional antiandrogens allylestrenol and gestonorone caproate are also approved in some countries for the treatment of benign prostatic hyperplasia.

Scalp hair loss

5α-Reductase inhibitors like finasteride, dutasteride, and alfatradiol and the

topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

nonsteroidal AR antagonist topilutamide (fluridil) are approved for the treatment of pattern hair loss, also known as scalp hair loss or baldness. This condition is generally caused by androgens, so antiandrogens can slow or halt its progression. Systemic antiandrogens besides 5α-reductase inhibitors are not generally used to treat scalp hair loss in males due to risks like feminization (e.g., gynecomastia) and sexual dysfunction. However, they have been assessed and reported to be effective for this indication.

Acne

Systemic antiandrogens are generally not used to treat acne in males due to their high risk of feminization (e.g., gynecomastia) and sexual dysfunction. However, they have been studied for acne in males and found to be effective. Clascoterone, a topical antiandrogen, is effective for acne in males, albeit modestly, and has been approved by the FDA in August 2020.

Paraphilias

Androgens increase sex drive, and for this reason, antiandrogens are able to reduce sex drive in men. In accordance, antiandrogens are used in the treatment of conditions such as hypersexuality (excessively high sex drive) and

s (atypical and sometimes societally unacceptable sexual interests) like

pedophilia Pedophilia ( alternatively spelled paedophilia) is a psychiatric disorder in which an adult or older adolescent experiences a primary or exclusive sexual attraction to prepubescent children. Although girls typically begin the process of pube ...

(sexual attraction to children). They have been used to decrease sex drive in

sex offender A sex offender (sexual offender, sex abuser, or sexual abuser) is a person who has committed a Sex and the law, sex crime. What constitutes a sex crime differs by culture and legal jurisdiction. The majority of convicted sex offenders have convi ...

s so as to reduce the likelihood of

recidivism Recidivism (; from 'recurring', derived from 'again' and 'to fall') is the act of a person repeating an undesirable behavior after they have experienced negative consequences of that behavior, or have been trained to Extinction (psycholo ...

(repeat offenses). Antiandrogens used for these indications include

cyproterone acetate Cyproterone acetate (CPA), sold alone under the brand name Androcur or Ethinylestradiol/cyproterone acetate, with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the tre ...

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 ...

, and GnRH modulators.

Early puberty

Antiandrogens are used to treat precocious puberty in boys. They work by opposing the effects of androgens and delaying the development of

secondary sexual characteristic A secondary sex characteristic is a physical characteristic of an organism that is related to or derived from its sex, but not directly part of its reproductive system. In humans, these characteristics typically start to appear during puberty ...

s and onset of changes in sex drive and function until a more appropriate age. Antiandrogens that have been used for this purpose include

, GnRH modulators,

, bicalutamide, and

. Spironolactone and bicalutamide require combination with an aromatase inhibitor to prevent the effects of unopposed

s, while the others can be used alone.

Long-lasting erections

Antiandrogens are effective in the treatment of recurrent priapism (potentially painful penile erections that last more than four hours).

Women and girls

Skin and hair conditions

Antiandrogens are used in the treatment of androgen-dependent

skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different ...

and hair conditions including acne, seborrhea, hidradenitis suppurativa, hirsutism, and pattern hair loss in women. All of these conditions are dependent on androgens, and for this reason, antiandrogens are effective in treating them. The most commonly used antiandrogens for these indications are

and

. Flutamide has also been studied extensively for such uses, but has fallen out of favor due to its association with

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

. Bicalutamide, which has a relatively minimal risk of hepatotoxicity, has been evaluated for the treatment of hirsutism and found effective similarly to flutamide and may be used instead of it. In addition to AR antagonists, oral contraceptives containing

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

are effective in treating these conditions, and may be combined with AR antagonists.

High androgen levels

Hyperandrogenism is a condition in women in which androgen levels are excessively and abnormally high. It is commonly seen in women with PCOS, and also occurs in women with intersex conditions like

congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) is a group of Genetic disorder#Autosomal recessive, autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the Biosy ...

. Hyperandrogenism is associated with

virilization 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 a medical term commonly used in three medical a ...

– that is, the development of masculine

s like male-pattern facial and body hair growth (or hirsutism), voice deepening, increased

muscle Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

mass Mass is an Intrinsic and extrinsic properties, intrinsic property of a physical body, body. It was traditionally believed to be related to the physical quantity, quantity of matter in a body, until the discovery of the atom and particle physi ...

and

strength Strength may refer to: Personal trait *Physical strength, as in people or animals *Character strengths like those listed in the Values in Action Inventory *The exercise of willpower Physics * Mechanical strength, the ability to withstand ...

, and broadening of the shoulders, among others. Androgen-dependent skin and hair conditions like acne and pattern hair loss may also occur in hyperandrogenism, and menstrual disturbances, like

amenorrhea Amenorrhea or amenorrhoea is the absence of a menstrual period in a female organism who has reached reproductive age. Physiological states of amenorrhoea are most commonly seen during pregnancy and lactation (breastfeeding). In humans, it is wher ...

, are commonly seen. Although antiandrogens do not treat the underlying cause of hyperandrogenism (e.g., PCOS), they are able to prevent and reverse its manifestation and effects. As with androgen-dependent skin and hair conditions, the most commonly used antiandrogens in the treatment of hyperandrogenism in women are cyproterone acetate and spironolactone. Other antiandrogens, like bicalutamide, may be used alternatively.

