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Insulin-Like Growth Factor (IGF)-I Controls Prostate Fibromuscular Development: IGF-I Inhibition Prevents Both Fibromuscular and Glandular Development in Eugonadal Mice

The Bunnie Joan Sachs Laboratory (D.L.K., W.R.), Neuroendocrine Unit, Department of Medicine, New York University School of Medicine, New York, New York 10016; Department of Medicine (D.Y.), University of Minnesota, Minneapolis, Minnesota 55455; Department of Pathology (K.T.K.), St. Michaels Hospital, University of Toronto, Toronto, Ontario, Canada M5B 1W8; and University of Santiago de Compostela (S.V.), Campus Universitario de Lugo, Department of Anatomy, Lugo 2700-2, Spain

Address all correspondence and requests for reprints to: David L. Kleinberg, The Bunnie Joan Sachs Laboratory, Neuroendocrine Unit, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016. E-mail: david.kleinberg{at}med.nyu.edu.

Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I^(–/–) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.