Steroids 76 (2011) 416–423 Contents lists available at ScienceDirect Steroids journal homepage: www.elsevier.com/locate/steroids Relative influence of testosterone and insulin in the regulation of prostatic cell proliferation and growth A. Vikram, S. Kushwaha, G.B. Jena ∗ Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160062, India article info Article history: Received 28 October 2010 Received in revised form 22 December 2010 Accepted 28 December 2010 Available online 6 January 2011 Keywords: Testosterone Diabetes Insulin Prostate Androgens abstract Prostatic hyperplasia is a common problem of the aged men population. Recent experimental and clinical studies provide sufficient evidence that apart from androgens, insulin also plays an important role in the pathogenesis of prostatic hyperplasia. The present study was aimed to investigate the relative influence of testosterone and insulin on the cellular proliferation and prostatic growth. Effect of testosterone on the prostate of hypoinsulinemic, and glandular injection of insulin-receptor antagonist S961 on the prostate of castrated Sprague–Dawley rat (220 ± 10 g) was examined. Significant decrease in the weight of the ventral prostate was observed in the streptozotocin-induced hypoinsulinemic rats (∼6 fold), which is restored by the intervention of testosterone. Although, glandular injection of S961 did not led to any change in the frequency of proliferating cell nuclear antigen (PCNA) positive cells in normal rats, sig- nificant decrease was observed in the castrated rats. Castration led to increase in the frequency of the caspase-3 and the TUNEL positive cells in the ventral prostate. Further, long-term (6 weeks) adminis- tration of S961 induced significant decrease in the weight of the ventral prostate. Results of the present study provide that both testosterone and insulin promote prostatic cell proliferation and change in the level of either of the hormone results in the destabilization of cellular equilibrium, and modulation of the insulin-receptor signaling in the prostate may provide an alternative strategy for the treatment of prostatic enlargement. Further, studies are required to better understand the interplay between these hormones in the regulation of prostatic growth. © 2011 Elsevier Inc. All rights reserved. 1. Introduction Androgens (testosterone, dihydrotestosterone) and mesenchymal–epithelial interactions are required for the normal prostatic development and are known to play an important role in the pathogenesis of benign prostatic hyperplasia (BPH) [1]. However, recent experimental [2–9] and clinical [10–14] studies provide convincing evidence that apart from androgens, insulin also plays an important role in the prostatic enlargement. High incidence of BPH in the insulin-resistant individuals, further high- lights the critical role of insulin in the pathogenesis of the disease [15], as insulin-resistance is often associated with compensatory hyperinsulinemia [16]. Hyperinsulinemic condition may lead to the over-activation of the insulin-receptor signaling. One path- way of insulin signaling that is dependent on IRS/PI-3Kinase is mainly concerned with the metabolic effects, whereas MEK/ERK- dependent signaling is responsible for its growth-stimulating actions. However, recently it has been acknowledged that the ∗ Corresponding author. Tel.: +91 172 2214697; fax: +91 172 2214692. E-mail addresses: ajitvikram@gmail.com (A. Vikram), sapna.pharm@gmail.com (S. Kushwaha), gbjena@gmail.com (G.B. Jena). IRS/PI-3Kinase dependent downstream signaling of insulin can activate androgen signaling through direct interaction of Foxo-1 with the androgen receptor [17]. Activation of androgen signaling by insulin signaling (through IRS/PI-3Kinase dependent down- stream) suggests another possible mechanism for the insulin induced prostatic growth without affecting the serum testos- terone level. Further, prostatic atrophy and enlargement in the hypoinsulinemic and hyperinsulinemic rats respectively under- lines the critical role of insulin in the prostatic growth [8,9,17–19]. Taken together, the previous reports from others as well as our laboratory provides that (i) hyperinsulinemia can promote pro- static growth without changing the plasma testosterone level, (ii) hyperinsulinemia augments the growth-promoting effect of testosterone and (iii) hyperinsulinemic condition fails to promote prostatic growth in castrated rats [2,5,8]. Experimental evidences support the hypothesis of the synergistic interaction between insulin and testosterone in the regulation of prostatic growth [20]. Although, both testosterone and insulin play a critical role in the prostatic growth, their relative influence remains to be delineated. To address this vital question, the present study was aimed to investigate the relative influence of testosterone and insulin in the growth and development of the prostate gland. Results of the present study clearly demonstrates that intervention 0039-128X/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.steroids.2010.12.014