Selective androgen receptor modulator
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Selective androgen receptor modulators (SARMs) are a class of drugs that selectively activate 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 ...
in specific tissues, promoting
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 ...
and
bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
growth while having less effect on male reproductive tissues like 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 ...
. Non-selective
steroidal A steroid is an organic compound with four 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 that alter membr ...
drugs, called anabolic androgenic steroids (AAS), have been used for various medical purposes, but their side effects limit their use. In 1998, researchers discovered a new class of non-steroidal compounds, the SARMs. These compounds selectively stimulate the androgen receptor, offering potent effects on bone and muscle to increase bone density and lean body mass while having minimal impact on reproductive tissues. SARMs have been investigated in human studies for the treatment of
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 ...
,
cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...
(wasting syndrome),
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 ...
,
stress urinary incontinence Stress incontinence, also known as stress urinary incontinence (SUI) or effort incontinence is a form of urinary incontinence. It is due to inadequate closure of the bladder outlet by the urethral sphincter. Pathophysiology Stress incontinence i ...
, and
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 ...
. , there are no SARMs which have been approved by the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
or the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
. Although adverse effects in clinical studies have been infrequent and mild, SARMs can cause elevated liver enzymes, reduction of
HDL cholesterol High-density lipoprotein (HDL) is one of the five major groups of lipoproteins. Lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. They are t ...
levels, and
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) suppression, among other side effects. Since the early twenty-first century, SARMs have been used in doping; they were banned by the
World Anti-Doping Agency The World Anti-Doping Agency (WADA; , AMA) is an international organization co-founded by the governments of over 140 nations along with the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against d ...
in 2008. SARMs are readily available on internet-based gray markets and are commonly used recreationally to stimulate muscle growth.


History


Steroidal androgens

Anabolic androgenic steroids (AAS) are used to treat a variety of medical conditions, but their side effects have fueled a search for a new class of drugs, with a better separation between desirable anabolic and undesirable androgenic effects. The first clinically used AAS was
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 ...
which was discovered in 1935 and first approved for medical use in 1939. AAS including those produced
endogenous Endogeny, in biology, refers to the property of originating or developing from within an organism, tissue, or cell. For example, ''endogenous substances'', and ''endogenous processes'' are those that originate within a living system (e.g. an ...
ly such as
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), bind to and activate 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) to produce their effects. AAS effects can be separated into androgenic (the development and maintenance of male
sexual characteristics Sexual characteristics are physical traits of an organism (typically of a sexually dimorphic organism) which are indicative of or resultant from biological sexual factors. These include both primary sex characteristics, such as gonads, and ...
) and anabolic (increasing
bone density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although medicine#Clinical practice, clinically it is measured by ...
, muscle mass and strength). AAS also affect
hematopoiesis Haematopoiesis (; ; also hematopoiesis in American English, sometimes h(a)emopoiesis) is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten ...
,
coagulation Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a thrombus, blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of co ...
,
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 cognition. For most medical applications, an AAS with potent anabolic and minimal androgenic and cardiovascular effects would be an advantage. In the 1930s, 17α-alkylated anabolic steroids were discovered. These have increased metabolic stability and are orally active, but are not tissue selective. These alkylated anabolic steroids still have significant androgenic effects, and are also
hepatotoxic 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 ...
. In 1950,
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 ...
(19-nortestosterone) was first synthesized, which is sometimes considered a SARM due to greater tissue selectivity than testosterone. In addition, 7α-alkyl substitution of testosterone (for example trestolone) has also been reported to increase its anabolic effects. However, efforts to develop a steroid with anabolic but minimal androgenic effects were not successful.


