A nonsteroidal antiandrogen (NSAA) is an
antiandrogen
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking th ...
with a
nonsteroidal A nonsteroidal compound is a drug that is not a steroid nor a steroid derivative. Nonsteroidal anti-inflammatory drugs (NSAIDs) are distinguished from corticosteroids as a class of anti-inflammatory agents.
List of nonsteroidal steroid receptor mo ...
chemical structure
A chemical structure determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target molecule or other solid. Molecular geometry refers to the spatial arrangement of a ...
.
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 the ...
(AR) and act by directly
blocking the effects of
androgen
An androgen (from Greek ''andr-'', the stem of the word meaning "man") is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors. This incl ...
s like
testosterone
Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of male reproductive tissues such as testes and prostate, as well as promoting secondary sexual characteristic ...
and
dihydrotestosterone
Dihydrotestosterone (DHT, 5α-dihydrotestosterone, 5α-DHT, androstanolone or stanolone) is an endogenous androgen sex steroid and hormone. The enzyme 5α-reductase catalyzes the formation of DHT from testosterone in certain tissues includi ...
(DHT).
NSAAs are used in the treatment of
androgen-dependent condition An androgen-dependent condition, disease, disorder, or syndrome, is a medical condition that is, in part or full, dependent on, or is sensitive to, the presence of androgenic activity in the body.
Known androgen-dependent conditions include acne, s ...
s in men and women.
They are the converse of
steroidal antiandrogens (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 ...
s and are structurally related to testosterone.
Medical uses
NSAAs are used in clinical medicine for the following indications:
*
Prostate cancer in men
*
Androgen-dependent skin and hair conditions like
acne
Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and po ...
,
hirsutism,
seborrhea, and
pattern hair loss (androgenic alopecia) in women
*
Hyperandrogenism
Hyperandrogenism is a medical condition characterized by high levels of androgens. It is more common in women than men. Symptoms of hyperandrogenism may include acne, seborrhea (inflamed skin), hair loss on the scalp, increased body or facial ...
, such as due to
polycystic ovary syndrome or
congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders characterized by impaired cortisol synthesis. It results from the deficiency of one of the five enzymes required for the synthesis of cortisol in the adrenal cortex. M ...
, 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 h ...
for
transgender women
A trans woman or a transgender woman is a woman who was assigned male at birth. Trans women have a female gender identity, may experience gender dysphoria, and may transition; this process commonly includes hormone replacement therapy and so ...
*
Precocious puberty
In medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
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
An antimineralocorticoid, also known as a mineralocorticoid receptor antagonist (MRA or MCRA) or aldosterone antagonist, is a diuretic drug which antagonizes the action of aldosterone at mineralocorticoid receptors. This group of drugs is often u ...
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 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
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair grow ...
(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, inability to urinate, or loss o ...
.
Now little-used due to high incidence of
elevated liver enzymes
In medicine, the presence of elevated transaminases, commonly the transaminases alanine transaminase (ALT) and aspartate transaminase (AST), may be an indicator of liver dysfunction. Other terms include transaminasemia, transaminitis, and elevated ...
and
hepatotoxicity
Hepatotoxicity (from ''hepatic toxicity'') implies chemical-driven liver damage. Drug-induced liver injury is a cause of acute and chronic liver disease caused specifically by medications and the most common reason for a drug to be withdrawn fr ...
and the availability of safer agents.
*
Nilutamide
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer.https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020169s008lbl.pdf It has also been ...
(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
Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde (produced from the metabolism of alcohol by alcohol dehydrogenase). This polymorphism is most often r ...
.
*
Bicalutamide
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical remo ...
(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 medicine, precocious puberty is puberty occurring at an unusually early age. In most cases, the process is normal in every aspect except the unusually early age and simply represents a variation of normal development. In a minority of childr ...
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 (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
Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer. It is specifically indicated for use in conjunction with castration in the treatmen ...
(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
Potency may refer to:
* Potency (pharmacology), a measure of the activity of a drug in a biological system
* Virility
* Cell potency, a measure of the differentiation potential of stem cells
* In homeopathic dilutions, potency is a measure of how ...
and shows no risk of elevated liver enzymes or hepatotoxicity. However, it has a small (1%) risk of
seizure
An epileptic seizure, informally known as a seizure, is a period of symptoms due to abnormally excessive or synchronous neuronal activity in the brain. Outward effects vary from uncontrolled shaking movements involving much of the body with los ...
s and has
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...
side effects like
anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
and
insomnia due to off-target inhibition of the
GABAA 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 superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various comp ...
enzymes. Currently
on-patent with no
generic
Generic or generics may refer to:
In business
* Generic term, a common name used for a range or class of similar things not protected by trademark
* Generic brand, a brand for a product that does not have an associated brand or trademark, other ...
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-resistan ...
(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 or viral replication, mitosi ...
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
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the b ...
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
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
histamine H2 receptor antagonist that also shows very weak activity as an AR antagonist. Also
inhibits
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various comp ...
enzymes and thereby inhibits hepatic
estradiol
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of ...
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 inhibitor An androgen synthesis inhibitor is a type of drug which inhibits the enzymatic synthesis of androgens, such as testosterone and dihydrotestosterone (DHT). They include:
* CYP17A1 inhibitors (17α-hydroxylase/17,20-lyase inhibitors): inhibit the syn ...
s like
ketoconazole 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
__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 ...
(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
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, inability to urinate, or loss o ...
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.
See also
*
Selective androgen receptor modulator
Selective Androgen Receptor Modulators or SARMs are a class of androgen receptor ligands that maintain some of the desirable effects of androgens, such as preventing osteoporosis and muscle loss while reducing risks of developing prostate cance ...
*
N-Terminal domain antiandrogen
''N''-Terminal domain antiandrogens are a novel type of antiandrogen that bind to the ''N''-terminal domain of the androgen receptor (AR) instead of the ligand-binding domain (where all currently-available antiandrogens bind) and disrupt inter ...
*
Discovery and development of antiandrogens This article is about the discovery and development of antiandrogens, or androgen receptor (AR) antagonists.
In the 1960s, the first antiandrogen was discovered. Antiandrogens antagonise the androgen receptor (AR) and thereby block the biological ...
*
Nonsteroidal estrogen
References
Further reading
*
*
*
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*
External links
*
{{Androgen receptor modulators
Anti-acne preparations
Antiandrogens
Hair loss medications
Hair removal
Hormonal antineoplastic drugs
Progonadotropins
Prostate cancer
Sex hormones