title: Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy.
abstract: 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.
authors.affiliation: 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, 221 Longwood Avenue, Boston, MA, 02115, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Jasuja
authors.forename: James C
authors.initials: JC
authors.lastname: Costello
authors.forename: Rajan
authors.initials: R
authors.lastname: Singh
authors.forename: Vandana
authors.initials: V
authors.lastname: Gupta
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Spina
authors.forename: Gianluca
authors.initials: G
authors.lastname: Toraldo
authors.forename: Hyeran
authors.initials: H
authors.lastname: Jang
authors.forename: Hu
authors.initials: H
authors.lastname: Li
authors.forename: Carlo
authors.initials: C
authors.lastname: Serra
authors.forename: Wen
authors.initials: W
authors.lastname: Guo
authors.forename: Pratibha
authors.initials: P
authors.lastname: Chauhan
authors.forename: Navjot S
authors.initials: NS
authors.lastname: Narula
authors.forename: Tyler
authors.initials: T
authors.lastname: Guarneri
authors.forename: Ayla
authors.initials: A
authors.lastname: Ergun
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Travison
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.forename: Shalender
authors.initials: S
authors.lastname: Bhasin
mesh_terms: D045930:Anabolic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D000518:Eflornithine / Q000008:administration & dosage / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D038681:Follistatin / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009929:Organ Size / Q000187:drug effects; D059351:Organ Sparing Treatments; D009955:Ornithine Decarboxylase / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D011467:Prostate / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013739:Testosterone / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D045930:Anabolic Agents; D004791:Enzyme Inhibitors; D038681:Follistatin; D065108:Ornithine Decarboxylase Inhibitors; D011994:Recombinant Proteins; D013739:Testosterone; D009955:Ornithine Decarboxylase; D000518:Eflornithine
keywords: aging; anti-aging; sarcopenia; sex hormones; skeletal muscle; steroids