SERMs

Interest in nonsteroidal AR mixed agonists/antagonists increased after the therapeutic uses of
selective estrogen receptor modulators Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–Receptor antagonist, antagonists (e.g., full a ...
(SERMs) became evident. The first SERM,
tamoxifen Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome ...
, was originally developed as an anti-estrogen contraceptive. However, it was discovered it promoted ovulation in humans by acting as an agonist in ovaries. The drug was then successfully repurposed as a treatment for breast cancer where it was found to act as a full antagonist in breast tissue. Somewhat unexpectedly, it was also discovered that tamoxifen preserves bone density by acting as an agonist in bone resorbing
osteoclast An osteoclast () is a type of bone cell that breaks down bone tissue. This function is critical in the maintenance, repair, and bone remodeling, remodeling of bones of the vertebrate, vertebral skeleton. The osteoclast disassembles and digests th ...
s. The clinical success of SERMs stimulated interest in analogous tissue selective drugs that target the AR.


Non-steroidal AR antagonists

The chemical starting point for AR mixed agonist/antagonists were nonsteroidal AR
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 t ...
s such as
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, hirsutism, excessive ...
, nilutamide,
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 ...
. These antagonists work by binding to the AR to prevent androgenic action; this class of chemicals dates to the 1970s. The discovery of arylpropionamides, which share structural similarity with bicalutamide and
hydroxyflutamide Hydroxyflutamide (HF, OHF) (developmental code name SCH-16423), or 2-hydroxyflutamide, is a nonsteroidal antiandrogen (NSAA) and the major active metabolite of flutamide, which is considered to be a prodrug of hydroxyflutamide as the active form. ...
, suggested a way to make compounds that bind to the AR and produce both anabolic and antiandrogenic effects. Selective androgen receptor modulators (SARMs) were developed out of a desire to maintain the anabolic effects of androgens on muscle and bone, while avoiding side effects on other tissues such as the
prostate 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 ...
and cardiovascular system.


Non-steroidal SARMs

The first non-steroidal SARMs were developed in 1998 independently by two research groups, one at the
University of Tennessee The University of Tennessee, Knoxville (or The University of Tennessee; UT; UT Knoxville; or colloquially UTK or Tennessee) is a Public university, public Land-grant university, land-grant research university in Knoxville, Tennessee, United St ...
that created an arylpropionamide SARM and Ligand Pharmaceuticals that made a SARM with a
quinolone Quinolone may refer to: * 2-Quinolone * 4-Quinolone * Quinolone antibiotic Quinolone antibiotics constitute a large group of broad-spectrum bacteriocidals that share a bicyclic core structure related to the substance 4-quinolone. They ar ...
core structure. The name was adopted by analogy with SERMs. Other SARMs include
tetrahydroquinoline Tetrahydroquinoline is an organic compound that is the semi-hydrogenated derivative of quinoline. It is a colorless oil. Use Substituted derivatives of tetrahydroquinoline are common in medicinal chemistry. Oxamniquine, dynemycin, viratmycin, ...
s,
tricyclic Tricyclics are cyclic chemical compounds that contain three fused rings of atoms. Many compounds have a tricyclic structure, but in pharmacology, the term has traditionally been reserved to describe heterocyclic drugs. They include antidepr ...
s, bridged tricyclics,
aniline Aniline (From , meaning ' indigo shrub', and ''-ine'' indicating a derived substance) is an organic compound with the formula . Consisting of a phenyl group () attached to an amino group (), aniline is the simplest aromatic amine. It is an in ...
, diaryl aniline, bicylclic hydantoins,
benzimidazole Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound may be viewed as fused rings of the aromatic compounds benzene and imidazole. It is a white solid that appears in form of tabular crystals. Preparation Benzimi ...
, imidazolopyrazole,
indole Indole is an organic compound with the formula . Indole is classified as an aromatic heterocycle. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered pyrrole ring. Indoles are derivatives of indole ...
, and
pyrazoline Pyrazoline is a heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic organic chemistry is the branch of organic chemistry dea ...
derivatives. SARMs can be
agonists An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agon ...
,
antagonists 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.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 of the AR depending on the tissue, which can enable targeting specific medical conditions while minimizing side effects. Those that have advanced to human trials show stronger effects in bone and muscle tissue and weaker effects in the prostate. Unlike most current forms of testosterone replacement, SARMs are orally
bioavailable In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...
and largely eliminated via hepatic metabolism and metabolized through amide hydrolysis in the case of arylpropionamides and A-ring nitro reduction of
andarine Andarine (developmental code names GTx-007, S-4) is a selective androgen receptor modulator (SARM) which was developed by GTX, Inc for the treatment of conditions such as muscle wasting, osteoporosis, and benign prostatic hyperplasia (BPH), us ...
.


