Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy

Authors

  • Ravi Jasuja,

    Corresponding author
    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    • Correspondence

      Shalender Bhasin and Ravi Jasuja, Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Tel.: +1 617 525 9043; fax: +1 617 732 5764; e-mails: sbhasin@partners.org; rjasuja@partners.org

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  • James C. Costello,

    1. Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA
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  • Rajan Singh,

    1. Division of Endocrinology and Metabolism, Charles Drew University of Medicine and Science, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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  • Vandana Gupta,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Catherine S. Spina,

    1. Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA
    2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
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  • Gianluca Toraldo,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Hyeran Jang,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Hu Li,

    1. Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA
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  • Carlo Serra,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Wen Guo,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Pratibha Chauhan,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Navjot S. Narula,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Tyler Guarneri,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • Ayla Ergun,

    1. Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA
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  • Thomas G. Travison,

    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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  • James J. Collins,

    1. Howards Hughes Medical Institute, Center for BioDynamics, Boston University, Boston, MA, USA
    2. Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA
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  • Shalender Bhasin

    Corresponding author
    1. Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center for Function, Promoting Anabolic Therapies, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
    • Correspondence

      Shalender Bhasin and Ravi Jasuja, Research Program in Men's Health: Aging and Metabolism, Boston Claude D. Pepper Older Americans Independence Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Tel.: +1 617 525 9043; fax: +1 617 732 5764; e-mails: sbhasin@partners.org; rjasuja@partners.org

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Summary

Because of its anabolic effects on muscle, testosterone is being explored as a function-promoting anabolic therapy for functional limitations associated with aging; however, concerns about testosterone's adverse effects on prostate have inspired efforts to develop strategies that selectively increase muscle mass while sparing the prostate. Testosterone's promyogenic effects are mediated through upregulation of follistatin. We show here that the administration of recombinant follistatin (rFst) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of rFst administration, follistatin transgenic mice with constitutively elevated follistatin levels displayed greater muscle mass than controls, but had similar prostate weights. To elucidate signaling pathways regulated differentially by testosterone and rFst in prostate and muscle, we performed microarray analysis of mRNAs from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or rFst. Testosterone and rFst shared the regulation of many transcripts in levator ani; however, in prostate, 593 transcripts in several growth-promoting pathways were differentially expressed after testosterone treatment, while rFst showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase (Odc1), an enzyme in polyamine biosynthesis, as a testosterone-responsive gene that is unresponsive to rFst. Accordingly, we administered testosterone with and without α-difluoromethylornithine (DFMO), an Odc1 inhibitor, to castrated mice. DFMO selectively blocked testosterone's effects on prostate, but did not affect testosterone's anabolic effects on muscle. Co-administration of testosterone and Odc1 inhibitor presents a novel therapeutic strategy for prostate-sparing anabolic therapy.

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