Transgender hormone therapy

Antiandrogens are used to prevent or reverse

masculinization 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 a medical term commonly used in three medical a ...

and to facilitate feminization in transgender women and some

non-binary Non-binary or genderqueer Gender identity, gender identities are those that are outside the male/female gender binary. Non-binary identities often fall under the transgender umbrella since non-binary people typically identify with a gende ...

transfeminine individuals who are undergoing

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 hormonal therap ...

and who have not undergone

sex reassignment surgery Gender-affirming surgery (GAS) is a surgical procedure, or series of procedures, that alters a person's physical appearance and sexual characteristics to resemble those associated with their gender identity. The phrase is most often associat ...

. Besides estrogens, the main antiandrogens that have been used for this purpose are cyproterone acetate, spironolactone, and GnRH modulators. Nonsteroidal antiandrogens like bicalutamide are also used for this indication. In addition to use in transgender women, antiandrogens, mainly GnRH modulators, are used as puberty blockers to prevent the onset of

puberty Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...

in transgender girls until they are older and ready to begin hormone therapy.

Available forms

There are several different types of antiandrogens, including the following: * Androgen receptor antagonists: Drugs that bind directly to and block the AR. These drugs include the

, megestrol acetate, chlormadinone acetate,

, oxendolone, and osaterone acetate (veterinary) and the

s flutamide, bicalutamide, nilutamide, topilutamide, enzalutamide, apalutamide, and darolutamide. Aside from cyproterone acetate and chlormadinone acetate, a few other

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. ...

s used in oral contraceptives and/or in menopausal HRT including dienogest, drospirenone, medrogestone, nomegestrol acetate, promegestone, and trimegestone also have varying degrees of AR antagonistic activity. * Androgen synthesis inhibitors: Drugs that directly inhibit the enzymatic

biosynthesis Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-Catalysis, catalyzed processes where chemical substances absorbed as nutrients (or previously converted through biosynthe ...

of androgens like testosterone and/or DHT. Examples include the CYP17A1 inhibitors

, and

seviteronel __NOTOC__ Seviteronel (developmental codes VT-464 and, formerly, INO-464) is an experimental cancer medication which is under development by Viamet Pharmaceuticals and Innocrin Pharmaceuticals for the treatment of prostate cancer and breast canc ...

, the CYP11A1 (P450scc) inhibitor

, and the 5α-reductase inhibitors

, epristeride, alfatradiol, and saw palmetto extract ('' Serenoa repens''). A number of other antiandrogens, including cyproterone acetate, spironolactone, medrogestone, flutamide, nilutamide, and bifluranol, are also known to weakly inhibit androgen synthesis. * Antigonadotropins: Drugs that suppress the

gonadotropin-releasing hormone Gonadotropin-releasing hormone (GnRH) is a releasing hormone responsible for the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. GnRH is a tropic peptide hormone synthesized and rele ...

(GnRH)-induced release of gonadotropins and consequent activation of gonadal androgen production. Examples include GnRH modulators like leuprorelin (a GnRH agonist) and cetrorelix (a GnRH antagonist),

s like allylestrenol, chlormadinone acetate, cyproterone acetate, gestonorone caproate,

hydroxyprogesterone caproate Hydroxyprogesterone caproate, sold under the brand name Delalutin among others, is a medication used to reduce the risk of preterm birth in women pregnant with one baby who have a history of spontaneous preterm birth. In March 2023, the manuf ...

, megestrol acetate, osaterone acetate (veterinary), and oxendolone, and

s like

estradiol Estradiol (E2), also called oestrogen, oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of female reproductive cycles such as estrous and menstrual cycles. Estradiol is responsible ...

estradiol ester This is a list of estrogen esters, or ester prodrugs of estrogens. It includes esters, as well as ethers, of steroidal estrogens like estradiol, estrone, and estriol and of nonsteroidal estrogens like the stilbestrols diethylstilbestrol an ...

, conjugated estrogens, and

diethylstilbestrol Diethylstilbestrol (DES), also known as stilbestrol or stilboestrol, is a nonsteroidal estrogen medication, which is presently rarely used. In the past, it was widely used for a variety of indications, including pregnancy support for those with ...

. * Miscellaneous: Drugs that oppose the effects of androgens by means other than the above. Examples include estrogens, especially

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 ora ...

and synthetic (e.g.,

), which stimulate sex hormone-binding globulin (SHBG) production in the

liver The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

and thereby decrease free and hence bioactive levels of testosterone and DHT; anticorticotropins such as

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...

s, which suppress the

adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH; also adrenocorticotropin, corticotropin) is a polypeptide tropic hormone produced by and secreted by the anterior pituitary gland. It is also used as a medication and diagnostic agent. ACTH is an important ...

(ACTH)-induced production of adrenal androgens; and immunogens and

vaccine A vaccine is a biological Dosage form, preparation that provides active acquired immunity to a particular infectious disease, infectious or cancer, malignant disease. The safety and effectiveness of vaccines has been widely studied and verifi ...

s against androstenedione like ovandrotone albumin and androstenedione albumin, which decrease levels of androgens via the generation of

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

against the androgen and androgen precursor androstenedione (used only in

veterinary medicine Veterinary medicine is the branch of medicine that deals with the prevention, management, medical diagnosis, diagnosis, and treatment of disease, disorder, and injury in non-human animals. The scope of veterinary medicine is wide, covering all a ...