Proposed treatment of hypogonadism

Because of the potentially better side effect profile of SARMs compared to testosterone, SARMs have been proposed for use in the treatment of hypogonadism and for androgen replacement therapy. Phase I and II trials have provided preliminary evidence that the SARMs
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 ...
and GSK-2881078 (in elderly men and postmenopausal women), and OPL-88004 (prostate cancer survivors with low levels of testosterone) increase lean body mass and muscle size with little effect on the prostate, supporting the potential of SARMs for use in hormone replacement therapy. However, it has been argued that SARMs are not ideal for use in androgen replacement therapy and could not replace testosterone in this context as they do not reproduce testosterone's full spectrum of effects, including androgenic potentiation via 5α-reduction and aromatization into estrogen. Estrogenic signaling in particular is essential for normal male physiology and health, including for instance maintenance of bone strength.


Mechanism

The mechanism of action of SARMs' tissue-specific effects continues to be debated . A number of hypotheses have been advanced. These include the non-activation of SARMs by 5α-reductase, tissue selective expression of androgen receptor coregulators, non-genomic signaling, and tissue selective uptake of SARMs.


5α-Reductase

Testosterone is active in non-reproductive tissue without activation. In contrast, tissue selective activation by 5α-reductase to the more active form DHT is required for significant activity in reproductive tissue. The net result is that testosterone and its metabolite together are not tissue selective. SARMs are not substrates of 5α-reductase, hence they are not selectively activated like testosterone in tissues such as prostate. This lack of activation effectively imparts a degree of tissue selectivity to SARMs.


Androgen receptor coregulators

Tissue selective
transcription coregulator In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription ar ...
expression is another possible contributor to the selectivity of SARMs. Like other type I nuclear receptors, the un liganded androgen receptor (AR) resides in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
complexed with
heat shock protein Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including ex ...
s (HSP). Upon ligand binding, the AR freed from HSPs and translocated into the nucleus where it binds to androgen
response element ''Response elements'' are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein bi ...
s on DNA to regulate gene expression. AR agonists such as testosterone recruit
coactivator A coactivator is a type of transcriptional coregulator that binds to an activator (a transcription factor) to increase the rate of transcription of a gene or set of genes. The activator contains a DNA binding domain that binds either to a DNA ...
proteins to AR that facilitate upregulation of gene expression while antagonists recruit
corepressor In genetics and molecular biology, a corepressor is a molecule that represses the expression of genes. In prokaryotes A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membra ...
s which down regulate gene expression. Furthermore, the ratio of coactivators to corepressors is known to vary depending on tissue type. Structurally, pure AR agonists stabilize the position of helix-12 (H12) in the
ligand binding domain In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the expre ...
of AR near H3 and H4 to produce a surface cleft that binds to a FxxLF motif contained in coactivators. Conversely, antagonists destabilize the agonist conformation of H12 blocking the binding of the FXXLF coactivator motif while facilitating the binding of the corepressor LXX(I/H)IXXX(I/L) motif found in NCOR1 and SMRT corepressors. In analogy to SERMs, SARMs are mixed agonists/antagonists displaying agonist androgen receptor activity in bone and muscle and partial agonist or antagonist activity in other tissues such as prostate. Non-selective agonists such as testosterone are able to recruit coactivators when bound to AR but not corepressors and hence are agonists in all tissues. In contrast, SARMs can recruit both coactivators and corepressors by partially destabilizing the agonist conformation of H12. In tissues where coactivators are in excess (as in bone and muscle), SARMs act as agonists. Conversely, in tissues where corepressors are in excess (such as prostate), SARMs act as partial agonists or antagonists. ''
In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' testing of the SARMs
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 ...
(ostarine) and YK-11 showed that they bound to the AR, but unlike full AR agonists, they blocked interaction between the
N-terminus 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 ...
and
C-terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, carboxy tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein Proteins are large biomolecules and macromolecules that comp ...
of AR which resulted in a mixed agonist/antagonist mode of action.


