Authors: Richard Berges Andrea Gsur Elisabeth Feik Klaus Höfner Theodor Senge Ludger Pientka Andreas Baierl Martin C Michel Anton Ponholzer Stephan Madersbacher
Publish Date: 2009/11/17
Volume: 29, Issue: 2, Pages: 143-148
Abstract
The known importance of testosterone for the development of benign prostatic hyperplasia BPH prompted us to test the hypothesis whether polymorphisms of two genes CYP19A1 and CYP3A4 involved in testosterone metabolism are associated with clinical BPHparametersA random sample of the populationbased Herne lower urinary tract symptoms cohort was analysed All these men underwent a detailed urological workup Two polymorphisms in the CYP19A1 gene rs700518 in exon 4 A57G rs10046 at the 3′UTRC268T and one in the 3′UTR of CYP3A4 rs2740574 A392G were determined by TaqMan assay from genomic DNA of peripheral blood These polymorphisms were correlated to clinical and laboratory BPHparametersA total of 392 men 654 ± 70 years 52–79 years were analysed Mean International Prostate Symptom Score IPSS 75 Q max 154 ml/s prostate volume 31 ml and prostate specific antigen PSA 18 ng/ml indicated a typical elderly population Both polymorphisms in the CYP19A1 gene were not correlated to age IPSS Q max prostate volume and postvoid residual volume Serum PSA was higher in men carrying the heterozygous rs10046 genotype 20 ± 01 ng/ml than in those with the CCgenotype 17 ± 02 ng/ml P = 0012 Men carrying one a mutated allele of the CYP3A4 gene had smaller prostates 270 ± 20 vs 32 ± 08 ml P = 002 and lower PSA levels 16 ± 03 vs 19 ± 01 ng/mlThe inconsistent associations observed herein and for other gene polymorphisms warrant further studies In general the data regarding the association of gene polymorphism to BPHparameters suggest that this disease is caused by multiple rather than a single genetic variant A rigorous patient selection based on anatomopathological and hormonal profile may possible reduce the number of confounders for future studies thus enabling a more detailed assessment of the association between genetic factors and BPHparametersBenign prostatic hyperplasia BPH benign prostatic enlargement BPE and benign prostatic obstruction BPO are progressive disorders that can cause lower urinary tract symptoms LUTS and ultimately lead to acute urinary retention AUR or the need for prostatic surgery 1 Predictors for disease progression are age symptom status postvoid residual volume maximum flow rate Q max and—currently most widely used—prostate volume with prostate specific antigen PSA as a proxy parameter 2 Progression risk assessment is used in contemporary medical BPH management treatment algorithms 3Longterm treatment with 5αreductase inhibitors 5ARIs results in a 50 risk reduction for AUR or the need for surgery indicating that the disease progression can be altered by medical therapy 4 5 The magnitude of this effect is dependent on various parameters such as prostate volume The prostate cancer PCa prevention trial PCPT has also shown that longterm treatment with finsterid in healthy men without LUTS leads to a favourable outcome regarding several BPHparameters AUR need for surgery urinary tract infection thus supporting the concept of a preventive strategy 6The development of LUTS in men is a multifactorial process with multiple factors involved such as BPH BPE BPO inflammatory processes in the prostate changes in detrusor function alterations of the peripheral and central nervous system and—potentially—genetic factors A genetic marker predictive for the development of BPE BPO or LUTS would be a major improvement for preventive strategies and patient management In contrast to clinical parameters such as prostate volume or PSA genetic markers would allow a much earlier risk assessment with earlier and potentially more effective intervention eg by 5ARIsPolymorphisms of genes involved in the testosterone metabolism are currently under intense evaluation as biomarkers for PCa risk 7 8 The CYP19A1 gene is located on chromosome 15 15q211 and encodes the enzyme aromatase catalysing the irreversible conversion of androstenedione to estrone and testosterone to estradiol 8 Aromatase is present in the gonads and in the extragonadal tissue including the prostate and adipose tissue 8 Aromatase mRNA and protein have both been detected in BPH and PCa tissue Polymorphisms in the CYP19A1gene showed borderline increased risks for PCA 8 CYP3A4 is located on chromosome 7 7q211 and involved in the oxidation of testosterone to 2β 6β or 15βhydroxytestosterone which is biologically less active than testosterone or dihydroxytestosterone 8 A variant in the 5′ untranslated region of CYP3A4 rs2740574 has been associated with PCa risk in some studies and also in men with a history of BPH 9
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