). Certain antiandrogens combine multiple of the above mechanisms. An example is the steroidal antiandrogen cyproterone acetate, which is a potent AR antagonist, a potent progestogen and hence antigonadotropin, a weak glucocorticoid and hence anticorticotropin, and a weak androgen synthesis inhibitor.

Side effects

The side effects of antiandrogens vary depending on the type of antiandrogen – namely whether it is a selective AR antagonist or lowers androgen levels – as well as the presence of

off-target activity Off-target activity is biological activity of a drug that is different from and not at that of its intended biological target. It most commonly contributes to side effects. However, in some cases, off-target activity can be taken advantage of for t ...

in the antiandrogen in question. For instance, whereas antigonadotropic antiandrogens like GnRH modulators and cyproterone acetate are associated with pronounced

and

in men, selective AR antagonists like bicalutamide are not associated with osteoporosis and have been associated with only minimal sexual dysfunction. These differences are thought related to the fact that antigonadotropins suppress androgen levels and by extension levels of bioactive

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, c ...

s of androgens like

s and neurosteroids whereas selective AR antagonists similarly neutralize the effects of androgens but leave levels of androgens and hence their metabolites intact (and in fact can even increase them as a result of their progonadotropic effects). As another example, the steroidal antiandrogens cyproterone acetate and spironolactone possess off-target actions including

ic, antimineralocorticoid, and/or

activity in addition to their antiandrogen activity, and these off-target activities can result in additional side effects. In males, the major

side effect In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually use ...

s of antiandrogens are

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 a medical terminology, term commonly used in thr ...

and feminization. These side effects include breast pain/tenderness and gynecomastia (

breast development Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life. It occurs across several phases, including prenatal development, puberty, and pregnancy. At menopause, breas ...

/ enlargement), reduced body hair growth/density, decreased muscle mass and

feminine Femininity (also called womanliness) is a set of attributes, behaviors, and Gender roles, roles generally associated with women and girls. Femininity can be understood as Social construction of gender, socially constructed, and there is also s ...

changes in fat mass and distribution, and reduced penile length and testicular size. The rates of gynecomastia in men with selective AR antagonist monotherapy have been found to range from 30 to 85%. In addition, antiandrogens can cause

es,

(including loss of

libido In psychology, libido (; ) is psychic drive or energy, usually conceived of as sexual in nature, but sometimes conceived of as including other forms of desire. The term ''libido'' was originally developed by Sigmund Freud, the pioneering origin ...

and

erectile dysfunction Erectile dysfunction (ED), also referred to as impotence, is a form of sexual dysfunction in males characterized by the persistent or recurring inability to achieve or maintain a Human penis, penile erection with sufficient rigidity and durat ...

), depression,

fatigue Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...

, and decreased semen/ejaculate volume in males. Conversely, the side effects of selective AR antagonists in women are minimal. However, antigonadotropic antiandrogens like cyproterone acetate can produce hypoestrogenism,

, and osteoporosis in premenopausal women, among other side effects. In addition, androgen receptor antagonists can produce unfavorable effects on

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

levels, which long-term may increase the risk of

cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

. A number of antiandrogens have been associated with

. These include, to varying extents, cyproterone acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, and ketoconazole. In contrast, spironolactone, enzalutamide, and other antiandrogens are not associated with significant rates of hepatotoxicity. However, although they do not pose a risk of hepatotoxicity, spironolactone has a risk of

hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0 mmol/L (3.5 and 5.0 mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Oc ...

and enzalutamide has a risk of

seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...

s. In women who are

pregnant Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...

, antiandrogens can interfere with the androgen-mediated sexual differentiation of the

genitalia A sex organ, also known as a reproductive organ, is a part of an organism that is involved in sexual reproduction. Sex organs constitute the primary sex characteristics of an organism. Sex organs are responsible for producing and transporting ...

and

brain The brain is an organ (biology), organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head (cephalization), usually near organs for ...

of male

fetus A fetus or foetus (; : fetuses, foetuses, rarely feti or foeti) is the unborn offspring of a viviparous animal that develops from an embryo. Following the embryonic development, embryonic stage, the fetal stage of development takes place. Pren ...

es. This manifests primarily as

ambiguous genitalia Intersex people are those born with any of several Sexual characteristics, sex characteristics, including chromosome patterns, gonads, or sex organ, genitals that, according to the Office of the United Nations High Commissioner for Human ...

– that is, undervirilized or feminized genitalia, which, anatomically, are a cross between a

penis A penis (; : penises or penes) is a sex organ through which male and hermaphrodite animals expel semen during copulation (zoology), copulation, and through which male placental mammals and marsupials also Urination, urinate. The term ''pen ...

and a

vagina In mammals and other animals, the vagina (: vaginas or vaginae) is the elastic, muscular sex organ, reproductive organ of the female genital tract. In humans, it extends from the vulval vestibule to the cervix (neck of the uterus). The #Vag ...

– and theoretically also as

femininity Femininity (also called womanliness) is a set of attributes, behaviors, and Gender roles, roles generally associated with women and girls. Femininity can be understood as Social construction of gender, socially constructed, and there is also s ...

. As such, antiandrogens are teratogens, and women who are pregnant should not be treated with an antiandrogen. Moreover, women who can or may become pregnant are strongly recommended to take an antiandrogen only in combination with proper

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

Overdose

Antiandrogens are relatively safe in acute

overdose A drug overdose (overdose or OD) is the ingestion or application of a drug or other substance in quantities much greater than are recommended. Retrieved on September 20, 2014.