Non-genomic signaling

In addition to the regulation of gene expression by nuclear AR, membrane associated AR is known to have rapid non-genomic effects on cells through
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
cascades. Non-genomic effects appear to significantly contribute to the anabolic effects of androgens whereas genomic effects are primarily responsible for the development of male sexual organs. Furthermore, each steroidal androgen or non-steroidal SARM uniquely influences distinct pathways depending on cell type.


Tissue distribution

Tissue selective uptake into anabolic tissues presents another potential mechanism for SARM tissue selectivity. However
autoradiography An autoradiograph is an image on an X-ray film or nuclear emulsion produced by the pattern of decay emissions (e.g., beta particles or gamma rays) from a distribution of a radioactive substance. Alternatively, the autoradiograph is also availab ...
studies with radiolabeled SARMs show no preferential distribution to anabolic tissues.


Drug candidates

Certain anabolic steroids, like trestolone,
dimethandrolone undecanoate Dimethandrolone undecanoate (DMAU), also known by its developmental code name CDB-4521, is an experimental androgen/anabolic steroid (AAS) and progestogen medication which is under development as a potential birth control pill for men. It is tak ...
, and 11β-methyl-19-nortestosterone dodecylcarbonate, have also sometimes been classified as SARMs.


Possible therapeutic applications

Due to their tissue selectivity, SARMs have the potential to treat a wide variety of conditions, including debilitating diseases. They have been investigated in human studies for the treatment of
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 ...
,
cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...
,
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 ...
,
stress urinary incontinence Stress incontinence, also known as stress urinary incontinence (SUI) or effort incontinence is a form of urinary incontinence. It is due to inadequate closure of the bladder outlet by the urethral sphincter. Pathophysiology Stress incontinence i ...
,
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, ...
, and
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 ...
and have also been considered for the treatment of
Alzheimer's disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
,
Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pe ...
,
hypogonadism Hypogonadism means diminished functional activity of the human gonad, gonads—the testicles or the ovary, ovaries—that may result in diminished biosynthesis, production of sex hormones. Low androgen (e.g., testosterone) levels are referred t ...
and as a
male contraceptive Male contraceptives, also known as male birth control, are methods of preventing pregnancy by interrupting the function of sperm. The main forms of male Birth control, contraception available today are condoms, vasectomy, and Coitus interruptus, w ...
. , there are no SARMs which have been approved for therapeutic use by the United States
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
or the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
. Most SARMs have been tested ''
in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...
'' or on rodents, while limited clinical trials in humans have been carried out. Initial research focused on muscle wasting.
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 ...
(ostarine) is the most well-studied SARM; according to its manufacturer, GTx Incorporated, 25 studies have been carried out on more than 1,700 humans involving doses from 1 to 18 mg each day. , there is little research distinguishing different SARMs from each other. Much of the research on SARMs has been conducted by corporations and has not been made publicly available.


Benign prostatic hyperplasia

In rat models 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 ...
(BPH), a condition where the
prostate 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 ...
is enlarged in the absence 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, ...
, SARMs reduced the weight of the prostate. OPK-88004 advanced to a phase II trial in humans, but it was terminated due to difficulty in measuring prostate size, the trial's primary endpoint.


