Objective: To explore the effects and mechanisms of simvastatin on prostate hyperplasia in spontaneously hypertensive rats (SHRs). Methods: Thirty-six male SHRs were randomly divided into three groups: the 10 and the 20 mg/kg/d simvastatin group and the control group. After 6 weeks the ultra-microscopic prostate structures were observed. The serum levels of interleukin-6 (IL-6), insulin-like growth factor (IGF-1) and angiotensin II (Ang-II) were measured by enzyme-linked immunosorbent assays. The endothelium-derived nitric oxide synthase (eNOS) expression was evaluated with immunohistochemistry. Results: Compared to the control group, the 20 mg/kg/d simvastatin group presented with lower absolute (p = 0.005) and relative prostate weight (p = 0.009). The basal cells and columnar cells presented with edema, condensed heterochromatin in interstitial fibroblast nuclei, widened nucleus gaps, and decreased mitochondria and endoplasmic reticulum in the 10 mg/kg/d simvastatin group, these changes were more pronounced in the 20 mg/kg/d simvastatin group. The IL-6 levels in the 10 and 20 mg/kg/d simvastatin groups were lower than those of the controls (p = 0.005 and p = 0.008). The IGF-1 levels of the 20 mg/kg/d simvastatin group were reduced compared to the control group (p = 0.016). Conclusions: Simvastatin can delay and inhibit prostatic hyperplasia and progression in SHR. These actions may be mediated through the suppression of inflammatory and growth factors.

1.
Ploumidou K, Kyroudi-Voulgari A, Perea D, Perea D, Anastasiou I, Mitropoulos D: Effect of a hypercholesterolemic diet on serum lipid profile, plasma sex steroid levels, and prostate structure in rats. Urology 2010;76:1517.e1-e5.
2.
Pace G, Di Massimo C, De Amicis D, Vicentini C, Ciancarelli MG: Inflammation and endothelial activation in benign prostatic hyperplasia and prostate cancer. Int Braz J Urol 2011;37:617-622.
3.
Dinh DT, Frauman AG, Zhou J, Ohishi M, Zhou J, Casley DJ, Johnston CI, Fabiani ME: Evidence for activation of the renin-angiotensin system in the human prostate: increased angiotensin II and reduced AT1 receptor expression in benign prostatic hyperplasia. J Pathol 2002;196:213-219.
4.
Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP: Dyslipidaemia of Obesity, Metabolic Syndrome and Type 2 Diabetes Mellitus: the Case for Residual Risk Reduction After Statin Treatment. Open Cardiovasc Med J 2011;5:24-34.
5.
St Sauver JL, Jacobsen SJ, Jacobson DJ, McGree ME, Girman CJ, Nehra A, Roger VL, Lieber MM: Statin use and decreased risk of benign prostatic enlargement and lower urinary tract symptoms. BJU Int 2011;107:443-450.
6.
Matityahou A, Rosenzweig N, Golomb E: Rapid proliferation of prostatic epithelial cells in spontaneously hypertensive rats: a model of spontaneous hypertension and prostate hyperplasia. J Androl 2003;24:263-269.
7.
Lujan M, Ferruelo A, Paez A, Moreno A, Berenguer A: Prostate apoptosis after doxazosin treatment in the spontaneous hypertension rat model. BJU Int 2004;93:410-414.
8.
Milman HA, Bosland MC, Walden PD, Heinze JE: Evaluation of the adequacy of published studies of low dose effects of bisphenol A on rodent prostate for use in human risk assessment. Regul Toxicol Pharmacol 2002;35:338-346.
9.
Steiner GE, Stix U, Handisurya A, Willheim M, Haitel A, Reithmayr F, Paikl D, Ecker RC, Hrachowitz K, Kramer G, Lee C, Marberger M: Cytokine expression pattern in benign prostatic hyperplasia infiltrating T cells and impact of lymphocytic infiltration on cytokine mRNA profile in prostatic tissue. Lab Invest 2003;83:1131-1146.
10.
Song L, Zhu Y, Han P, Chen N, Lin D, Lai J, Wei Q: A retrospective study: correlation of histologic inflammation in biopsy specimens of Chinese men undergoing surgery for benign prostatic hyperplasia with serum prostate-specific antigen. Urology 2011;77:688-692.
11.