Interactions

Inhibitor Inhibitor or inhibition may refer to: 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 neurotransmi ...

s and inducers of

cytochrome P450 Cytochromes P450 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

s may interact with various antiandrogens.

Mechanism of action

Androgen receptor antagonists

AR antagonists act by directly binding to and competitively displacing androgens like testosterone and DHT from the AR, thereby preventing them from activating the receptor and mediating their biological effects. AR antagonists are classified into two types, based on

chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...

: steroidal and nonsteroidal. Steroidal AR antagonists are structurally related to

steroid hormone A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids (typically made in the adrenal cortex, hence ''cortico-'') and sex steroids (typically made in the gonads or placenta). Wit ...

s like testosterone and

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 ma ...

, whereas nonsteroidal AR antagonists are not steroids and are structurally distinct. Steroidal AR antagonists tend to have off-target hormonal actions due to their structural similarity to other steroid hormones. In contrast, nonsteroidal AR antagonists are selective for the AR and have no off-target hormonal activity. For this reason, they are sometimes described as "pure" antiandrogens. Although they are described as antiandrogens and indeed show only such effects generally, most or all steroidal AR antagonists are actually not silent antagonists of the AR but rather are weak

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

s and are able to activate the receptor in the absence of more potent AR agonists like testosterone and DHT. This may have clinical implications in the specific context of prostate cancer treatment. As an example, steroidal AR antagonists are able to increase prostate weight and accelerate prostate cancer cell growth in the absence of more potent AR agonists, and spironolactone has been found to accelerate progression of prostate cancer in case reports. In addition, whereas cyproterone acetate produces ambiguous genitalia via feminization in male fetuses when administered to pregnant animals, it has been found to produce masculinization of the genitalia of female fetuses of pregnant animals. In contrast to steroidal AR antagonists, nonsteroidal AR antagonists are silent antagonists of the AR and do not activate the receptor. This may be why they have greater efficacy than steroidal AR antagonists in the treatment of prostate cancer and is an important reason as to why they have largely replaced them for this indication in medicine. Nonsteroidal antiandrogens have relatively low

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Pa ...

for the AR compared to steroidal AR ligands. For example, bicalutamide has around 2% of the affinity of DHT for the AR and around 20% of the affinity of CPA for the AR. Despite their low affinity for the AR however, the lack of weak partial agonist activity of NSAAs appears to improve their potency relative to steroidal antiandrogens. For example, although flutamide has about 10-fold lower affinity for the AR than CPA, it shows equal or slightly greater potency to CPA as an antiandrogen in

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

s. In addition, circulating therapeutic concentrations of nonsteroidal antiandrogens are very high, on the order of thousands of times higher than those of testosterone and DHT, and this allows them to efficaciously compete and block AR signaling. AR antagonists may not bind to or block

membrane androgen receptor Membrane androgen receptors (mARs) are a group of G protein-coupled receptors (GPCRs), which bind and are activated by testosterone and/or other androgens. Unlike the androgen receptor (AR), a nuclear receptor which mediates its effects via genomic ...

s (mARs), which are distinct from the classical nuclear AR. However, the mARs do not appear to be involved in

. This is evidenced by the perfectly

female An organism's sex is female ( symbol: ♀) if it produces the ovum (egg cell), the type of gamete (sex cell) that fuses with the male gamete (sperm cell) during sexual reproduction. A female has larger gametes than a male. Females and ...

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

of women with complete androgen insensitivity syndrome. These women have a 46,XY

karyotype A karyotype is the general appearance of the complete set of chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is discerned by de ...

(i.e., are genetically "male") and high levels of androgens but possess a defective AR and for this reason never masculinize. They are described as highly feminine, both physically as well as mentally and behaviorally.

N-Terminal domain antagonists

N-Terminal domain AR antagonists are a new type of AR antagonist that, unlike all currently marketed AR antagonists, bind to the

N-terminal domain The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...

(NTD) of the AR rather than the ligand-binding domain (LBD). Whereas conventional AR antagonists bind to the LBD of the AR and competitively displace androgens, thereby preventing them from activating the receptor, AR NTD antagonists bind covalently to the NTD of the AR and prevent

protein–protein interaction Protein–protein interactions (PPIs) are physical contacts of high specificity established between two or more protein molecules as a result of biochemical events steered by interactions that include electrostatic forces, hydrogen bonding and t ...

s subsequent to activation that are required for transcriptional activity. As such, they are non-competitive and irreversible antagonists of the AR. Examples of AR NTD antagonists include bisphenol A diglycidyl ether (BADGE) and its derivatives

EPI-001 EPI-001 is the first inhibitor of the androgen receptor amino-terminal domain. The single stereoisomer of EPI-001, EPI-002, is a first-in-class drug that the USAN council assigned a new stem class "-aniten" and the generic name "ralaniten". This ...

ralaniten Ralaniten (developmental code name EPI-002) is an N-terminal domain antiandrogen which was never marketed. It is a derivative (chemistry), derivative of bisphenol A and one of the four stereoisomers of EPI-001. A prodrug of ralaniten, ralaniten a ...

(EPI-002), and

ralaniten acetate Ralaniten acetate (developmental code name EPI-506) is a first-in-class antiandrogen that targets the ''N''-terminal domain (NTD) of the androgen receptor (AR) developed by ESSA Pharmaceuticals and was under investigation for the treatment of p ...

