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Combined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate-sparing anabolic therapy.
Jasuja, Ravi; Costello, James C; Singh, Rajan; Gupta, Vandana; Spina, Catherine S; Toraldo, Gianluca; Jang, Hyeran; Li, Hu; Serra, Carlo; Guo, Wen; Chauhan, Pratibha; Narula, Navjot S; Guarneri, Tyler; Ergun, Ayla; Travison, Thomas G; Collins, James J; Bhasin, Shalender.
Afiliação
  • Jasuja R; 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.
Aging Cell ; 13(2): 303-10, 2014 Apr.
Article em En | MEDLINE | ID: mdl-24305501
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Próstata / Testosterona / Inibidores Enzimáticos / Tratamentos com Preservação do Órgão / Inibidores da Ornitina Descarboxilase / Anabolizantes Limite: Animals / Humans / Male Idioma: En Revista: Aging Cell Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Próstata / Testosterona / Inibidores Enzimáticos / Tratamentos com Preservação do Órgão / Inibidores da Ornitina Descarboxilase / Anabolizantes Limite: Animals / Humans / Male Idioma: En Revista: Aging Cell Ano de publicação: 2014 Tipo de documento: Article