Selective Androgen Receptor Modulators or SARMs are a class 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 inc ...
receptor
ligands
In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
that maintain some of the desirable effects of androgens, such as preventing
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to bone fragility, and consequent increase in fracture risk. It is the most common reason for a broken bone ...
and
muscle loss
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
while reducing risks of developing
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 the late 1990s, the first nonsteroidal SARM, an analog of
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 ...
, was discovered. They are intended to have the same kind of effects as androgenic drugs, such as
anabolic-androgenic steroid
Anabolic steroids, also known more properly as anabolic–androgenic steroids (AAS), are steroidal androgens that include natural androgens like testosterone (medication), testosterone as well as synthetic androgens that are structurally related ...
s, but be more selective in their action.
At present, there are no SARMs which have been approved for therapeutic use by the
U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
.
Comparison to testosterone
![Testosterone](https://upload.wikimedia.org/wikipedia/commons/f/ff/Testosterone.PNG)
As previously mentioned, the purpose of research in relation to SARMs is to replace testosterone supplementation in disease treatment with selective
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 inc ...
receptor molecules.
This is due to the fact that testosterone supplementation can have adverse effects on patients, which are detailed on the
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 system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
page.
Thinking of testosterone as a model molecule, several SARMs have been manufactured to mimic the proven effects of testosterone on the body. For example, there have been meta-analyses conducted showing that testosterone supplementation increases fat-free mass, body mass, strength, and a decrease in fat mass.
However, nonsteroidal SARMs purposefully differ in their mechanism of action, as the
5-α reduction or aromatization seen in testosterone’s mechanism is not present in these molecules.
Mechanism
The binding of ligands to the androgen receptor (AR) results in a conformational change, this consequentially alters surface topology which will lead to tissue-specific gene regulation. This tissue-specific regulation then allows for the selective stimulation or inhibition of the AR; this requires androgen response elements, co-regulators, and transcription factors. Although the exact mechanisms still remain unclear, tissue specificity and complexity of the pathway is known to dictate the transcriptional and cellular response.
Therapeutic Application and Promise
![RAD140 structure](https://upload.wikimedia.org/wikipedia/commons/0/01/RAD140_structure.png)
There has been extensive research on selective estrogen receptor modulators (SERMs) such as
tamoxifen
Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has b ...
, which is used to treat
breast cancer. There have been experiments using a SARMs C-6 and S-23 on male mice as a contraceptive agent. Treatment of osteoporosis has been explored as SARMs have been found to have trophic effects on bone density and mineralization.
The mechanism of many SARMs may also allow for the treatment of prostate cancer through the activation of AR-induced expression profiles, cytotoxic to cancer cells with fewer negative effects than seen in traditional antiandrogen therapies. Additionally, studies done on female rats have shown that SARMs can be designed to have effects on female libido and reproductive organs. Experimental results have also raised the possibility of using SARMs as adjuncts or monotherapy for benign prostatic hyperplasia through immunomodulatory mechanisms. Also, there is a relationship between Amyloid β, androgens, and circulating testosterone levels which all can affect the course of
Alzheimer’s disease
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
; a novel SARM, NEP28 has been studied and found to increase the up-regulation of neprilysin, which suppresses the plaques.
Theoretically, diseases such as
Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy that primarily affects boys. Muscle weakness usually begins around the age of four, and worsens quickly. Muscle loss typically occurs first in the thighs and pelvis fol ...
can be treated with SARMs in which mice had gained muscle mass, however, side effects such as hepatoxicity and off-target effects on genitalia limited the success of pilot studies.
Cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart f ...
is a response to a disease state or its therapy; SARMs have the potential to reverse or prevent this response while having minimal effects based on several studies performed on mice. As of 2020, there has been a clinical trial using enobosarm as co-therapy with pembrolizumab for the treatment of AR positive metastatic triple negative breast cancer.
Examples
As of 2020, only four SARMs have been clinically tested on humans; Ostarine, LGD-4033, GSK2881078, and PF-06260414. While others are still in phases of testing on model organisms such as mice.