(EPI-506). AR NTD antagonists are under investigation for the potential treatment of prostate cancer, and it is thought that they may have greater

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 betwee ...

as antiandrogens relative to conventional AR antagonists. In accordance with this notion, AR NTD antagonists are active against

splice variant Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...

s of the AR, which conventional AR antagonists are not, and AR NTD antagonists are immune to

gain-of-function mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosi ...

s in the AR LBD that convert AR antagonists into AR agonists and commonly occur in prostate cancer.

Androgen receptor degraders

Selective androgen receptor degraders (SARDs) are another new type of antiandrogen that has recently been developed. They work by enhancing the degradation of the AR, and are analogous to selective estrogen receptor degraders (SERDs) like fulvestrant (a drug used to treat estrogen receptor-positive

breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...

). Similarly to AR NTD antagonists, it is thought that SARDs may have greater efficacy than conventional AR antagonists, and for this reason, they are under investigation for the treatment of prostate cancer. An example of a SARD is dimethylcurcumin (ASC-J9), which is under development as a

topical medication A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surface area, body surfaces such as the skin or mucous membranes to treat ailments via a large ...

for the potential treatment of acne. SARDs like dimethylcurcumin differ from conventional AR antagonists and AR NTD antagonists in that they may not necessarily bind directly to the AR.

Androgen synthesis inhibitors

Androgen synthesis inhibitors are

enzyme inhibitor An enzyme inhibitor is a molecule that binds to an enzyme and blocks its Enzyme activity, activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which Substrate (biochemistry), substrate molecules are converted ...

s that prevent the

of androgens. This process occurs mainly in the

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

s and

adrenal gland The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer adrenal corte ...

s, but also occurs in other tissues like the

, and

hair follicle The hair follicle is an organ found in mammalian skin. It resides in the dermal layer of the skin and is made up of 20 different cell types, each with distinct functions. The hair follicle regulates hair growth via a complex interaction betwee ...

s. These drugs include aminoglutethimide, ketoconazole, and abiraterone acetate. Aminoglutethimide inhibits cholesterol side-chain cleavage enzyme, also known as P450scc or CYP11A1, which is responsible for the conversion of

into

pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...

and by extension the production of all steroid hormones, including the androgens. Ketoconazole and abiraterone acetate are inhibitors of the enzyme CYP17A1, also known as 17α-hydroxylase/17,20-lyase, which is responsible for the conversion of pregnane steroids into androgens, as well as the conversion of

mineralocorticoid Mineralocorticoids are a class of corticosteroids, which in turn are a class of steroid hormones. Mineralocorticoids are produced in the adrenal cortex and influence salt and water balances (electrolyte balance and fluid balance). The primary ...

s into glucocorticoids. Because these drugs all prevent the formation of glucocorticoids in addition to androgens, they must be combined with a glucocorticoid like

prednisone Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...

to avoid

adrenal insufficiency Adrenal insufficiency is a condition in which the adrenal glands do not produce adequate amounts of steroid hormones. The adrenal glands—also referred to as the adrenal cortex—normally secrete glucocorticoids (primarily cortisol), mineraloco ...

. A newer drug currently under development for treatment of prostate cancer,

, is selective for inhibition of the 17,20-lyase functionality of CYP17A1, and for this reason, unlike earlier drugs, does not require concomitant treatment with a glucocorticoid.

5α-Reductase inhibitors

5α-Reductase inhibitors such as finasteride and dutasteride are inhibitors of 5α-reductase, an enzyme that is responsible for the formation of DHT from testosterone. DHT is between 2.5- and 10-fold more potent than testosterone as an androgen and is produced in a tissue-selective manner based on expression of 5α-reductase. Tissues in which DHT forms at a high rate include the

, and

s. In accordance, DHT is involved in the

pathophysiology Pathophysiology (or physiopathology) is a branch of study, at the intersection of pathology and physiology, concerning disordered physiological processes that cause, result from, or are otherwise associated with a disease or injury. Pathology is ...

of benign prostatic hyperplasia, pattern hair loss, and hirsutism, and 5α-reductase inhibitors are used to treat these conditions.

Antigonadotropins

Estradiol and testosterone levels with a single intramuscular injection of 320 mg polyestradiol phosphate in men

Antigonadotropins are drugs that suppress the GnRH-mediated

secretion 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 classical mec ...

of gonadotropins from the

pituitary gland The pituitary gland or hypophysis is an endocrine gland in vertebrates. In humans, the pituitary gland is located at the base of the human brain, brain, protruding off the bottom of the hypothalamus. The pituitary gland and the hypothalamus contr ...

. Gonadotropins include

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 (G ...

(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, puberty, pubertal maturat ...

(FSH) and are

peptide hormone Peptide hormones are hormones composed of peptide molecules. These hormones influence the endocrine system of animals, including humans. Most hormones are classified as either amino-acid-based hormones (amines, peptides, or proteins) or steroid h ...

s that signal the

s to produce

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 effects a ...

s. By suppressing gonadotropin secretion, antigonadotropins suppress gonadal sex hormone production and by extension circulating androgen levels. GnRH modulators, including both GnRH agonists and GnRH antagonists, are powerful antigonadotropins that are able to suppress androgen levels by 95% in men. In addition, estrogens and progestogens are antigonadotropins via exertion of

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused ...

on the

hypothalamic–pituitary–gonadal axis The hypothalamic–pituitary–gonadal axis (HPG axis, also known as the hypothalamic–pituitary–ovarian/testicular axis) refers to the hypothalamus, pituitary gland, and gonadal glands as if these individual endocrine glands were a single en ...

