Kleinberg David L, Ruan Weifeng, Yee Douglas, Kovacs Kalman T, Vidal Sergio
The Bunnie Joan Sachs Laboratory, Neuroendocrine Unit, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Endocrinology. 2007 Mar;148(3):1080-8. doi: 10.1210/en.2006-1272. Epub 2006 Nov 30.
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 5alpha-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.
尽管抗雄激素疗法已被证明对治疗前列腺肿瘤有效，但在治疗良性前列腺增生（BPH）方面相对无效。为了更好地理解雄激素在正常前列腺和BPH发育中的作用，我们研究了睾酮和IGF-I对去势的IGF-I（-/-）雄性小鼠前列腺两个部分发育的相对影响。在此我们报告，IGF-I刺激纤维肌性部分的发育，但睾酮抑制它（基质上皮比分别为2.17和0.83；P<0.001）。睾酮还损害IGF-I诱导的胰岛素受体底物-1磷酸化和细胞分裂，并增加纤维肌性组织中的细胞凋亡。与之形成鲜明对比的是，IGF-I和睾酮单独或共同刺激腺性部分的发育。它们对腺性部分大小、细胞分裂、胰岛素受体底物-1磷酸化和前列腺素产生的联合作用是相加或协同的。它们共同对腺组织中的细胞凋亡也有更大的抑制作用。为了确定抑制IGF-I是否会抑制纤维肌性和腺性部分，我们在两种不同模型中测试了IGF结合蛋白-1对前列腺发育的影响：去势的艾姆斯侏儒小鼠和性腺功能正常的正常雄性小鼠。IGF结合蛋白-1在两者中均阻断牛生长激素诱导的纤维肌性和腺性发育。它还抑制性腺功能正常小鼠前列腺两个部分的上皮细胞分裂并增加细胞凋亡。观察到的IGF-I和睾酮对前列腺部分发育控制的不一致，可能解释了5α还原酶抑制剂在BPH中相对无效的原因，以及为什么理论上抑制睾酮可能会减少腺体体积但增加纤维肌性组织。这项工作也为将抑制IGF-I作为治疗BPH以减小前列腺两个部分大小的疗法提供了理论依据。
