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 which is under development for the treatment of androgen receptor-positive breast cancer in women and for improvement of body composition in people taking GLP-1 receptor agonists like semaglutide. It was also under development for a variety of other indications, including treatment of cachexia, Duchenne muscular dystrophy, muscle atrophy or sarcopenia, and stress urinary incontinence, but development for all other uses has been discontinued. Enobosarm was evaluated for the treatment of muscle wasting related to cancer in late-stage clinical trials, and the drug improved lean body mass in these trials, but it was not effective in improving muscle strength. As a result, enobosarm was not approved and development for this use was terminated. Enobosarm is taken by mouth.
Known possible side effects of enobosarm include headache, fatigue, anemia, nausea, diarrhea, back pain, adverse lipid changes like decreased high-density lipoprotein cholesterol levels, changes in sex hormone concentrations like decreased testosterone levels, elevated liver enzymes, and liver toxicity, among others. The potential masculinizing effects of enobosarm, for instance in women, have largely not been evaluated and are unknown. The potential adverse effects and risks of high doses of enobosarm are also unknown. Enobosarm is a nonsteroidal SARM, acting as an agonist of the androgen receptor, the biological target of androgens and anabolic steroids like testosterone and dihydrotestosterone. However, it shows dissociation of effect between tissues in preclinical studies, with agonistic and anabolic effects in muscle and bone, agonistic effects in breast, and partially agonistic or antagonistic effects in the prostate gland and seminal vesicles. The AR-mediated effects of enobosarm in many other androgen-sensitive tissues are unknown.
Enobosarm was first identified in 2004 and has been under clinical development since at least 2005. It is the most well-studied SARM of all of the agents that have been developed. According to GTx, its developer, a total of 25 clinical studies have been carried out on more than 1,700 people involving doses from 1 to 100mg as of 2020. However, enobosarm has not yet completed clinical development or been approved for any use. As of November 2023, it is in phase 3 clinical trials for the treatment of breast cancer and is in phase 2 studies for improvement of body composition in people taking GLP-1 receptor agonists. Enobosarm was developed by GTx, Inc., and is now being developed by Veru, Inc.
Aside from its development as a potential pharmaceutical drug, enobosarm is on the World Anti-Doping Agency list of prohibited substances and is sold for physique- and performance-enhancing purposes by black-market Internet suppliers. In one survey, 2.7% of young male gym users reported using SARMs. In addition, a London wastewater analysis found that enobosarm was the most abundant "pharmaceutical drug" detected and was more prevalent than "classical" recreational drugs like MDMA and cocaine. Enobosarm is often used in these contexts at doses greatly exceeding those evaluated in clinical trials, with unknown effectiveness and safety. Many products sold online that are purported to be enobosarm either contain none or contain other unrelated substances. Social media has played an important role in facilitating the widespread non-medical use of SARMs.
Medical uses
Enobosarm is not approved for any medical use and is not available as a licensed pharmaceutical drug as of 2023.Side effects
General side effects that have been reported with enobosarm in clinical trials include headache, fatigue, anemia, nausea, diarrhea, and back pain.Enobosarm has shown dose-related adverse effects on serum lipids, sex hormone and gonadotropin levels, and carrier protein levels in clinical trials. It decreases HDL cholesterol levels, reducing them dose-dependently by 17% at a dose of 1mg/day and by 27% at a dose of 3mg/day. Decreases in total cholesterol levels and in triglyceride levels have also been seen, whereas LDL cholesterol levels are unchanged. In healthy elderly men, total testosterone levels decreased significantly at doses of 1 and 3mg/day, whereas levels of free testosterone, dihydrotestosterone, estradiol, luteinizing hormone, and follicle-stimulating hormone did not change significantly at doses up to 3mg/day. In healthy postmenopausal women, LH and FSH decreased significantly only at the 3mg/day dose, whereas levels of total testosterone, free testosterone, DHT, and estradiol did not clearly change relative to placebo. SHBG levels were lowered at doses of 1 to 3mg/day, decreasing dramatically by 61% in men and by 80% in women at the 3mg/day dose. For comparison, testosterone enanthate by intramuscular injection at a highly supraphysiological dose of 600mg/week resulted in only a 31% decrease in SHBG levels. Despite the large changes in SHBG levels, levels of free testosterone did not significantly change in either men or women. Small but significant increases in hemoglobin and hematocrit, and small but significant decreases in fasting blood glucose, insulin levels, and insulin resistance, have been observed with enobosarm at 3mg/day.