(HPG axis). High-dose estrogens are able to suppress androgen levels to castrate levels in men similarly to GnRH modulators, while high-dose progestogens are able to suppress androgen levels by up to approximately 70 to 80% in men. Examples of GnRH agonists include leuprorelin (leuprolide) and goserelin, while an example of a GnRH antagonist is cetrorelix. Estrogens that are or that have been used as antigonadotropins include estradiol,

s like estradiol valerate, estradiol undecylate, and polyestradiol phosphate, conjugated estrogens, ethinylestradiol, diethylstilbestrol (no longer widely used), and bifluranol. Progestogens that are used as antigonadotropins include chlormadinone acetate, cyproterone acetate, gestonorone caproate,

, medroxyprogesterone acetate, megestrol acetate, and oxendolone.

Miscellaneous

Sex hormone-binding globulin modulators

In addition to their antigonadotropic effects, estrogens are also functional antiandrogens by decreasing free concentrations of androgens via increasing the

hepatic The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...

production of sex hormone-binding globulin (SHBG) and by extension circulating SHBG levels. Combined oral contraceptives containing ethinylestradiol have been found to increase circulating SHBG levels by 2- to 4-fold in women and to reduce free testosterone concentrations by 40 to 80%. However, combined oral contraceptives that contain the particularly androgenic progestin

levonorgestrel Levonorgestrel is a hormonal medication 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 names Plan B One-Step and Julie, ...

have been found to increase SHBG levels by only 50 to 100%, which is likely because activation of the AR in the liver has the opposite effect of estrogen and suppresses production of SHBG. Levonorgestrel and certain other 19-nortestosterone progestins used in combined oral contraceptives like

norethisterone Norethisterone, also known as norethindrone and sold under the brand name Norlutin among others, is a progestin medication used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medicatio ...

also directly bind to and displace androgens from SHBG, which may additionally antagonize the functional antiandrogenic effects of ethinylestradiol. In men, a study found that treatment with a relatively low dosage of 20 μg/day ethinylestradiol for 5 weeks increased circulating SHBG levels by 150% and, due to the accompanying decrease free testosterone levels, increased total circulating levels of testosterone by 50% (via reduced negative feedback by androgens on the HPG axis).

Corticosteroid-binding globulin modulators

Estrogens at high doses can partially suppress adrenal androgen production. A study found that treatment with a high-dose

(100 μg/day) reduced levels of major circulating adrenal androgens by 27 to 48% in transgender women. Decreased adrenal androgens with estrogens is apparent with

and synthetic estrogens like

and estramustine phosphate but is minimal with

parenteral In pharmacology and toxicology, a route of administration is the way by which a drug, fluid, poison, or other substance is taken into the body. Routes of administration are generally classified by the location at which the substance is applied. ...

bioidentical

forms like polyestradiol phosphate. It is thought to be mediated via a

mechanism, probably increased corticosteroid-binding globulin (CBG) production and levels and compensatory changes in adrenal steroid production (e.g., shunting of adrenal androgen synthesis to

cortisol Cortisol is a steroid hormone in the glucocorticoid class of hormones and a stress hormone. When used as medication, it is known as hydrocortisone. Cortisol is produced in many animals, mainly by the ''zona fasciculata'' of the adrenal corte ...

production). It is notable in this regard that oral and synthetic estrogens, due to the oral first pass and resistance to hepatic

metabolism Metabolism (, from ''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 cellular processes; the co ...

, have much stronger influences on liver protein synthesis than parenteral estradiol. The decrease in adrenal androgen levels with high-dose estrogen therapy may be beneficial in the treatment of

Anticorticotropins

Anticorticotropins such as

s and

s work by exerting

on the

hypothalamic–pituitary–adrenal axis The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus (a part of the brain located below the thalamus), the pituitary gland ( ...

(HPA axis), thereby inhibiting the secretion of

corticotropin-releasing hormone Corticotropin-releasing hormone (CRH) (also known as corticotropin-releasing factor (CRF) or corticoliberin; corticotropin may also be spelled corticotrophin) is a peptide hormone involved in stress responses. It is a releasing hormone that b ...

(CRH) and hence

(ACTH; corticotropin) and consequently suppressing the production of

androgen prohormone An androgen prohormone, or proandrogen, is a prohormone (or prodrug) of an anabolic-androgenic steroid (AAS). They can be prohormones of testosterone or of synthetic compound, synthetic AAS, for example, nandrolone (19-nortestosterone). Dehydroepia ...

s like

dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...

(DHEA),

dehydroepiandrosterone sulfate Dehydroepiandrosterone sulfate, abbreviated as DHEA sulfate or DHEA-S, also known as androstenolone sulfate, is an endogenous androstane steroid that is produced by the adrenal cortex. It is the 3β-sulfate ester and a metabolite of dehydroepia ...

(DHEA-S), and androstenedione in the

. They are rarely used clinically as functional antiandrogens, but are used as such in the case of

in girls and women, in which there are excessive production and levels of adrenal androgens due to glucocorticoid deficiency and hence HPA axis overactivity.

Insulin sensitizers

In women with insulin resistance, such as those with

, androgen levels are often elevated.

Metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome, ...

, an insulin-sensitizing medication, has indirect antiandrogenic effects in such women, decreasing

levels by as much as 50% secondary to its beneficial effects on insulin sensitivity.

