User:Katievans/sandbox

Selective Androgen Receptor Modulators or SARMs are a novel class of androgen receptor ligands. In the late 1990s researchers were successful in finding the first nonsteroidal SARM, it was the discovery of an analog to bicalutamide; the search for these new drug candidates was driven by the undesirable side effects that come with androgenic-anabolic steroids. They are intended to have the same kind of effects as androgenic drugs, such as anabolic-androgenic steroids, but be more selective in their action. SARMs signify a novel class of tissue-selective androgens with an unknown clinical application that could benefit the treatment of diseases.

Contents

 * 1Comparison to testosterone
 * 1.1Selectivity in men
 * 1.2Selectivity in women
 * 2Examples
 * 2.1Clinical testing
 * 2.2Pre-clinical
 * 2.3Abandoned drug candidates
 * 3Availability
 * 3.1Use in sports
 * 4See also
 * 5References

Comparison to testosterone[edit]
Structure of testosterone Currently used androgens for male hormone replacement therapy are typically injectable or skin delivery formulations of testosterone or testosterone esters. Injectable forms of testosterone esters (such as testosterone enanthate, propionate, or cypionate) produce undesirable fluctuations in testosterone blood levels, with overly high levels shortly after injection and overly low afterward. Skin patches do provide a better blood level profile of testosterone, but skin irritation and daily application still limit their usefulness.

SARMs provide the ability to design molecules that can be delivered orally, but that selectively target the androgen receptors in different tissues differently. The goal of research in this area is to allow a customized response: Tissues that are the target of the therapy will respond as they would to testosterone; other tissues where undesirable side-effects are produced will not.

None of the SARMs yet developed are truly selective for anabolic effects in muscle or bone tissues without producing any androgenic effects in tissues such as the prostate gland; however, several nonsteroidal androgens show a ratio of anabolic to androgenic effects of greater than 3:1 and up to as much as 90:1 (RAD-140), compared to testosterone, which has a ratio of 1:1. Structure of RAD-140 Research is continuing into more potent and selective SARMs, as well as optimizing characteristics such as oral bioavailability and increased half-life in vivo, and seeing as the first tissue-selective SARMs were only demonstrated in 2003, the compounds tested so far represent only the first generation of SARMs and future development may produce more selective agents compared to those available at present.

CONDENSE:

As previously mentioned, the purpose of research in relation to SARMs is to replace testosterone supplementation in disease treatment with selective androgen receptor molecules. This is due to the fact that testosterone supplementation can have adverse effects on patients, which are detailed on the testosterone 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. (CITE Bhasin). *Maybe insert how it has been studied in relation to diseases*

However, nonsteroidal SARMs purposefully differ in their mechanism of action, as the 5-α reduction or aromatizaion seen in testosterones mechanism is not present in these molecules. (might need to reword) --> transition into mechanism section.

want to delete (most of the section above is about men anyway) Selectivity in men[edit]
For example, if the target is bone growth in elderly men with osteopenia or osteoporosis, but with no overt signs of hypogonadism, a SARM targeting bone and muscle tissue but with lesser activity on the prostate or testes would be more desirable.

want to delete (suggestive) Selectivity in women[edit]
A SARM for women  would ideally stimulate bone retention, or libido and other function that androgens can influence, without negative side-effects such as development of male sex characteristics (virilization), increased LDL/HDL ratios, liver dysfunction, and so forth.

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. (CITE txtbk)

Something about human tests / side effects
As of 2020, only four SARMs have been clinically tested on humans; Ostarine, LGD-4033, GSK2881078, and PF-06260414.

Ostarine
Ostarine also known as Enobosarm, GTx-024 and MK-2866 has a significant amount of anabolic activity relative to androgenic activity, which shows potential in the treatment of diseases that negatively effect muscles and bones (MPMD cite). 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 effected 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.

Clinical testing[edit]
MK-2866 also known as Ostarine or Enobosarm


 * Enobosarm (Ostarine, MK-2866, GTx-024, S-22) – (suggestive) One of the most popular SARMs, affects both muscle and bone, intended mainly for osteoporosis but also general treatment for andropause and reversing muscle sarcopenia in the elderly and for cachexia in cancer patients.
 * BMS-564,929 – Mainly affects muscle growth, intended as general treatment for symptoms of andropause
 * LGD-4033 (Ligandrol) – pharmacological profile similar to that of enobosarm.

Pre-clinical[edit]

 * AC-262,356
 * LGD-2226 – Affects both muscle and bone
 * LGD-3303
 * S-40503 – 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[edit]

 * Acetothiolutamide – High-affinity AR full agonist in vitro, but very low activity in vivo due to poor pharmacokinetics
 * Andarine ("S-4") – Partial agonist, intended mainly for treatment of benign prostatic hypertrophy
 * LG-121071
 * TFM-4AS-1
 * YK-11

Availability[edit]
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 (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[edit]
In 2015, quarterback of the Florida Gators, Will Grier, allegedly tested positive for Ligandrol, a claim that the University of Florida denies.

In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for Ligandrol.

Sean O'Malley, the 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 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, the 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.

See also[edit]

 * Selective receptor modulator
 * Selective estrogen receptor modulator
 * Selective progesterone receptor modulator
 * Selective glucocorticoid receptor agonist


 * 1) Thevis, M; Schanzer, W. (2010). Doping in Sports. Vol. 195. Springer. pp. 100–120. ISBN  978-3-540-79087-7.
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 * 31) ^ "Shayna Jack reveals banned substance Ligandrol was behind her doping suspension from swimming". July 28, 2019. Retrieved 19 March 2020.