In small short-term clinical trials in healthy elderly or postmenopausal women, enobosarm at doses ranging from 0.1 to 3mg/day had mixed effects on sebum production and did not increase body hair growth or cause hirsutism. These effects are measures of androgenic action in skin and hair follicles. In the first study, at doses of 0.1 to 3mg/day, there were no significant changes relative to placebo in sebum tape scores with enobosarm and there were no consistent increases in Ferriman–Gallwey score, with most women having no change in score or a decreased score and only one having an increase in score. In the second study, which employed 3mg/day enobosarm, there was a significant 1.25-fold increase in sebum production from baseline and a significant 1.5-fold increase in sebum production relative to placebo. No differences in sebaceous gland volume were apparent upon histological examination in this study.
At doses ranging from 0.1 to 18mg/day in clinical trials, enobosarm has been associated with elevated liver enzymes in subsets of individuals. Rates of elevated liver enzymes or of elevated alanine aminotransferase levels have ranged from 0.6% to 33% in these trials. Liver enzyme elevations with enobosarm are often transient and resolve spontaneously. However, markedly elevated liver enzymes have occasionally occurred with enobosarm in clinical trials and have necessitated discontinuation. There have been several published case reports of hepatotoxicity with enobosarm as of 2023. Between 2020 and 2022, there has been a rapid increase in reported cases of liver toxicity with SARMs. The hepatotoxicity with SARMs may be related to their resistance to hepatic metabolism, analogously to the case of 17α-alkylated anabolic steroids.
SARMs are often advertised and sold on the Internet at doses higher than have been described in the literature. Sometimes doses are recommended as several-fold or more greater than the doses used in clinical trials, or seemingly arbitrary doses are advised. For instance, enobosarm has been provided at doses of greater than or equal to 20mg per serving and recommended by bodybuilders and fitness enthusiasts at doses of 10 to 30mg/day, relative to the most widely assessed highest dose in clinical trials of 3mg/day—an up to 10-fold difference. SARMs, particularly when used at high or excessive doses for prolonged periods of time, may result in substantial suppression of endogenous sex hormones like testosterone and estradiol, in turn producing widespread unintended deleterious effects on physiological function. As examples, SARMs may produce potent anabolic effects with deficiency in important androgenic effects, may result in estrogen deficiency with consequences like bone loss among others, and, due to suppression of the hypothalamic–pituitary–gonadal axis, may cause infertility.
Androgens and anabolic steroids like testosterone, dihydrotestosterone, nandrolone, and oxandrolone, which are full agonists of the androgen receptor, produce virilizing or masculinizing effects like increased sebum production and acne, increased body hair growth, scalp hair loss, voice deepening, increased muscle mass, android fat redistribution, skeletal changes like widening of the shoulders and skull/facial changes, and genital growth both in males and females. SARMs, which are tissue-selective mixed or partial agonists of the androgen receptor, are largely uncharacterized in terms of their masculinizing effects, but are likely to produce many of the same effects. SARMs specifically may be expected to retain masculinizing effects like increased muscle mass and bone changes, while possibly having reduced virilizing effects in certain other areas like androgenic skin and hair changes. Anecdotal reports of masculinization with SARMs in women exist in online forums.
The United States Food and Drug Administration has cautioned that SARMs could have serious adverse effects ranging from risk of heart attack to stroke and liver damage and has warned against their use in bodybuilding products.