Cancer

SARMs may help treat AR and
estrogen receptor Estrogen receptors (ERs) are proteins found in cell (biology), cells that function as receptor (biochemistry), receptors for the hormone estrogen (17β-estradiol). There are two main classes of ERs. The first includes the intracellular estrogen ...
(ER) 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 ...
, which comprise the majority of breast cancers. AAS were historically used successfully to treat AR positive breast cancer, but were phased out after the development of antiestrogen therapies, due to androgenic side effects and concerns about
aromatization Aromatization is a chemical reaction in which an aromaticity, aromatic system is formed from a single nonaromatic precursor. Typically aromatization is achieved by dehydrogenation of existing cyclic compounds, illustrated by the conversion of cycl ...
to estrogen (which does not occur with SARMs). Although a trial on AR positive
triple negative breast cancer Triple-negative breast cancer (TNBC) is any breast cancer that either lacks or shows low levels of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) overexpression and/or gene amplification (i.e ...
(which is ER-) was ended early due to lack of efficacy, enobosarm showed benefits in some patients with ER+, AR+ breast cancer in a phase II study. In patients with more than 40 percent AR positivity as determined by
immunohistochemistry Immunohistochemistry is a form of immunostaining. It involves the process of selectively identifying antigens in cells and tissue, by exploiting the principle of Antibody, antibodies binding specifically to antigens in biological tissues. Alber ...
, the clinical benefit rate (CBR) was 80 percent and the
objective response rate Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of disease, symptom, sign or laboratory abnormality constituting a target outcome in clinical research trials. The term may also refer to any disease or sign th ...
(ORR) was 48 percent—which was considered promising given that the patients had advanced disease and had been heavily pretreated. In 2022, the FDA granted fast track designation to enobosarm for AR+, ER+,
HER2 Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ''ERBB2'' gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The ...
-
metastatic Metastasis is a pathogenic agent's spreading from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, ...
breast cancer. Other SARMs such as vosilasarm have reached clinical trials in breast cancer patients.


Bone and muscle wasting

, there are no drugs approved to treat muscle wasting in people with chronic diseases, and there is therefore an unmet need for anabolic drugs with few side effects. One aspect hindering drug approval for treatments for
cachexia Cachexia () is a syndrome that happens when people have certain illnesses, causing muscle loss that cannot be fully reversed with improved nutrition. It is most common in diseases like cancer, Heart failure, congestive heart failure, chronic o ...
and
sarcopenia Sarcopenia ( ICD-10-CM code M62.84) is a type of muscle loss that occurs with aging and/or immobility. It is characterized by the degenerative loss of skeletal muscle mass, quality, and strength. The rate of muscle loss is dependent on exer ...
(two types of muscle wasting) is disagreement in what outcomes would demonstrate the efficacy of a drug. Several clinical trials have found that SARMs improve lean mass in humans, but it is not clear whether strength and physical function are also improved. After promising results in a phase II trial, a phase III trial of enobosarm was proven to increase
lean body mass Lean body mass (LBM), sometimes conflated with , is a component of body composition. Fat-free mass (FFM) is calculated by subtracting body fat weight from total body weight: total body weight is lean plus fat. In equations: :LBM = BW ...
but did not show significant improvement in function. It and other drugs have been refused regulatory approval due to a lack of evidence that they increased physical performance; preventing decline in functionality was not considered an acceptable endpoint by the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
. It is not known how SARMs interact with dietary protein intake and resistance training in people with muscle wasting. Phase II trials of enobosarm for
stress urinary incontinence Stress incontinence, also known as stress urinary incontinence (SUI) or effort incontinence is a form of urinary incontinence. It is due to inadequate closure of the bladder outlet by the urethral sphincter. Pathophysiology Stress incontinence i ...
—considered promising, given that the
levator ani The levator ani is a broad, thin muscle group, situated on either side of the pelvis. It is formed from three muscle components: the pubococcygeus, the iliococcygeus, and the puborectalis. It is attached to the inner surface of each side of the ...
muscle in the
pelvic floor The pelvic floor or pelvic diaphragm is an anatomical location in the human body which has an important role in urinary and anal continence, sexual function, and support of the pelvic organs. The pelvic floor includes muscles, both skeletal and ...
has a high androgen receptor density—did not meet their endpoint and were abandoned. Unlike other treatments for osteoporosis, which work by decreasing bone loss, SARMs have shown potential to promote growth in bone tissue. LY305 showed promising results in a phase I trial in humans.


