Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

Abstract

Several regulatory concerns have hindered development of androgens as anabolic therapies, despite unequivocal evidence that testosterone supplementation increases muscle mass and strength in men; it induces hypertrophy of type I and II muscle fibers, and increases myonuclear and satellite cell number. Androgens promote differentiation of mesenchymal multipotent cells into the myogenic lineage and inhibit their adipogenic differentiation, by facilitating association of androgen receptors with beta-catenin and activating T-cell factor 4. Meta-analyses indicate that testosterone supplementation increases fat-free mass and muscle strength in HIV-positive men with weight loss, glucocorticoid-treated men, and older men with low or low-normal testosterone levels. The effects of testosterone on physical function and outcomes important to patients have not, however, been studied. In older men, increased hematocrit and increased risk of prostate biopsy and detection of prostate events are the most frequent, testosterone-related adverse events. Concerns about long-term risks have restrained enthusiasm for testosterone use as anabolic therapy. Selective androgen-receptor modulators that are preferentially anabolic and that spare the prostate hold promise as anabolic therapies. We need more studies to determine whether testosterone or selective androgen-receptor modulators can induce meaningful improvements in physical function and patient-important outcomes in patients with physical dysfunction associated with chronic illness or aging.

Figure 1

Changes in body composition in testosterone-treated HIV-infected men and women. Meta-analysis plots of contrasts between androgen-treated and placebo-treated HIV-infected men with weight loss, showing the change in whole body mass (A), and lean body mass (B) and HIV-infected women with weight loss, showing the change in whole body mass (C) and fat-free mass (D). A positive difference is a favorable testosterone effect on body mass, lean body mass, and fat-free mass. Some studies reported fat-free mass and some lean body mass. Fat-free mass equals lean body mass plus bone mineral content. Confidence intervals that do not overlap with zero represent significant differences between placebo and testosterone groups.

Figure 2

Changes in body composition in testosterone-treated older men. Meta-analysis plots of contrasts between testosterone-treated and placebo-treated men in the change (in kilograms) in whole body mass (A), lean body mass change (B), right-hand grip strength (C), and whole body fat mass (D) in middle-aged and older men more than 45 years of age. A positive difference is a favorable testosterone effect on body mass, lean body mass, and fat-free mass, and a negative difference is a favorable testosterone effect on fat mass. Confidence intervals that do not overlap with zero represent significant differences between placebo and testosterone groups.

Figure 3

Steroidal (dihydrotestosterone) and nonsteroidal (R-bicalutamide) ligand interactions with the androgen receptor ligand-binding domain binding-pocket. R-bicalutamide (green) W741L complex and dihydrotestosterone (gold) wild-type complex, shown as side views (A and B) and top views (C and D) of the steroidal plane. Ligand and receptor interact mainly through H-bonds (labeled as yellow dotted lines) and hydrophobic interactions. The A-ring and amide bond of the bicalutamide molecule overlaps the steroidal plane of dihydrotestosterone (rings A–D) and shares similar H-bonding pattern, whereas the B-ring (B) folds away from the plane, pointing to the top of the ligand-binding pocket and forming the unique structural feature of this ligand class.

Figure 4

Four general classes of selective androgen receptor modulator pharmacophores. Information about the stage of development was obtained through company websites.

Figure 5

Structures and relative binding affinities of some selective androgen receptor modulators. DHT, dihydrotestosterone; RBA, relative binding affinity compared with synthetic ligand R1881; THQ, tetrahydroquinolone.