LGD-4033. By Yikrazuul (Own work) [Public domain], via Wikimedia Commons

LGD-4033 is a selective androgen receptor modulator (SARMs). It has a high affinity (approximately 1nM) for the receptor, and has attracted much interest in some areas of medical research¹. SARMs are associated with potential in the treatment of age-related decreases in muscle mass and function and in bone density¹. These effects may be due to decreases in circulating levels of androgen-receptor agonists (e.g. testosterone and its analogs found in the body) and/or degradations in the receptor protein or its regulators (which are proteins that are required to form a complex with the androgen receptor and ensure that it carries out its functions, which are mainly binding to certain locations on DNA following activation) over time².

Age-related bone and muscle loss (or osteopenia and sarcopenia respectively) are associated with reductions in mobility, function and life quality¹. They may also be associated with conditions such as some types of cancer, kidney failure and chronic obstructive pulmonary disease¹. SARMs may also have potential in the treatment of muscle loss related to causes other than aging. These may include hypogonadism, recovering from burns, osteoporosis or cancer³. Some researchers assert that these compounds have additional therapeutic applications related to conditions and applications such as depression, anemia, wound healing and benign prostate growths⁴.

However, many SARMs are testosterone analogs (i.e. steroids). These are linked to prostate disease and other adverse effects. LGD-4033, on the other hand, binds to the androgen receptor, but is not a steroid¹. Therefore, it may have positive effects on muscle and bone mass retention, without adverse effects on other organs and systems. It has demonstrated these effects in animal studies, without reports of damage or diseases of the prostate in males¹. Another advantage of LGD-4033 and other similar SARMs is that they may be administered orally¹. LGD-4033 and other SARMs interact with the ligand-binding domain (LBD) of the androgen receptor, but in a different manner to natural androgens².

LGD-4033 is associated with improvements in the bending strength, density and growth of bone in preclinical studies¹. Other similar nonsteroidal SARMs have demonstrated similar effects on bone and muscle, and also on sexual function, in rats, compared to control animals⁵. Administration with these has also been associated with the prevention of prostate tumor growth in rats, and a significant reduction in the rate of tumor growth in mice transfected with human prostate cancer cells⁶.

Some models of age-related bone loss (or osteopenia) are achieved through orchidectomy (or castration) of older male rats⁶. The administration of non-steroidal SARMs resulted in significantly reduced rates of bone volume and mineral density loss compared to these values in control orchidectomized rats⁶. This intervention was also associated with improvements in the conservation of lean body mass in orchidectomized rats⁶. The administration of another non-steroidal SARM significantly increased muscle strength in a mouse model of Duchenne's muscular dystrophy⁷. The SARM also had beneficial effects on the running ability of these mice, whereas similar animals in control groups or groups receiving a steroid instead (nandrolone or alpha-methylprednisolone), exhibited significant increases in fatigue⁷.

 References: 

1. 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. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences. 2013;68(1):87-95.

2. Narayanan R, Mohler ML, Bohl CE, Miller DD, Dalton JT. Selective androgen receptor modulators in preclinical and clinical development. Nuclear Receptor Signaling. 2008;6:e010.

3. Segal S, Narayanan R, Dalton JT. Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery. Expert opinion on investigational drugs. 2006;15(4):377-387.

4. Omwancha J, Brown TR. Selective androgen receptor modulators: in pursuit of tissue-selective androgens. Current opinion in investigational drugs (London, England : 2000). 2006;7(10):873-881.

5. Miner JN, Chang W, Chapman MS, et al. An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate. Endocrinology. 2007;148(1):363-373.

6. Allan G, Lai MT, Sbriscia T, et al. A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats. The Journal of steroid biochemistry and molecular biology. 2007;103(1):76-83.

7. Cozzoli A, Capogrosso RF, Sblendorio VT, et al. GLPG0492, a novel selective androgen receptor modulator, improves muscle performance in the exercised-mdx mouse model of muscular dystrophy. Pharmacological research : the official journal of the Italian Pharmacological Society. 2013;72:9-24.