Side effects

In contrast to AAS and testosterone replacement, which have many side effects that have curtailed their medical use, SARMs are well tolerated and have mild and infrequent adverse events in
randomized controlled trials A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
. SARMs are sometimes claimed to be non- virilizing (non-masculinizing). However, SARMs are largely uncharacterized clinically in terms of potential virilizing effects. In addition, SARMs cannot be aromatized to
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 ...
, thus causing no estrogenic side effects, for instance
gynecomastia Gynecomastia (also spelled gynaecomastia) is the non-cancerous enlargement of one or both breasts in men due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse (10 Novemb ...
. SARM use can cause elevated liver enzymes and reduction in HDL cholesterol.
Transdermal Transdermal is a route of administration wherein active ingredients are delivered across the skin for systemic distribution. Examples include transdermal patches used for medicine delivery. The drug is administered in the form of a patch or ointm ...
administration via a skin patch may reduce these effects. Several case reports have associated SARMs with hepatocellular
drug-induced liver injury 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 inhalation, injection, smoking, ingestion, ...
when used recreationally, it is not known if the risk is significant for medical use. Whether SARMs increase the risk of cardiovascular events is unknown. SARMs have less effect on blood lipid profiles than testosterone replacement; it is not known whether androgen-induced HDL reductions increase cardiovascular risk; and SARMs increase
insulin sensitivity Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a hormone ...
and lower
triglycerides A triglyceride (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and oth ...
. Although they cause less suppression of 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) than testosterone, studies have found that gonadotropins, free and total testosterone, and
SHBG Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it is called androgen-binding prot ...
can be reduced in a compound- and dose-dependent fashion in men from SARM usage. Typically, SHBG is reduced along with total testosterone and
total 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 ...
, while
hematocrit The hematocrit () (Ht or HCT), also known by several other names, is the volume percentage (vol%) of red blood cells (RBCs) in blood, measured as part of a blood test. The measurement depends on the number and size of red blood cells. It is nor ...
is increased. Most studies have found that
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),
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), prostate-specific antigen,
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 ...
, and DHT levels are not altered. Of SARMs that have been investigated, enobosarm is one of the least suppressive of gonadotropins, even in doses much higher than used in clinical trials. How the HPG axis is affected in women using SARMs is unknown. SARMs' effect in suppressing the gonadotropins FSH and LH is what makes SARMs potentially useful as a male contraceptive.


