A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal

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 ...

. They are typically selective and full or silent antagonists of the

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

(AR) and act by directly blocking the effects of

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 (DHT). NSAAs are used in the treatment of androgen-dependent conditions in men and women. They are the converse of

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 (SAAs), which are antiandrogens that are

steroid A steroid is an organic compound with four fused compound, fused rings (designated A, B, C, and D) arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes t ...

s and are structurally related to testosterone.

Medical uses

NSAAs are used in clinical medicine for the following indications: *

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, ...

in men * Androgen-dependent skin and hair conditions like

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, ...

, hirsutism, seborrhea, and pattern hair loss (androgenic alopecia) in women * Hyperandrogenism, such as due to

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 ...

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 ...

, in women * As a component of

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

for transgender women * Precocious puberty in boys * Priapism in men

Available forms

Pharmacology

Unlike SAAs, NSAAs have little or no capacity to activate the AR, show no off-target hormonal activity such as progestogenic,

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 ...

, or antimineralocorticoid activity, and lack antigonadotropic effects. For these reasons, they have improved

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 ...

and selectivity as antiandrogens and do not lower androgen levels, instead acting solely by directly blocking the actions of androgens at the level of their

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

, the AR.

List of NSAAs

Marketed

First-generation

* Flutamide (Eulexin): Marketed for the treatment of prostate cancer and also used in the treatment of acne, hirsutism, and hyperandrogenism in women. It has also been studied in the treatment of

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 ...

. Now little-used due to high incidence of elevated liver enzymes and hepatotoxicity and the availability of safer agents. * Nilutamide (Anandron, Nilandron): Marketed for the treatment of prostate cancer. Very little-used due to a high incidence of interstitial pneumonitis and high rates of several unique and unfavorable

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 such as

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

and

vomiting Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pre ...

, visual disturbances, and alcohol intolerance. * Bicalutamide (Casodex): Marketed for the treatment of prostate cancer and also used in the treatment of hirsutism in women, as a component of hormone therapy for transgender women, to delay precocious puberty in boys, to prevent or alleviate priapism, and for other indications. It has also been studied in the treatment of benign prostatic hyperplasia. By far the most widely used NSAA, due to its favorable profile of efficacy, tolerability, and

safety Safety is the state of being protected from harm or other danger. Safety can also refer to the control of recognized hazards in order to achieve an acceptable level of risk. Meanings The word 'safety' entered the English language in the 1 ...

. * Topilutamide (Eucapil): Also known as fluridil. Marketed 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 treatment of pattern hair loss (androgenic alopecia) in the

Czech Republic The Czech Republic, also known as Czechia, and historically known as Bohemia, is a landlocked country in Central Europe. The country is bordered by Austria to the south, Germany to the west, Poland to the northeast, and Slovakia to the south ...

and

Slovakia Slovakia, officially the Slovak Republic, is a landlocked country in Central Europe. It is bordered by Poland to the north, Ukraine to the east, Hungary to the south, Austria to the west, and the Czech Republic to the northwest. Slovakia's m ...

. Limited availability and lack of an oral formulation for systemic use make it a very little-known drug.

Second-generation

* Apalutamide (Erleada): Marketed for the treatment of prostate cancer. Very similar to enzalutamide, but with reduced central nervous system distribution and hence is expected to have a reduced risk of seizures and other central side effects. * Enzalutamide (Xtandi): Marketed for the treatment of prostate cancer. More effective than the first-generation NSAAs due to increased efficacy and potency and shows no risk of elevated liver enzymes or hepatotoxicity. However, it has a small (1%) 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 and has

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...

side effects like

anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...

and

insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...

due to off-target inhibition of the GABA_A receptor that the first-generation NSAAs do not have. In addition, it has prominent

drug interaction In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect ...

s due to moderate to strong induction of multiple

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. Currently on-patent with no generic availability and hence is very expensive. * Darolutamide (Nubeqa): Marketed for the treatment of prostate cancer. Structurally distinct from enzalutamide, apalutamide, and other NSAAs. Relative to enzalutamide and apalutamide, shows greater efficacy as an AR antagonist, improved activity against

mutated 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 replication, DNA or viral rep ...

AR variants in prostate cancer, little or no inhibition or induction of cytochrome P450 enzymes, and little or no central nervous system distribution. However, has a much shorter terminal half-life and lower potency.

Miscellaneous

* Cimetidine (Tagamet): An over-the-counter

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

H₂ receptor antagonist that also shows very weak activity as an AR antagonist. Also inhibits

s and thereby inhibits hepatic estradiol

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 ...

and increases circulating estradiol levels. It has been investigated in the treatment of hirsutism but showed minimal effectiveness. Sometimes causes gynecomastia as a rare side effect. Nonsteroidal androgen synthesis inhibitors like

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 ...

can also be described as "NSAAs", although the term is usually reserved to describe AR antagonists.

Not marketed

Under development

* Proxalutamide (GT-0918): A second-generation NSAA. It is under development for the treatment of prostate cancer. Similar to enzalutamide and apalutamide, but with increased efficacy as an AR antagonist, little or no central nervous system distribution, and no induction of seizures in animals. * Seviteronel (VT-464) is a nonsteroidal androgen biosynthesis inhibitor which is under development for the treatment of prostate cancer.

Development discontinued

* Cioteronel (CPC-10997; Cyoctol, Ethocyn, X-Andron): A structurally unique first-generation NSAA. It was under development as an oral medication for the treatment of

and as a topical medication for the treatment of acne and pattern hair loss. It reached phase II and phase III

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 for these indications prior to discontinuation due to insufficient effectiveness. * Inocoterone acetate (RU-38882, RU-882): A steroid-like NSAA. It was under development as a topical medication for the treatment of acne but was discontinued due to insufficient effectiveness in clinical trials. * RU-58841 (PSK-3841, HMR-3841): A first-generation NSAA related to nilutamide. It was under development as a topical medication for the treatment of acne and pattern hair loss but its development was discontinued during phase I clinical trials.

References

External links

* {{Androgen receptor modulators Anti-acne preparations Antiandrogens Hair loss medications Hair removal Hormonal antineoplastic drugs Progonadotropins Prostate cancer Sex hormones