Both substances — RAD-140 and ligandrol (LGD-4033) — are agonists of the androgen receptor, but researchers studied them in completely different tissues: ligandrol — in muscles, RAD-140 — in the brain and breast tumors. The editors break down what this difference says about the mechanism of action, what side effects are documented, and where the data ends and speculation begins.
Common mechanism: androgen receptor agonism
RAD-140 and LGD-4033 bind to the ligand-binding domain of the androgen receptor and convert it into an active conformation. Next, as in the case of testosterone, the receptor moves into the nucleus of the cell and regulates gene expression. In skeletal muscles, this is manifested by an increase in protein synthesis, in bones by an effect on remodeling.
Both compounds are nonsteroidal, so they do not undergo the transformations characteristic of testosterone: 5-alpha-reductase does not turn them into DHT, and aromatase does not turn them into estradiol. This removes two important mechanisms that determine the effects of testosterone in the prostate, skin, adipose tissue, and bone.
The tissue selectivity of SARM is also explained by how exactly the shape of the receptor changes after binding the ligand and which auxiliary proteins (coactivators) it attracts in one or another tissue. Different SARMs can produce different "conformational signatures", so their profiles are not necessarily identical, even if the target is the same.
However, in the hypothalamus and pituitary gland, both substances act like normal androgens: they signal an "excess" of the hormone and inhibit the production of gonadotropins. This is why suppressing your own testosterone is an expected effect of any sufficiently active SARM.
RAD-140: tissue effects in preclinical models
In the original publication by Miller et al. (2011), RAD-140 in rodents and monkeys increased muscle mass, while stimulation of the prostate and seminal vesicles was weaker than that from testosterone. Such a profile gave reason to call the compound "selective". However, animal results often do not translate directly to humans, either quantitatively or qualitatively.
A study by Jayaraman et al (2014) showed that RAD-140 protected neurons from death in culture and in a kainic acid injury model in rats. The authors associated this effect with the activation of the androgen receptor and cell survival signaling pathways. There are no clinical data on this effect in humans.
In androgen and estrogen receptor-positive breast cancer models (Yu et al., 2017), RAD-140 inhibited tumor growth. The mechanism, according to the authors, was that the activated androgen receptor inhibited the expression of genes that depend on the estrogen receptor. That is, in this tissue, AR-agonism worked as a "brake" for estrogen signals.
This fact is interesting from a scientific point of view, but for a person considering RAD-140 as a training agent, it means only one thing: the compound has pronounced effects in tissues far from the muscles. Almost nothing is known about the consequences of such effects in healthy people, especially in women.
LGD-4033: what human studies have shown
In a randomized, placebo-controlled trial by Basaria et al. (2013), healthy men received 0.1 for 21 days; 0.3 or 1 mg of LGD-4033 per day. The compound had a long half-life and accumulated with daily intake. In the 1 mg group, fat-free mass increased compared to placebo; fat mass did not change significantly.
At the same time, a dose-dependent decrease in total testosterone, SHBG, HDL and triglycerides, as well as a decrease in FSH, were observed. PSA and hematocrit levels did not change significantly, but the short duration of the study does not allow conclusions about long-term safety for the prostate or blood. After withdrawal, the indicators returned to baseline during the observation period.
The authors emphasized that the study was small and short. In a phase II study in elderly patients after hip fracture (like VK5211), the company reported gains in lean mass, but that's a different population with different treatment goals.
So for LGD-4033, we have limited but real data on what happens to human hormones and lipids. This allows us to see an important pattern: even in microgram and low milligram doses, SARMs are able to significantly change the endocrine system.