Ostarine
Ostarine also known as Enobosarm, GTx-024 and MK-2866 has a significant amount of
anabolic
Anabolism () is the set of metabolic pathways that construct molecules from smaller units. These reactions require energy, known also as an endergonic process. Anabolism is the building-up aspect of metabolism, whereas catabolism is the breaking-do ...
activity relative to
androgenic
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 ...
activity, which shows potential in the treatment of diseases that negatively affect muscles and bones. A common, negative effect of SARMs and other anabolic steroids is the reduction of HDL and LDL, this has been confirmed in human clinical trials when comparing Ostarine to a placebo. Additionally, in trials where 1 mg of Ostarine (or more) was administered, there was a statistically significant lowering of Sex Hormone-Binding Globulin (SHBG) and serum total testosterone levels. Alanine Transaminase (ALT), an enzyme present in the liver, has been shown to fluctuate abnormally while clinical patients were given no more than 3 mg per day. However, the elevated levels seem to be resolved after the discontinuation of the SARM.
LGD-4033
LGD-4033, previously known as Ligandrol, currently known as VK5211 after being licensed to a different pharmaceutical company; was developed as a potential treatment to musculoskeletal degenerative diseases. The potency of a SARM can be thought of as its potential anabolic activity in relation to its androgenic activity, VK5211 has the largest ratio of clinically tested SARMs. In human trials thus far, the compound has been considered generally safe with some side effects. Similarly to Ostarine, VK5211 affected both lipid levels and testosterone levels, by suppressing HDL, luteinizing hormone (LH), and follicle stimulating hormone (FSH).
GSK2881078
Like VK5211, GSK2881078 has been clinically tested in relation to its potential in treating musculoskeletal degenerative diseases. The SARM was found to lower HDL levels, while some reported constipation, dyspepsia, and nausea. A small percentage of women studied had elevated ALT values and some men had elevated creatine kinase levels and muscle soreness.
PF-06260414
PF-06260414 was found to be well tolerated among the male population clinically tested. As expected with SARMs there was a decrease in HDL levels as well as an increase in ALT levels. Few participants experienced headaches, decreased appetite, dizziness, upper respiratory infection, fatigue, and anxiety.
Other
*
BMS-564,929
BMS-564,929 is an investigational selective androgen receptor modulator (SARM) which is being developed by Bristol-Myers Squibb for treatment of the symptoms of age-related decline in androgen levels in men ("andropause"). These symptoms may incl ...
– Mainly affects muscle growth, intended as general treatment for symptoms of
andropause
*
AC-262,356
AC-262536 is a drug developed by Acadia Pharmaceuticals which acts as a selective androgen receptor modulator (SARM). Chemically it possesses endo-exo isomerism, with the endo form being the active form. It acts as a partial agonist for the andr ...
*
LGD-2226
LGD-2226 is an investigational selective androgen receptor modulator (SARM), which is being developed for treatment of muscle wasting and osteoporosis.
LGD-2226 is an orally active, potent and selective agonist for androgen receptors which w ...
– Affects both muscle and bone
*
LGD-3303
LGD-3303 is a drug which acts as a selective androgen receptor modulator (SARM), with good oral bioavailability. It is a selective agonist for the androgen receptor, producing functional selectivity with effective dissociation of anabolic and an ...
*
S-40503
S-40503 is an investigational selective androgen receptor modulator (SARM) developed by the Japanese company Kaken Pharmaceuticals, which was developed for the treatment of osteoporosis. SARMs are a new class of drugs which produce tissue-speci ...
– Selective for bone tissue, particularly low virilization, intended for osteoporosis and may be suitable for use in women.
*
S-23 – Under development as a male hormonal contraceptive
*
RAD140 (Testolone)
Abandoned drug candidates
*
Acetothiolutamide
Acetothiolutamide is a selective androgen receptor modulator (SARM) derived from the nonsteroidal antiandrogen bicalutamide that was described in 2002 and was one of the first SARMs to be discovered and developed. It is a high-affinity, selective ...
– High-affinity AR
full agonist
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 ago ...
''
in vitro
''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...
'', but very low activity ''
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
'' due to poor
pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
*
Andarine
Andarine (developmental code names GTx-007, S-4) is an investigational selective androgen receptor modulator (SARM) developed by GTX, Inc for treatment of conditions such as muscle wasting, osteoporosis and benign prostatic hypertrophy, using th ...
("S-4")
– Partial agonist, intended mainly for treatment of
benign prostatic hypertrophy
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 ...
*
LG-121071
LG121071 (or LGD-121071) is a selective androgen receptor modulator (SARM) developed by Ligand Pharmaceuticals that was first described in 1999 and was the first orally active nonsteroidal androgen to be discovered. It is a tricyclic quinolone ...
