ReviewSelective Androgen Receptor Modulators: Current Knowledge and Clinical Applications
Introduction
The androgen receptor (AR) belongs to the superfamily of steroid hormone nuclear receptors, and the binding of its endogenous ligands (ie, testosterone and dihydroxytestosterone [DHT]) modulates its function as a transcription factor.1 The effects of the interaction between the AR and androgens are complex and vary depending on sex, age, tissue type, and hormonal status. Although the AR is widely known for its role in male sexual development and maintenance, it also has important effects on bone density, strength, muscle mass, hematopoiesis, coagulation, metabolism, and cognition.2, 3
Testosterone and synthetic steroid hormones have found many applications in the clinical setting. One can broadly categorize their effects as anabolic (increased bone density, muscle mass) or androgenic (impaired fertility, virilization, acne). Despite the wide array of medical conditions that potentially could be addressed with the supplementation of steroid hormones, their therapeutic use is often curtailed owing to potential side effects, including erythrocytosis, prostate hypertrophy, hepatotoxicity, aromatization to estrogen, and testicular atrophy.4 The use of testosterone therapy in prostate cancer (PCa) is a topic of controversy and was debated in an article by Jannini et al.5 The authors conclude that PCa is indeed testosterone dependent. However, AR saturation in the prostate is thought to occur at subphysiologic serum testosterone levels (60–120 ng/dL). As such, increases in serum testosterone levels above this concentration are not expected to result in further AR activation and activity.6 There is no conclusive evidence demonstrating an increased risk of PCa in the setting of testosterone therapy. Of interest, Gravina et al7 demonstrated a significant reduction in the tumor growth of PCa cells in the setting of supraphysiologic intraprostatic testosterone concentrations.
Selective androgen receptor modulators (SARMs) are small-molecule drugs that can exert varying degrees of both agonist and antagonist effects on ARs in different tissues. Their actions can be understood by considering the selective estrogen receptor modulators (SERMs) that preceded them. One SERM widely used to treat breast cancer, tamoxifen, acts as an antagonist in the breast, an agonist in the bone, and a partial agonist in the uterus. The tissue-specific effects of these agents are precisely what makes them attractive, because they can be tailored to address specific medical conditions while minimizing off-target effects.
Basic laboratory experiments have sought to investigate and optimize the pharmacodynamic and pharmacokinetic properties of SARMs according to their desired site of action. SARMs have been chemically engineered to more specifically target AR function in certain tissues while minimizing off-target effects.8 There is minimal variation between AR structure, but the regulatory milieu of each tissue allows SARMs to possess relative tissue specificity. Animal models have been used to investigate the effect of SARMs on skeletal muscle in both eugonadal and hypogonadal rats.9 Animal models of muscular dystrophy have been used to investigate the use of SARMs in muscle pathology, demonstrating encouraging results.9, 10 SARMs have also been trialed as reversible hormonal contraceptives in rats.11 Although still preliminary studies, researchers have investigated the possible use of SARMs in Alzheimer’s disease, PCa, benign prostatic hyperplasia (BPH), and osteoporosis.12, 13, 14 SARMs have begun to be studied in the preclinical and clinical phases as treatment options for cancer-related cachexia, breast cancer, BPH, and hypogonadism.2, 15, 16 There are several ongoing Phase 1 and Phase 2 clinical trials investigating the use of SARMs.
In this review, we present the background, mechanisms, and current and future clinical applications of SARMs. We also consider the risks and benefits of SARMs and discuss their potential for misuse.
Section snippets
Methods
A literature review was performed in the PubMed/Medline database using the terms selective androgen receptor modulator, hypogonadism, cachexia, breast cancer, benign prostatic hyperplasia, and lean muscle mass. Both basic and clinical studies were included. Currently ongoing clinical trials listed on http://www.clinicaltrials.gov that are investigating SARMs were reviewed as well.
History of SARMS
An improved understanding of SERMs and their mechanisms of action in the 1990s, as well as the growing use of tamoxifen in the treatment of breast cancer, stimulated interest in analogous drugs to modulate the AR.17, 18 Several laboratories began working on identifying lead candidates and specific pharmacophores, with early work centered around a class of aryl-propionamides identified from hydroxyflutamide analogs in 1998.15 Over the past 20 years, the number of bioactive SARMs under
Biochemical and Basic Science Background
As demonstrated by the development and clinical use of SERMs such as tamoxifen, the key characteristic underlying the therapeutic potential of SARMs is their tissue specificity. While steroid hormone replacement therapy offers many benefits, it can be associated with a high rate of adverse effects (AEs), partly owing to widespread and non-specific activation of the AR in many different tissues. The most basic distinction in tissue selectivity lies between anabolic and androgenic effects of
Male Contraception
SARMs show promise for use as a method of male contraception in animals. Exogenous testosterone interferes with spermatogenesis via negative feedback on the hypothalamic–pituitary–gonadal (HPG) axis.11, 22 Chen et al11 demonstrated that administration of a SARM, C-6, markedly suppressed spermatogenesis and reduced peripheral testosterone levels while decreasing testicular and epididymal size. Similar experiments by Jones et al23 using a SARM, S-23, combined with estradiol benzoate, demonstrated
Conclusion
The AR is a complex signaling apparatus with important effects on tissue development, growth, and maintenance. Although steroid hormones have valuable clinical applications, their widespread activation of AR receptors gives rise to treatment-limiting side effects. Like the SERMs before them, SARMs and their tissue selectivity demonstrate the potential to revolutionize the treatment of many debilitating diseases. Depending on their chemical structure, SARMs can act as agonists, antagonists,
Statement of Authorship
Category 1 Conception and Design Zachary Solomon, Jorge Rivera Mirabal, Daniel Mazur, Taylor Kohn, Alexander Pastuszak
Acquisition of Data
Zachary Solomon, Jorge Rivera Mirabal
Analysis and Interpretation of Data
Zachary Solomon, Jorge Rivera Mirabal, Daniel Mazur, Taylor Kohn, Larry Lipshultz, Alexander Pastuszak
- (a)
Drafting the Article
Zachary Solomon, Jorge Rivera Mirabal, Daniel Mazur, Taylor Kohn, Alexander Pastuszak
- (b)
Revising It for Intellectual Content
Zachary Solomon, Jorge Rivera Mirabal, Alexander Pastuszak,
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Conflicts of Interest: The authors report no conflicts of interest.
Funding: A.W.P. is a National Institutes of Health K08 Scholar supported by a Mentored Career Development Award (K08DK115835-01) from the National Institute of Diabetes and Digestive and Kidney Diseases. This work is also supported in part through a Urology Care Foundation Rising Stars in Urology Award (to A.W.P.).