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 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 androgens like testosterone 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 antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) ...

s (SAAs), which are antiandrogens that are

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

s and are structurally related to testosterone.

Medical uses

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

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

in men * Androgen-dependent skin and hair conditions like acne, hirsutism, seborrhea, and pattern hair loss (androgenic alopecia) in women * Hyperandrogenism, such as due to polycystic ovary syndrome or congenital adrenal hyperplasia, 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 oncologic horm ...

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

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

ic, glucocorticoid, or antimineralocorticoid activity, and lack

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

effects. 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 pragmatic clinical trial#Efficacy versu ...

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, 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. 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 effects such as nausea and vomiting,

visual disturbance A vision disorder is an impairment of the sense of vision. Vision disorder is not the same as an eye disease. Although many vision disorders do have their immediate cause in the eye, there are many other causes that may occur at other locations in ...

s, 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. *

Topilutamide Topilutamide, known more commonly as fluridil and sold under the brand name Eucapil, is an antiandrogen medication which is used in the treatment of pattern hair loss in men and women. It is used as a topical medication and is applied to the sc ...

(Eucapil): Also known as fluridil. Marketed as a topical medication for the treatment of pattern hair loss (androgenic alopecia) in the Czech Republic and Slovakia. 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 Distribution may refer to: Mathematics *Distribution (mathematics), generalized functions used to formulate solutions of partial differential equations * Probability distribution, the probability of a particular value or value range of a vari ...

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 seizures and has central nervous system side effects like anxiety and insomnia due to off-target inhibition of the GABA_A receptor that the first-generation NSAAs do not have. In addition, it has prominent drug interactions due to moderate to strong induction of multiple

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

enzymes. Currently on-patent with no generic availability and hence is very expensive. *

Darolutamide Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of non-metastatic castration-resistant prostate cancer in men. It is specifically approved to treat non-metastatic castration-resista ...

(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 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 Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...

(Tagamet): An over-the-counter histamine H₂ receptor antagonist that also shows very weak activity as an AR antagonist. Also inhibits

enzymes and thereby inhibits hepatic estradiol metabolism 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 and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candid ...

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 Cioteronel (, ) (developmental code name CPC-10997; former tentative brand names Cyoctol, X-Andron) is a nonsteroidal antiandrogen (NSAA) that was never marketed. It was under development between 1989 and 2001 for the topical treatment of androge ...

(CPC-10997; Cyoctol, Ethocyn, X-Andron): A structurally unique first-generation NSAA. It was under development as an oral medication for the treatment of benign prostatic hyperplasia and as a topical medication for the treatment of acne and pattern hair loss. It reached

phase II Phase II, Phase 2 or Phase Two may refer to: Media * Marvel Cinematic Universe: Phase Two, six American superhero films from 2013–2015 * ''Star Trek: Phase II'', an unrealized television series based on the characters of Gene Roddenberry's ''S ...

and phase III clinical trials for these indications prior to discontinuation due to insufficient effectiveness. *

Inocoterone acetate Inocoterone acetate () (developmental code names RU-38882, RU-882) is a steroid-like nonsteroidal antiandrogen (NSAA) that was developed for topical administration to treat acne but was never marketed. It is the acetate ester of inocoterone, whi ...

(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 Phase 1, Phase I or Phase One may refer to: Media * Marvel Cinematic Universe: Phase One, six American superhero films from 2008–2012 * ''Phase One'' (Art Ensemble of Chicago album), 1971 * ''Phase One'' (Saga album), 1998 * ''Phase One'', r ...

clinical trials.

References

External links

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