S4 or Ostarine: what is the difference

S4 (andarine) and Ostarine (enobosarm) are “relatives” from the same laboratory: both are nonsteroidal SARMs of the arylpropionamide series, developed by the group of James Dalton and the company GTx. Yet their paths diverged: Ostarine reached large clinical studies, while the development of andarine was stopped at early stages. The editorial team examines how these substances differ.

Common origin

In the late 1990s, researchers at the University of Tennessee, working with molecules related to the antiandrogens bicalutamide and hydroxyflutamide, found that small changes in structure turn an androgen receptor antagonist into an agonist. This gave rise to the series of arylpropionamide SARMs to which both andarine and enobosarm belong.

Andarine received the laboratory designations S-4 and GTx-007. It became one of the first molecules of the class for which tissue selectivity was demonstrated in animal models: an anabolic effect in muscle and bone with a weaker effect on the prostate and seminal vesicles.

Enobosarm (GTx-024, known in sports circles as Ostarine or MK-2866) appeared later in the same program. It was chosen for clinical development as a candidate with better pharmacokinetic properties and an acceptable tolerability profile.

This kinship explains why the two substances are often sold side by side and credited with similar effects. But it is precisely the details — pharmacokinetics, adverse events and the volume of data — that make them different.

Pharmacological differences

Both molecules bind to the androgen receptor and are not substrates of 5α-reductase or aromatase, i.e. they are not converted into DHT or estradiol. This is a general feature of nonsteroidal SARMs that distinguishes them from testosterone and its derivatives.

In preclinical work andarine is described as a partial androgen receptor agonist. In a classic study on castrated rats (Gao et al., 2005) it restored muscle mass and strength, reduced bone loss and fat mass, while its effect on the prostate was much weaker than that of dihydrotestosterone. The pharmacokinetics of andarine in rats were described by the Kearbey group (2004): the substance was well absorbed when taken orally.

Enobosarm is a fuller agonist in muscle tissue with a longer half-life in humans, which allowed it to be taken once a day in clinical studies. That is precisely why it, rather than andarine, was chosen for muscle-wasting treatment programs.

So the main pharmacological difference lies in the degree of agonism and in pharmacokinetics. For andarine there are no reliable data on its behavior in the human body; for enobosarm such data have been published within clinical studies.

Evidence base

For Ostarine the results of randomized phase II studies have been published. In healthy elderly men and postmenopausal women, 12 weeks of 3 mg per day increased lean mass and improved indicators of physical function (Dalton et al., 2011). In patients with cancer cachexia, 1 and 3 mg per day also increased lean mass compared with baseline (Dobs et al., 2013). Phase III studies in lung cancer did not meet all primary endpoints, and the drug was not approved.

For andarine the main body of data comes from studies in rats. There are no full published clinical trials of effectiveness in humans. Everything circulating online about the “dosing” of andarine comes from users’ own experiments.

This difference is fundamental for assessing safety. When a substance goes through clinical studies, side effects are recorded systematically, with laboratory monitoring. When the source of information is forums, one can learn only about the effects a person noticed and chose to describe.

It is also worth remembering that even for Ostarine the clinical data concern short courses, specific doses and specific patient groups. Transferring them to young athletes with higher doses and a product of unknown origin is incorrect.

Side-effect profile

The best-known “calling card” of andarine is reports of vision disturbances: a yellowish tinge to color perception and impaired dark adaptation. It is important to say honestly: these data are mostly anecdotal, drawn from user reports, and the mechanism has not been established in controlled studies. Yet the very frequency of such reports makes them a signal that should not be ignored.

For Ostarine, clinical studies recorded a dose-dependent decrease in HDL and sex hormone levels, and outside of studies cases of drug-induced liver injury have been described in people who used SARMs on their own.

The shared risks of both substances are suppression of the hypothalamic–pituitary–gonadal axis (lowering of LH, FSH and one’s own testosterone), unfavorable changes in the lipid profile and potential virilization in women. The nonsteroidal structure does not cancel out the fact that both substances are androgen receptor agonists.

A separate risk remains product quality. An analysis of online products sold as SARMs (Van Wagoner et al., 2017) showed that a significant share of them did not match the label in composition or content.

• Andarine:reports of vision disturbances, absence of clinical data.
• Ostarine:lowered HDL, hormone suppression, described cases of liver injury.
• Both:product adulteration, ban in sport, risk of virilization in women.

Legal status

Andarine and Ostarine belong to class S1.2 “Other anabolic agents” of the WADA Prohibited List and are banned for athletes at all times. Ostarine ranks among the top SARMs by number of positive samples, in particular because of contaminated supplements.

Neither substance is a registered medicine. Regulators, including the FDA, have repeatedly warned that selling SARMs as dietary supplements is illegal and that their use may be associated with serious health risks.

The label “for research, not for human consumption” on the packaging is a legal device used by the seller, not a guarantee of quality or safety. Such products do not undergo pharmaceutical manufacturing control.

For athletes the principle of strict liability applies: detection of a substance in a sample is a violation regardless of intent.

Editorial conclusions

S4 and Ostarine are chemical “brothers” from the same development program, but with different fates. Ostarine has clinical data on modest effectiveness and documented side effects; andarine remained at the preclinical level and is known chiefly for reports of vision disturbances.

Neither substance is approved for treatment, both are banned in sport, and both suppress one’s own hormonal system. If you are worried about loss of muscle mass or low testosterone, start with lab tests and a consultation with an endocrinologist.

The editorial team also recommends the materials “S4 vs Ostarine: what to choose and for whom”, an overview of the mechanism of action of SARMs and an article on the tests for monitoring hormonal status.

References

1. Gao W, Reiser PJ, Coss CC, et al. Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats. Endocrinology. 2005;146(11):4887–4897.
2. Kearbey JD, Wu D, Gao W, et al. Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator. Xenobiotica. 2004;34(3):273–280.
3. Dalton JT, Barnette KG, Bohl CE, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean body mass and physical function in healthy elderly men and postmenopausal women: results of a double-blind, placebo-controlled phase II trial. J Cachexia Sarcopenia Muscle. 2011;2(3):153–161.
4. Dobs AS, Boccia RV, Croot CC, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14(4):335–345.
5. Narayanan R, Coss CC, Dalton JT. Development of selective androgen receptor modulators (SARMs). Mol Cell Endocrinol. 2018;465:134–142.
6. Van Wagoner RM, Eichner A, Bhasin S, et al. Chemical composition and labeling of substances marketed as selective androgen receptor modulators and sold via the internet. JAMA. 2017;318(20):2004–2010.
7. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; чинна редакція.