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Current Bladder Dysfunction Reports

Erschienen in:

31.03.2016 | BPH-Related Voiding Dysfunction (R Lee, Section Editor)

Influence of Age and Obesity on 5α-Reductase 2 Gene Expression

verfasst von: Alexander Otsetov

Erschienen in: Current Bladder Dysfunction Reports | Ausgabe 2/2016

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Abstract

The most common non-malignant, age-related disease in men is the benign prostatic hyperplasia (BPH). Androgens and genetic predisposition play important roles in normal prostate growth and in BPH progression. However, accumulating evidence indicates that factors such as aging and obesity also can contribute to the BPH etiology. Management of BPH includes medical treatment or surgery. Currently, the drug therapy uses the alpha1-blockers and/or inhibitors of the 5-alpha reductase enzyme (5ARIs). Latest studies demonstrated that a fraction of patients (up to 30 %) are resistant to this therapy. This article reviews the new risk factors in BPH etiology as well as the mechanisms of resistance to 5ARI therapy.

1.••

Parsons JK. Modifiable risk factors for benign prostatic hyperplasia and lower urinary tract symptoms: new approaches to old problems. J Urol. 2007;178:395–401. Discusses the BPH etiology, other than sex-steroid hormones; identification of the new BPH risk factors, such as obesity and metabolic syndrome. This study suggests the potential therapeutic effect of the physical activity and diet in-between medical and surgical therapies in BPH- risk patients.

2.••

Parsons JK, Sarma AV, McVary K, Weiss JT. Obesity and benign prostatic h: clinical connections, emerging etiological paradigms and future directions. J Urol. 2013;189:S102–6. Summarizes evidence regarding the association between obesity and metabolic syndrome with increased prostate volume, BPH and LUTS, as well as the contribution of increased adiposity to the prostate growth.

3.••

Wang S, Mao Q, Lin Y, Wu X, Wang X, Zheng X, et al. Body mass index and risk of BPH: a meta-analysis. Prostate Cancer Prostatic Dis. 2012;15:265–72. This review of 19 studies suggests the strong association of BMI with the increased risk of BPH. The review also discusses endocrine changes seen in the elderly and the obese as well as the role of inflammation and oxidative stress in the etiology of BPH.

4.•

Kaplan S, O’Neill EA, Lowe R, Hanson M, Meehan AG. Prevalence of low testosterone in aging men with benign prostatic hyperplasia: data from Proscar Long-term Efficacy and Safety Study (PLESS). Aging Male. 2013;16(2):48–51. Analysis of baseline data from 299 patients, participating in the PLESS study, which demonstrates the impact of higher BMI on testosterone levels in patients with symptomatic BPH. Discusses the inverse relationship between testosterone and BMI as well as the role of adipose tissue in aromatization.

Kaplan S, Lee JY, O’Neill EA, Meehan AG, Kusek JW. Prevalence of low testosterone and its relationship body mass index in older men with lower urinary tract symptoms associated with benign prostatic hyperplasia. Aging Male. 2013;16(4):169–72.CrossRefPubMed

6.•

Artunes A, Araújo LH, Nakano E, Muracca E, Srougi M. Obesity may influence the relationship between sex hormones and lower urinary tract symptoms. Int Braz J Urol. 2014;40:240–6. In this cross-sectional analysis of 725 men, the effects of serum testosterone in patients with BPH and LUTS are discussed. Variables like age, BMI, prostate volume and AUA symptom score are analyzed; lower total testosterone levels are found in a subset of overweight and obese patients with BPH. In this study is demonstrated the clear influence of BMI on the relationship between testosterone and LUTS.

