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Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging

Nature Clinical Practice Endocrinology & Metabolism volume 2, pages 146–159 (2006)Cite this article

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 β-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.

Key Points

  • Meta-analyses of clinical trials provide unequivocal evidence that testosterone administration increases skeletal muscle mass, muscle strength, and leg power; these anabolic effects of testosterone are dose-related

  • The effects of testosterone supplementation on physical function and clinical outcomes in older men with physical dysfunction and in men with chronic illness are unknown

  • Testosterone induces skeletal muscle fiber hypertrophy and increases the number of satellite cells

  • Testosterone increases muscle mass and decreases fat mass by promoting the differentiation of mesenchymal multipotent cells into myogenic lineage and inhibiting their differentiation into the adipogenic lineage

  • An increase in hematocrit and increased risk of detection of prostate events are the most frequent adverse effects of testosterone administration in older men; the anabolic applications of testosterone are constrained by dose-limiting adverse events and concerns about long-term effects on the prostate and cardiovascular risk

  • Nonsteroidal selective androgen-receptor modulators that are free of adverse effects of testosterone and are preferentially anabolic hold great promise as anabolic therapies

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Figure 1: Changes in body composition in testosterone-treated HIV-infected men and women
Figure 2: Changes in body composition in testosterone-treated older men
Figure 3: Steroidal (dihydrotestosterone) and nonsteroidal (R-bicalutamide) ligand interactions with the androgen receptor ligand-binding domain binding-pocket
Figure 4: Four general classes of selective androgen receptor modulator pharmacophores
Figure 5: Structures and relative binding affinities of some selective androgen receptor modulators

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Author notes

  1. S Bhasin and TW Storer are Professors of Medicine, NA Mazer is an Associate Professor of Medicine, and R Jasuja is an Assistant Professor of Medicine

  2. W Gao is an Assistant Professor of Medicine, and JT Dalton is a Professor of Medicine

Authors and Affiliations

  1. Boston University School of Medicine, Boston, MA, USA

    Shalender Bhasin, Thomas W Storer, Norman A Mazer & Ravi Jasuja

  2. Assistant Professor of Medicine at Charles Drew University, Los Angeles, CA, USA

    Olga M Calof

  3. Professor of Mathematics and Biostatistics at UCLA School of Public Health, Los Angeles, CA, USA

    Martin L Lee

  4. Assistant Professor of Medicine at Mayo Clinic, Rochester, MN, USA

    Victor M Montori

  5. Ohio State University, Columbus, OH, USA

    Wenqing Gao & James T Dalton

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Correspondence to Shalender Bhasin.

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Competing interests

SB has received research grants from Solvay Pharmaceuticals, TAP Pharmaceuticals, and GSK and has served as a consultant for GTX, Merck, and Wyeth. OMC has received research a grant from Genentech, Inc. TWS has served as a consultant for GTX and Wyeth Pharmaceuticals. NAM was formerly an employee of Watson Pharmaceuticals. JTD is an employee of GTX, Inc. MLL, RJ, VMM and WG declared they have no competing interests.

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Bhasin, S., Calof, O., Storer, T. et al. Drug Insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging. Nat Rev Endocrinol 2, 146–159 (2006). https://doi.org/10.1038/ncpendmet0120

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