*
TFM-4AS-1
*
YK-11
Availability
In 2013, some supplement companies began selling various SARMs as supplements, in purported violation of both the Food and Drug Administration's
Dietary Supplement Health and Education Act of 1994
The Dietary Supplement Health and Education Act of 1994 ("DSHEA"), is a 1994 statute of United States Federal legislation which defines and regulates dietary supplements. Under the act, supplements are regulated by the FDA for Good Manufacturing P ...
(DSHEA) and the intellectual rights of the patent holders of the compounds. In 2017 it was found that many of the supplements being sold claiming to be SARMs do not actually contain the chemical in question. In reality, only 52% of the products contained any traces of SARMs at all.
In October 2017, the Food and Drug Administration issued warning letters to three supplement companies notifying them that SARMS are classed as unapproved drugs and can cause potential adverse side effects associated including cardiovascular and liver damage.
Use in sports
In 2015, quarterback of the
Florida Gators
The Florida Gators are the intercollegiate athletic teams that represent the University of Florida, located in Gainesville. The University of Florida, its athletic program, its alumni and its sports fans are often collectively referred to as t ...
,
Will Grier
William Grier (born April 3, 1995) is an American football quarterback for the Dallas Cowboys of the National Football League (NFL). He played college football at Florida and West Virginia and was drafted by the Carolina Panthers in the third ro ...
, allegedly tested positive for
Ligandrol
Ligandrol (VK5211, LGD-4033) is a novel nonsteroidal oral selective androgen receptor modulator (SARM) for treatment of conditions such as muscle wasting and osteoporosis, discovered by Ligand Pharmaceuticals and under development by Viking Thera ...
, a claim that the University of Florida denies.
In 2017,
Joakim Noah
Joakim Simon Noah ( ; born February 25, 1985) is an American-born French-Swedish former professional basketball player. He played college basketball for the Florida Gators, winning back-to-back NCAA championships in 2006 and 2007. The Chicago B ...
was banned for twenty games by the NBA for testing positive for Ligandrol.
Sean O'Malley, an American mixed martial artist who competes in the Bantamweight division of Ultimate Fighting Championship, was temporarily suspended by the Nevada State Athletic Commission in June 2019 after his sample tested positive for
Enobosarm
Enobosarm, also known as ostarine or MK-2866, is an investigational selective androgen receptor modulator (SARM) developed by GTx, Inc. for the treatment of conditions such as muscle wasting and osteoporosis, formerly under development by Merc ...
ahead of his fight against Marlon Vera at UFC 239 on July 6 in Las Vegas.
In July 2019, tennis player Beatriz Haddad Maia from Brazil received a provisional suspension after she tested positive for selective androgen receptor modulators.
Shayna Jack, an Australian swimmer, was forced to withdraw in July 2019 from the national squad before the world championships in Gwangju, South Korea after she tested positive for Ligandrol.
The British men's 4x100 relay team was stripped of their 2021 Tokyo Olympic silver medal after CJ Ujah tested positive for two SARMs after the race. The banned substances discovered in his system were enobosarm (Ostarine), and S-23.
See also
*
Selective receptor modulator
In the field of pharmacology, a selective receptor modulator or SRM is a type of drug that has different effects in different tissues. A SRM may behave as an agonist in some tissues while as an antagonist in others. Hence selective receptor modu ...
*
Selective estrogen receptor modulator
Selective estrogen receptor modulators (SERMs), also known as estrogen receptor agonist/antagonists (ERAAs), are a class of drugs that act on the estrogen receptor (ER). A characteristic that distinguishes these substances from pure ER agonists a ...
*
Selective progesterone receptor modulator
A selective progesterone receptor modulator (SPRM) is an agent that acts on the progesterone receptor (PR), the biological target of progestogens like progesterone. A characteristic that distinguishes such substances from full receptor agonists (e ...
*
Selective glucocorticoid receptor agonist
Selective glucocorticoid receptor modulators (SEGRMs) and selective glucocorticoid receptor agonists (SEGRAs) formerly known as dissociated glucocorticoid receptor agonists (DIGRAs) are a class of experimental drugs designed to share many of th ...
References
{{Androgen receptor modulators
World Anti-Doping Agency prohibited substances