Selective androgen receptor modulator

Structure of testosterone

As previously mentioned, the purpose of research in relation to SARMs is to replace testosterone supplementation in disease treatment with selective androgen receptor molecules.[5] 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.[5] 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.

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.[6] Although the exact mechanisms still remain unclear, tissue specificity and complexity of the pathway is known to dictate the transcriptional and cellular response.[5]

Structure of RAD-140[7]

There has been extensive research on selective estrogen receptor modulators (SERMs) such as tamoxifen, 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.[5] 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 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; a novel SARM, NEP28 has been studied and found to increase the upregulation of neprilysin which suppresses the plaques.[5] Theoretically, diseases such as Duchenne muscular dystrophy 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 is a response to a disease state or it’s therapy, SARMs have the potential to reverse or prevent this response while having a minimal effect based on several studies performed on mice. As of 2020, there was a clinical trial using enobosarm as a co-therapy with pembrolizumab for the treatment of AR positive metastatic triple negative breast cancer.

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.

MK-2866 also known as Ostarine or Enobosarm

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.[20] In 2017 it was found that many of the supplements being sold claiming to be SARMs do not actually contain the chemical in question.[21] In reality, only 52% of the products contained any traces of SARMs at all.[22]

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.[23]

In 2015, quarterback of the Florida Gators, Will Grier, allegedly tested positive for Ligandrol, a claim that the University of Florida denies.[24]

In 2017, Joakim Noah was banned for twenty games by the NBA for testing positive for Ligandrol.[25]

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 ahead of his fight against Marlon Vera at UFC 239 on July 6 in Las Vegas. [26]

In July 2019, tennis player Beatriz Haddad Maia from Brazil received a provisional suspension after she tested positive for selective androgen receptor modulators. [27]

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. [28]

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.[29]

• Selective receptor modulator
• Selective estrogen receptor modulator
• Selective progesterone receptor modulator
• Selective glucocorticoid receptor agonist