Roehrborn CG, Lee M, Meehan A, Waldstreicher J. Effects of Finasteride on serum testosterone and body mass index in men with benign prostatic hyperplasia. Urology. 2003;62:894–9.CrossRefPubMed

8.••

Raheem OA, Parsons JK. Associations of obesity, physical activity and diet with benign prostatic hyperplasia and lower urinary tract symptoms. Curr Opin. 2014;24:10–4. A new, updated study analyzing the role of modifiable risk factors, including obesity, physical activity and diet as risk factors for BPH and LUTS. A summarize of the associations of obesity with BPH. More importantly, a discussion concerning evidence from the secondary analysis of PCPT and REDUCE trials about the obesity-driven attenuation of 5ARIs efficacy is done in a separate section.

9.••

Parsons JK, Schenk JM, Arnold KB, Messer K, Till C, Thompson IM, et al. Finasteride reduces the risk of incident clinical benign prostatic hyperplasia. Eur Urol. 2012;62(2):234–41. Study investigating the primary prevention of clinical BPH. A secondary analysis of PCPT trial with evaluation of the efficacy of Finasteride in BPH. The study analysis demonstrates the potential of obesity in the diminished activity of Finasteride in obese men with further brief discussion of the possible factors, affecting the prostate growth by inflammatory pathways, oxidative stress and the role of peripheral serum testosterone aromatization into estrogen.

10.

Lopez DS, Peskoe SB, Tsilidis KK, Hoffman-Bolton J, Helzlsouer KJ, Isaacs WB, et al. Association of variants in genes related to the immune response and obesity with BPH in CLUE II. Prostate Cancer Prostatic Dis. 2014;17:353–8.CrossRefPubMedPubMedCentral

11.

Willder JM, Walker VC, Halbert GL, Dick CPC, Orange C, Qayyum T, et al. Body mass index predicts failure of surgical management in benign prostatic hyperplasia. Urol Int. 2013;90:150–5.CrossRefPubMed

12.•

Kupelian V, McVary KT, Kaplan SA, Hall SA, Link CL, Aiyer LP, et al. Association of lower urinary tract symptoms and the metabolic syndrome: results from the Boston Area Community Health Survey. J Urol. 2013;189:S107–16. In this study is investigated the relationships between lower urinary tract symptoms and metabolic syndrome. A significant association is demonstrated between metabolic syndrome and LUTS. Their data demonstrated the aforementioned associations to be stronger in younger men (<60 year old) compared to older (65 year or older). The role of abdominal obesity is regarded not only as a storage reservoir but also as an endocrine organ, as well as the role of pelvic atherosclerosis in the chronic ischemia of the bladder and prostate glande.

13.

Telli O, Demirbas A, Kabar M, Karagoz MA, Hasmet Sarici H, Resorlu B. Does metabolic syndrome or its components correlate with lower urinary tract symptoms in benign prostatic hyperplasia patients? Nephro Urol Mon. 2015;7(3):e27253.CrossRef

14.••

Muller RL, Gerber L, Daniel M, Moreira DM, Andriole Jr G, Hamilton RH, et al. Obesity is associated with increased prostate gland attenuated prostate volume reduction by dutasteride. Eur Urol. 2013;63:1115–21. Secondary analysis of the REDUCE trial with examination of the associations of obesity with enhanced prostatic growth by serial TRUS (transrectal ultrasound) measurements. This study evaluates the percentage changes in prostatic volume (PV) at 2 and 4 year from baseline and tests its link with baseline BMI in different groups. The conclusion made is that obesity enhanced the PV; the authors report attenuation of Dutasteride in obese men, which is in accordance with previously reported observations.

15.

Tewari R, Rajender S, Natu SM, Dalela D, Goel A, Goel MM, et al. Diet, obesity, and prostate health: are we missing the link? J Androl. 2012;33(5):763–76.CrossRefPubMed

16.••

Niu Y, Ge R, Hu L, Diaz C, Wang Z, Wu CL, et al. Reduced levels of 5-α reductase 2 in adult prostate tissue and implications for BPH therapy. Prostate. 2011;71(12):1317–24. This is the first study, discussing the role of epigenetics in 5AR-2 gene silencing in the normal aging. The authors showed a strong association between DNA methylation in the 5AR-2 promoter with the reduced or absent protein expression. Their data report a percentage of patients with BPH (up to 30-33%) who have methylated CpG islands in the promoter region with lack of protein expression, thus suggesting that these changes may alter not only the prostatic growth but also affect the 5ARIs efficacy treatment. This study first highlighted the role of the epigenetic factors in the BPH etiology.