Side effects: comparison
The editors summarized the documented and theoretically expected side effects. The RAD-140 column has more "not studied" marks - this is not a safety sign, but a reflection of a lack of data.
| System | RAD-140 | LGD-4033 |
|---|---|---|
| Gonadal axis | Expected suppression of LH/FSH and testosterone (mechanistically); there are no controlled data in healthy people | Dose-dependent ↓ testosterone, SHBG, FSH in 21 days |
| Lipids | Not studied in controlled studies | Dose-dependent ↓ HDL |
| Liver | Elevation of enzymes in oncological research; descriptions of cases of damage | Descriptions of cases of cholestatic damage |
| Brain, mood | Preclinical effects on neurons; not studied in humans | Not studied |
| Women | Studied only in oncology; the risk of virilization has not been assessed | The risk of virilization has not been assessed |
| Long-term consequences | Unknown | Unknown |
Liver injury associated with SARMs is the most frequent topic in clinical case reports. It is usually cholestasis with jaundice and itching that develops after a few weeks of use. Flores et al (2020) described such cases and emphasized the importance of taking a history of “sports supplements”.
The HDL lowering documented for LGD-4033 and other SARMs is considered a class effect of oral androgen receptor agonists. There is no reason to believe that RAD-140 is an exception, although there are no direct measurements in healthy humans.
Suppression of the gonadal axis may continue even after cessation of use. This is especially important for men who are planning to father a child: a violation of spermatogenesis may not be felt subjectively and can be detected only during an examination.
How doctors assess risks
If the patient reports SARM use, the doctor first of all finds out the symptoms: jaundice, dark urine, itching, pain in the right hypochondrium, decreased libido, erectile dysfunction, mood changes. According to them and to the general condition, an examination is planned.
- Liver tests: ALT, AST, bilirubin, alkaline phosphatase, HGT.
- Hormonal profile: total and free testosterone, LH, FSH, HGH, estradiol if necessary.
- Lipidogram: HDL, LDL, triglycerides.
- Fertility: spermogram in men planning children.
The interpretation of the results is complicated by the fact that the patient often does not know exactly what he used: according to Van Wagoner (2017), the content of products often does not correspond to the label. Therefore, doctors evaluate not "RAD-140" or "ligandrol", but real changes in the body.
Independent "recovery" with the help of prescription drugs without a doctor is not advised: such interventions have their own risks, and the cause of violations may be different than it seems.
Editorial conclusion
RAD-140 and LGD-4033 have a common mechanism — androgen receptor agonism without conversion to DHT and estradiol. The differences are in which tissues and on which models they were studied.
RAD-140 has shown effects in muscle, neurons and breast tumors mainly in preclinical models. LGD-4033 has controlled human data showing increases in lean mass along with suppression of testosterone and lowering of HDL.
Liver damage has been described for both. The lack of data on RAD-140 makes its safety profile more unpredictable than better.
We recommend that you also read our articles "RAD-140 or Ligandrol: What's the Difference", "SARM vs Anabolic Steroids: Comparison of Mechanism of Action and Side Effects" and our article on liver tests for athletes.
References
- Miller CP, Shomali M, Lyttle CR, et al. Design, synthesis, and preclinical characterization of the selective androgen receptor modulator (SARM) RAD140. ACS Med Chem Lett. 2011;2(2):124â129.
- Jayaraman A, Christensen A, Moser VA, et al. Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats. Endocrinology. 2014;155(4):1398â1406.
- Yu Z, He S, Wang D, et al. Selective androgen receptor modulator RAD140 inhibits the growth of androgen/estrogen receptor-positive breast cancer models with a distinct mechanism of action. Clin Cancer Res. 2017;23(24):7608â7620.
- Basaria S, Collins L, Dillon EL, et al. The safety, pharmacokinetics, and effects of LGD-4033, a novel nonsteroidal oral, selective androgen receptor modulator, in healthy young men. J Gerontol A Biol Sci Med Sci. 2013;68(1):87â95.
- Flores JE, Chitturi S, Walker S. Drug-induced liver injury by selective androgen receptor modulators. Hepatol Commun. 2020;4(3):450â452.
- 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):2004â2010.