Non-medical use

Outside of pharmaceutical research, SARMs are a
gray market A grey market or dark market (sometimes confused with the similar term " parallel market") is the trade of a commodity through distribution channels that are not authorised by the original manufacturer or trademark proprietor. Grey market prod ...
substance produced by small laboratories and often marketed as a research chemical supposedly not for human consumption. Marketing SARMs for human consumption is illegal in some jurisdictions and has led to criminal convictions in the United States and the largest-ever fine levied under Australia's
Therapeutic Goods Act 1989 The Therapeutic Goods Act 1989 is an Act of the Commonwealth of Australia which regulates therapeutic goods. The Act is administered by the Therapeutic Goods Administration (TGA), which is part of the Commonwealth Department of Health. The statut ...
. Although SARMs are readily available for purchase on the internet, one study found that a majority of products advertised as SARMs online were mislabeled. Anecdotes and guides on usage can also be found online and on
social media Social media are interactive technologies that facilitate the Content creation, creation, information exchange, sharing and news aggregator, aggregation of Content (media), content (such as ideas, interests, and other forms of expression) amongs ...
. Some compounds are commonly marketed for recreational use as SARMs despite having a different
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
. These substances include
ibutamoren Ibutamoren (; developmental code MK-677, MK-0677, LUM-201, L-163,191; former tentative brand name Oratrope) is a potency (pharmacology), potent, long-acting, oral administration, orally-active, binding selectivity, selective, and small molecule, ...
(MK-677), which increases secretion of
growth hormone Growth hormone (GH) or somatotropin, also known as human growth hormone (hGH or HGH) in its human form, is a peptide hormone that stimulates growth, cell reproduction, and cell regeneration in humans and other animals. It is thus important in ...
;
GW501516 GW501516 (also known as GW-501,516, GW1516, GSK-516, cardarine, and on the black market as endurobol) is a PPARδ receptor agonist that was invented in a collaboration between Ligand Pharmaceuticals and GlaxoSmithKline in the 1990s. It entered ...
(cardarine), an
exercise mimetic An exercise mimetic is a drug that mimics some of the biological effects of physical exercise. Exercise is known to have an effect in preventing, treating, or ameliorating the effects of a variety of serious illnesses, including cancer, type 2 diab ...
that works as an agonist of the PPARβ/δ; and SR9009 (Stenabolic), an agonist of the Rev-Erb, which plays a role in
circadian rhythm A circadian rhythm (), or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism (i.e., Endogeny (biology), endogenous) and responds to the env ...
. SARMs are used by bodybuilders and competitive athletes due to their anabolic and lack of androgenic effects, particularly in the United States, Europe, and other western countries. Some individuals using SARMs recreationally combine multiple SARMs or take a SARM along with other compounds, although there is no research on combining SARMs. The doses used often exceed those from clinical trials; nevertheless, the fat-free mass gained from SARMs is generally lower than what is obtained with moderate doses of testosterone derivatives. According to one study of SARM users, more than 90 percent were satisfied with their usage and 64 percent would take SARMs again even though a majority experienced adverse effects. SARMs were banned by the
World Anti-Doping Agency The World Anti-Doping Agency (WADA; , AMA) is an international organization co-founded by the governments of over 140 nations along with the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against d ...
(WADA) in 2008. SARMs can be detected in urine and hair after consumption. WADA reported its first adverse analytical finding for SARMs in 2010 and the number of positive tests has increased since then; the most commonly detected SARMs are enobosarm (ostarine) and
LGD-4033 LGD-4033, also known by the developmental code name VK5211 and by the black-market name Ligandrol, is a selective androgen receptor modulator (SARM) which is under development for the treatment of muscle atrophy in people with hip fracture. It w ...
(ligandrol). Athletes competing in the
NFL The National Football League (NFL) is a professional American football league in the United States. Composed of 32 teams, it is divided equally between the American Football Conference (AFC) and the National Football Conference (NFC). The N ...
,
NBA The National Basketball Association (NBA) is a professional basketball league in North America composed of 30 teams (29 in the United States and 1 in Canada). The NBA is one of the major professional sports leagues in the United States and Ca ...
,
UFC The Ultimate Fighting Championship (UFC) is an American mixed martial arts (MMA) promotion company based in Las Vegas, Nevada. It is owned and operated by TKO Group Holdings, a majority owned subsidiary of Endeavor Group Holdings. The larg ...
,
NCAA The National Collegiate Athletic Association (NCAA) is a nonprofit organization that regulates College athletics in the United States, student athletics among about 1,100 schools in the United States, and Simon Fraser University, 1 in Canada. ...
, and the
Olympics The modern Olympic Games (Olympics; ) are the world's preeminent international sporting events. They feature summer and winter sports competitions in which thousands of athletes from around the world participate in a variety of competit ...
have tested positive. There is limited evidence on how SARMs affect athletic performance.


Terminology

SARMs are sometimes also referred to as "nonsteroidal androgens", although not all SARMs are nonsteroidal in structure and steroidal SARMs also exist. In 1999, the term "selective androgen receptor modulator" or "SARM" was introduced, as the mixed agonist–antagonist and tissue-selective activity of these nonsteroidal androgen receptor agonists had similarities with
selective estrogen receptor modulator Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonists/antagonists (ERAAs), are a class of drugs that act on estrogen receptors (ERs). Compared to pure ER agonists–antagonists (e.g., full agonists and silent ...
s (SERMs). Despite its widespread use, the term "selective androgen receptor modulator" has been criticized by some authors, like David Handelsman, who argue that it is a misleading pharmaceutical marketing term rather than an accurate pharmacological description. He has also critiqued notions that SARMs isolate anabolic effects from androgenic or virilizing effects, as has been previously claimed in the case of
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.


References

{{Androgen receptor modulators