Endocrine Abstracts

Testosterone supplementation increases whole body and appendicular skeletal muscle mass, maximal voluntary muscle strength, and leg power. However, concerns about the long term risks of prostate and cardiovascular disorders in older men treated with testosterone have encouraged efforts to develop selective androgen receptor modulators (SARM) that increase skeletal muscle mass and improve physical function without the adverse effects on prostate and cardiovascular outcomes. These nonsteroidal SARMs do not serve as substrates for CYP19 aromatase or 5α-reductase, act as full agonists in muscle and bone and as partial agonists in prostate and seminal vesicles. The differing interactions of steroidal and nonsteroidal compounds with the AR may at least partially contribute to their unique pharmacologic actions. Bicalutamide adapts a greatly bent conformation in the AR. Although A-ring and amide bond of the bicalutamide molecule overlaps the steroidal plane, the B-ring of the molecule folds away from the plane, pointing to the top of the ligand binding pocket (LBP), which forms a unique structural feature of this class of ligands. These H bonding interactions are believed to be critical for high binding affinity. Structural modifications of aryl propionamide analogs bicalutamide and hydroxyflutamide led to the discovery of the first generation of SARMs. The first generation SARM pharmacophores can be classified into four categories: aryl-propionamide, bicyclic hydantoin, quinoline, and tetrahydroquinoline analogs.

The mechanistic basis of the tissue selective actions of SARMs is poorly understood, although several mechanisms have been proposed. Ligand binding induces specific conformational changes in the ligand binding domain, which could modulate surface topology and subsequent protein–protein interactions between AR and other coregulators involved in genomic transcriptional activation or cytosolic proteins involved in nongenomic signaling. Differences in ligand-specific receptor conformation and protein–protein interactions could result in tissue-specific gene regulation, due to potential changes in interactions with ARE, coregulators or transcription factors.

It is generally believed that the downstream signaling mechanisms that mediate the anabolic effects of SARMs on the skeletal muscle are similar to those of testosterone. Testosterone induces hypertrophy of both type I and type II fibers and an increase in the number of satellite cells. Testosterone promotes the differentiation of mesenchymal, multipotent cells into myogenic lineage and inhibits their differentiation into adipogenic lineage. Testosterone and DHT regulate mesenchymal multipotent cell differentiation by promoting the association of AR with β-catenin and translocation of the AR-β-catenin complex into the nucleus, resulting in activation of TCF-4. The activation of TCF-4 modulates a number of Wnt-regulated genes that promote myogenic differentiation and inhibit adipogenic differentiation. The effects of testosterone on myogenic differentiation are mediated through an AR pathway. Testosterone increases fractional muscle protein synthesis and improves the reutilization of amino acids by the muscle. We do not know whether conversion of testosterone to DHT is required for mediating androgen effects on the muscle.

Preclinical studies have demonstrated the ability of SARMs to increase levator ani muscle mass in the castrated rat and to increase bone mass and strength. Efficacy trials of several SARMs in humans are in early stages and have generally shown modest increments in fat-free mass. The first generation SARMs do not undergo aromatization or 5-alpha reduction; it is unknown whether this may pose long term risks. The efficacy and the safety of SARMs as function promoting therapy is just beginning to be evaluated.