Open AccessCombined administration of testosterone plus an ornithine decarboxylase inhibitor as a selective prostate‐sparing anabolic therapy
Author(s) -
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
Publication year - 2014
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.12174
Subject(s) - testosterone (patch) , endocrinology , medicine , follistatin , prostate cancer , androgen , anabolism , ornithine decarboxylase , prostate , biology , hormone , cancer , enzyme , biochemistry
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 (r F st) increased muscle mass in mice, but had no effect on prostate mass. Consistent with the results of r F st 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 r F st in prostate and muscle, we performed microarray analysis of m RNA s from prostate and levator ani of castrated male mice treated with vehicle, testosterone, or r F st. Testosterone and r F st 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 r F st showed a negligible effect with only 9 transcripts differentially expressed. Among pathways that were differentially responsive to testosterone in prostate, we identified ornithine decarboxylase ( O dc1), an enzyme in polyamine biosynthesis, as a testosterone‐responsive gene that is unresponsive to r F st. Accordingly, we administered testosterone with and without α‐difluoromethylornithine ( DFMO ), an O dc1 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.