Immunogens and vaccines

Ovandrotone albumin (Fecundin, Ovastim) and Androvax (androstenedione albumin) are immunogens and

s against androstenedione that are used in

to improve

fecundity Fecundity is defined in two ways; in human demography, it is the potential for reproduction of a recorded population as opposed to a sole organism, while in population biology, it is considered similar to fertility, the capability to produc ...

(reproductive rate) in ewes (adult female sheep). The generation of

against androstenedione by these agents is thought to decrease circulating levels of androstenedione and its metabolites (e.g., testosterone and estrogens), which in turn increases the activity of the HPG axis via reduced negative feedback and increases the rate of

ovulation Ovulation is an important part of the menstrual cycle in female vertebrates where the egg cells are released from the ovaries as part of the ovarian cycle. In female humans ovulation typically occurs near the midpoint in the menstrual cycle and ...

, resulting in greater

fertility Fertility in colloquial terms refers the ability to have offspring. In demographic contexts, fertility refers to the actual production of offspring, rather than the physical capability to reproduce, which is termed fecundity. The fertility rate ...

and fecundity.

Chemistry

Antiandrogens can be divided into several different types based on

, including

s, and

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

s. Steroidal antiandrogens include compounds like

, and

; nonsteroidal antiandrogens include compounds like bicalutamide, elagolix,

, and

; and peptides include GnRH analogues like leuprorelin and cetrorelix.

History

Antigonadotropins like estrogens and progestogens were both first introduced in the 1930s. The beneficial effects of androgen deprivation via surgical castration or high-dose estrogen therapy on prostate cancer were discovered in 1941. AR antagonists were first discovered in the early 1960s. The steroidal antiandrogen cyproterone acetate was discovered in 1961 and introduced in 1973, and is often described as the first antiandrogen to have been marketed. However, spironolactone was introduced in 1959, although its antiandrogen effects were not recognized or taken advantage of until later and were originally an unintended off-target action of the drug. In addition to spironolactone, chlormadinone acetate and megestrol acetate are steroidal antiandrogens that are weaker than cyproterone acetate but were also introduced earlier, in the 1960s. Other early steroidal antiandrogens that were developed around this time but were never marketed include benorterone (SKF-7690; 17α-methyl-''B''-nortestosterone), BOMT (Ro 7–2340), cyproterone (SH-80881), and trimethyltrienolone (R-2956). The nonsteroidal antiandrogen flutamide was first reported in 1967. It was introduced in 1983 and was the first nonsteroidal antiandrogen marketed. Another early nonsteroidal antiandrogen, DIMP (Ro 7–8117), which is structurally related to

thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...

and is a relatively weak antiandrogen, was first described in 1973 and was never marketed. Flutamide was followed by nilutamide in 1989, and bicalutamide in 1995. In addition to these three drugs, which have been regarded as first-generation nonsteroidal antiandrogens, the second-generation nonsteroidal antiandrogens enzalutamide and apalutamide were introduced in 2012 and 2018, respectively. They differ from the earlier nonsteroidal antiandrogens namely in that they are much more efficacious in comparison. The androgen synthesis inhibitors aminoglutethimide and ketoconazole were first marketed in 1960 and 1977, respectively, and the newer drug abiraterone acetate was introduced in 2011. GnRH modulators were first introduced in the 1980s. The 5α-reductase inhibitors finasteride and dutasteride were introduced in 1992. and 2002. respectively. Elagolix, the first orally active GnRH modulator to be marketed, was introduced in 2018.

Timeline

The following is a timeline of events in the history of antiandrogens: * 1941: Hudgins and Hodges show that androgen deprivation via high-dose estrogen therapy or surgical castration treats prostate cancer * 1957: The steroidal antiandrogen spironolactone is first synthesized * 1960: Spironolactone is first introduced for medical use, as an antimineralocorticoid * 1961: The steroidal antiandrogen cyproterone acetate is first synthesized * 1962: Spironolactone is first reported to produce gynecomastia in men * 1966: Benorterone is the first known antiandrogen to be studied clinically, to treat acne and hirsutism in women * 1963: The antiandrogenic activity of cyproterone acetate is discovered * 1967: A known antiandrogen, benorterone, is first reported to induce gynecomastia in males * 1967: The first-generation nonsteroidal antiandrogen flutamide is first synthesized * 1967: Cyproterone acetate was first studied clinically, to treat sexual deviance in men * 1969: Cyproterone acetate was first studied in the treatment of acne, hirsutism, seborrhea, and scalp hair loss in women * 1969: The antiandrogenic activity of spironolactone is discovered * 1972: The antiandrogenic activity of flutamide is first reported * 1973: Cyproterone acetate was first introduced for medical use, to treat sexual deviance * 1977: The first-generation antiandrogen nilutamide is first described * 1978: Spironolactone is first studied in the treatment of hirsutism in women * 1979: Combined androgen blockade is first studied * 1980: Medical castration via a GnRH analogue is first achieved * 1982: The first-generation antiandrogen bicalutamide is first described * 1982: Combined androgen blockade for prostate cancer is developed * 1983: Flutamide is first introduced, in Chile, for medical use, to treat prostate cancer * 1987: Nilutamide is first introduced, in France, for medical use, to treat prostate cancer * 1989: Combined androgen blockade via flutamide and a GnRH analogue is found to be superior to a GnRH analogue alone for prostate cancer * 1989: Flutamide is first introduced for medical use in the United States, to treat prostate cancer * 1989: Flutamide is first studied in the treatment of hirsutism in women * 1992: The androgen synthesis inhibitor abiraterone acetate is first described * 1995: Bicalutamide is first introduced for medical use, to treat prostate cancer * 1996: Nilutamide is first introduced for medical use in the United States, to treat prostate cancer * 2006: The second-generation nonsteroidal antiandrogen enzalutamide is first describedSawyers, C., Jung, M., Chen, C., Ouk, S., Welsbie, D., Tran, C., ... & Yoo, D. (2006). U.S. Patent Application No. 11/433,829. https://patents.google.com/patent/US2007000475