Schenk JM, Kristal AR, Neuhouser ML, Tangen CM, White E, Lin DW, Kratz M, Thompson IM: Biomarkers of systemic inflammation and risk of incident, symptomatic benign prostatic hyperplasia: results from the prostate cancer prevention trial. Am J Epidemiol 2010;171:571-582.
12.
Drachenberg DE, Elgamal AA, Rowbotham R, Peterson M, Murphy GP: Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999;41:127-133.
13.
Berthold HK, Berneis K, Mantzoros CS, Krone W, Gouni-Berthold I: Effects of simvastatin and ezetimibe on interleukin-6 and high-sensitivity C-reactive protein. Scand Cardiovasc J 2012; Early Online: 1-8.
14.
Cohen P, Peehl DM, Lamson G, Rosenfeld RG: Insulin-like growth factors (IGFs), IGF receptors, and IGF-binding proteins in primary cultures of prostate epithelial cells. Journal of Clinical Endocrinology and Metabolism 1991;93:401-407.
15.
Sarma AV, Jaffe CA, Schottenfeld D, Dunn R, Montie JE, Cooney KA, Wei JT: Insulin-like growth factor-1, insulin-like growth factor binding protein-3, and body mass index: clinical correlates of prostate volume among Black men. Urology 2002;59:362-367.
16.
Pollak MN, Schernhammer ES, Hankinson SE: Insulin-like growth factors and neoplasia. Nature Reviews 2004;4:505-518.
17.
Szkodziński J, Romanowski W, Hudzik B, Kaszuba A, Nowakowska-Zajdel E, Szkilnik R, Pietrasińska B, Zubelewicz-Szkodzińska B: Effect of HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) reductase inhibitors on the concentration of insulin-like growth factor-1 (IGF-1) in hypercholesterolemic patients. Pharmacol Rep 2009;61:654-664.
18.
Sekine Y, Furuya Y, Nishii M, Koike H, Matsui H, Suzuki K: Simvastatin inhibits the proliferation of human prostate cancer PC-3 cells via down-regulation of the insulin-like growth factor 1 receptor: Biochem Biophys Res Commun 2008;372:356-361.
19.
Rommel C, Clarke BA, Zimmermann S, Nuñez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ: Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 1999;286:1738-1741.
20.
Benigni A, Cassis P, Remuzzi G: Angiotensin II revisited: new roles in inflammation, immunology and aging. EMBO Mol Med 2010;2:247-257.
21.
Dinh DT, Frauman AG, Sourial M, Casley DJ, Johnston CI, Fabiani ME: Identification, distribution and expression of angiotensin II receptors in the normal human prostate and benign prostatic hyperplasia. Endocrinology 2001;10:10-20.
22.
Wennemuth G, Aumüller G: Angiotensin II-mediated calcium signals and mitogenesis in human prostate stromal cell line hPCPs. Br J Pharmacol 2005;144:3-10.
23.
Shen F, Dong LN, Zhang XY, Zhao XK, Zeng XF, Qu XB: Inhibitory effect of losartan onprostatic hyperplasia in spontaneous hypertension rats and its pathophysiological mechanism. Zhonghua Nan Ke Xue 2012;18:600-605.
24.
Herring N, Lee CW, Sunderland N, Wright K, Paterson DJ: Pravastatin normalises peripheral cardiac sympathetic hyperactivity in the spontaneously hypertensive rat. J Mol Cell Cardiol 2011;50:99-106.
25.
Dey A, Lang RJ, Exintaris B: Nitric oxide signaling pathways involved in the inhibition of spontaneous activity in the guinea pig prostate. J Urol 2012;187:2254-2260.
26.
Hedlund P: Nitric oxide/cGMP-mediated effects in the outflow region of the lower urinary tract - is there a basis for pharmacological targeting of cGMP? World J Urol 2005;23:362-367.
27.
Andersson KE: LUTS treatment: future treatment options. Neurourol Urodyn 2007;26:934-947.
28.
Uckert S, Kuczyk MA: Cyclic nucleotide metabolism including nitric oxide and phosphodiesterase-related targets in the lower urinary tract. Handb Exp Pharmacol 2011;202:527-542.
29.
Rossoni LV, Wareing M, Wenceslau CF, Al-Abri M, Cobb C, Austin C: Acute simvastatin increases endothelial nitric oxide synthase phosphorylation via AMP-activated protein kinase and reduces contractility of isolated rat mesenteric resistance arteries. Clin Sci 2011;121:449-458.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.