17.••

Bechis SK, Otsetov AG, Ge R, Wang Z, Vangel MG, Wu CL, et al. Age and obesity promote methylation and suppression of 5α-reductase 2: implications for personalized therapy of benign prostatic hyperplasia. J Urol. 2015;194(4):1031–7. Following the pilot study published in 2011, the authors here confirmed the strong association between 5AR-2 gene methylation and the absence of protein expression; next, analyzing epigenetics factors such as aging and obesity, it has been demonstrated the correlation between age and obesity with 5AR-2 gene methylation and lack of protein expression. Aging and elevated BMI were shown as important independent factors, contributing to BPH pathology and to the attenuation of the 5ARIs efficacy as well.

18.•

Mileva G, Baker SL, Konkle ATM, Bielajew C. Bisphenol-A: epigenetic reprogramming and effects on reproduction and behavior. Int J Environ Res Public Health. 2014;11:7537–61. This review in both human and animal studies attempted to synthesize the literature and examined the effects of BPA exposure on reproduction, behavior, and carcinogenesis with a focus on the potential epigenetic mechanisms by which it acts. It also provides new evidence about the role of endocrine disruptors, leading to DNA methylation that contributes to gene silencing.

19.

Kim WT, Yun SJ, Choi YD, Kim GY, Moon SK, Choi YH, et al. Prostate size correlates with fasting blood glucose in non-diabetic benign prostatic hyperplasia patients with normal testosterone levels. Korean Med Sci. 2011;26:1214–8.CrossRef

20.•

Ellem SJ, Wang H, Poutanen M, Risbridger GP. Increased endogenous estrogen synthesis leads to the sequential induction of prostatic inflammation (prostatitis) and prostatic pre-malignancy. Am J Pathol. 2009;175:1187–99. A study that shows the role of estrogens in the prostatic inflammation, linked with development of both BPH and prostatic carcinoma (PCa). The role of estrogen in the gene-alteration in the prostate and the impact of the changed androgen/estrogen ratio that contributes to promotion of the chronic prostatic inflammation, involved in the development of BPH and PCa.

21.•

McPhersona S, Hussaina S, Balanathana P, Hedwardsa SL, Niranjana B, Granta M, et al. Estrogen receptor–β activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNFα mediated. PNAS. 2010;107:3123–8. Study providing additional evidence of inflammation, inflammatory mediators and the apoptosis to the previously reported data, concerning the estrogen role in the BPH etiology.

22.

Singam P, Hong GE, Ho C, Hee TG, Jasman H, Inn FX, et al. Nocturia in patients with benign prostatic hyperplasia: evaluating the significance of ageing, co-morbid illnesses, lifestyle and medical therapy in treatment outcome in real life practice. Aging Male. 2015;18:112–7.CrossRefPubMed

23.••

Ge R, Wang Z, Bechis SK, Otsetov AG, Hua S, Wu S, et al. DNA methyl transferase 1 reduces expression of SRD5A2 in the aging adult prostate. Am J Pathol. 2015;185:870–82. This study shows that the expression of SRD5A2 is variable and not broadly expressed in the prostatic tissues. It also demonstrates the driving force of chronic inflammation for induction of epigenetic changes in aging males.

Titel: Influence of Age and Obesity on 5α-Reductase 2 Gene Expression
verfasst von: Alexander Otsetov
Publikationsdatum: 31.03.2016
Verlag: Springer US
Erschienen in: Current Bladder Dysfunction Reports / Ausgabe 2/2016
Print ISSN: 1931-7212
Elektronische ISSN: 1931-7220
DOI: https://doi.org/10.1007/s11884-016-0361-8

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