/ref> * 2007: The second-generation nonsteroidal antiandrogen apalutamide is first described * 2011: Abiraterone acetate is first introduced for medical use, to treat prostate cancer * 2012: Enzalutamide is first introduced for medical use, to treat prostate cancer * 2018: Apalutamide is first introduced for medical use, to treat prostate cancer * 2018: Elagolix is the first orally active GnRH antagonist to be introduced for medical use * 2019: Relugolix is the second orally active GnRH antagonist to be introduced for medical use * 2019: Darolutamide is first introduced for medical use, to treat prostate cancer

Society and culture

Etymology

The term ''antiandrogen'' is generally used to refer specifically to AR antagonists, as described by Dorfman (1970): However, in spite of the above, the term may also be used to describe ''functional'' antiandrogens like androgen synthesis inhibitors and antigonadotropins, including even estrogens and progestogens. For example, the progestogen and hence antigonadotropin medroxyprogesterone acetate is sometimes described as a steroidal antiandrogen, even though it is not an antagonist of the AR.

Research

Topical administration

There has been much interest and effort in the development of topical AR antagonists to treat androgen-dependent conditions like acne and pattern hair loss in males. Unfortunately, whereas systemic administration of antiandrogens is very effective in treating these conditions, topical administration has disappointingly been found generally to possess limited and only modest effectiveness, even when high-

steroidal AR antagonists like cyproterone acetate and spironolactone have been employed. Moreover, in the specific case of acne treatment, topical AR antagonists have been found much less effective compared to established treatments like

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and

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s. A variety of AR antagonists have been developed for topical use but have not completed development and hence have never been marketed. These include the steroidal AR antagonists cyproterone, rosterolone, and topterone and the nonsteroidal AR antagonists cioteronel, inocoterone acetate, RU-22930, RU-58642, and RU-58841. However, one topical AR antagonist, topilutamide (fluridil), has been introduced in a few European countries for the treatment of pattern hair loss in men. In addition, a topical 5α-reductase inhibitor and weak estrogen, alfatradiol, has also been introduced in some European countries for the same indication, although its effectiveness is controversial.

Spironolactone Spironolactone, sold under the brand name Aldactone among others, is classed as a diuretic medication. It can be used to treat edema, fluid build-up due to hepatic cirrhosis, liver disease or kidney disease. It is also used to reduce risk o ...

has been marketed in

Italy Italy, officially the Italian Republic, is a country in Southern Europe, Southern and Western Europe, Western Europe. It consists of Italian Peninsula, a peninsula that extends into the Mediterranean Sea, with the Alps on its northern land b ...

in the form of a topical cream under the brand name Spiroderm for the treatment of acne and hirsutism, but this formulation was discontinued and hence is no longer available. Topical clascoterone, brand name Winlevi, was approved to treat acne in males and females in the

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in 2020. However, although significantly more effective than

placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

, topical clascoterone, like previous topical antiandrogens that have been developed, showed modest effectiveness in treating acne in

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

s, and it appeared to be far less effective than systemic

Male contraception

Antiandrogens, such as cyproterone acetate, have been studied for potential use as male hormonal contraceptives. While effective in suppressing male fertility, their use as monotherapies is precluded by side effects, such as androgen deficiency (e.g.,

es,

) and feminization (e.g., gynecomastia). The combination of a primary antigonadotropin such as cyproterone acetate to prevent fertility and an androgen like testosterone to prevent systemic androgen deficiency, resulting in a selective antiandrogenic action locally in the testes, has been extensively studied and has shown promising results, but has not been approved for clinical use at this time. Dimethandrolone undecanoate (developmental code name CDB-4521), an orally active dual AAS and progestogen, is under investigation as a potential male contraceptive and as the first male birth control pill.

Breast cancer

Antiandrogens such as bicalutamide, enzalutamide, and

are under investigation for the potential treatment of

, including AR-expressing triple-negative breast cancer and other types of AR-expressing breast cancer.

Miscellaneous

Antiandrogens might be effective and useful in the treatment of

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(OCD).

Medical uses

Men and boys

Prostate cancer

Enlarged prostate

Scalp hair loss

Acne

Paraphilias

Early puberty

Long-lasting erections

Women and girls

Skin and hair conditions

High androgen levels

Transgender hormone therapy

Available forms

Side effects

Overdose

Interactions

Mechanism of action

Androgen receptor antagonists

N-Terminal domain antagonists

Androgen receptor degraders

Androgen synthesis inhibitors

5α-Reductase inhibitors

Antigonadotropins

Miscellaneous

Sex hormone-binding globulin modulators

Corticosteroid-binding globulin modulators

Anticorticotropins

Insulin sensitizers

Immunogens and vaccines

Chemistry

History

Timeline

Society and culture

Etymology

Research

Topical administration

Male contraception

Breast cancer

Miscellaneous

See also

References

Further reading