Takashi IIZUKAI; Makiko SUzuKI1; Nana MINAMIYAMAI; Akemi ANDOI; Chie KuRAM0T01; Takeo KUWABARAI; and Kunio YAMAGUCHI2

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1 HEP., , Vol. 33, No. 4, 2006 ORIGINAL ARTICLES Metabolic Syndrome as a Risk Factor for Developing Benign Prostatic Hyperplasia A Simple, Non-invasive Method of Transabdominal Ultrasonography for BPH Takashi IIZUKAI; Makiko SUzuKI1; Nana MINAMIYAMAI; Akemi ANDOI; Chie KuRAM0T01; Takeo KUWABARAI; and Kunio YAMAGUCHI2 1 Asahi Medical Clinic, and 2Yokohama Rosai Hospital, Department of Urology ABSTRACT The aim of this study was to clarify the effects of metabolic syndrome on benign prostatic hyperplasia (BPH) by use of transabdominal ultrasonography in healthy males, the subjects of this study were 333 Japanese men. All subjects were divided to two groups; 146 subjects in the smaller group (prostatic anteroposterior size<28.0 mm, mean age; 45.3yrs) and 187 subjects in the larger group (prostatic anteroposterior size 28.0 mm, mean age; 51.3yrs), respectively. The levels of age, systolic blood pressure (S-BP), diastolic blood pressure (D-BP), fasting insulin (FIRI), plasma triglyceride (TG), ƒáglutamyltranspeptidase (ƒá-gpt), Fe, plasma prostate-special antigen (PSA), insulin resistance (HOMA-IR) and pancreas ƒà cell function (HOMA-ƒÀ) were significantly higher in the larger group than those in the smaller group, however plasma high density lipoprotein cholesterol (HDL-ch) level was significantly lower in the larger group than that in the smaller group. The prostatic anteroposterior size was significantly and positively related with age (r=0.31, p<0.0001), HOMA-IR (r=0.14, p=0.027), body mass index (r=0.10, p=0.049), S-BP (r=0.11, p=0.046) and D-BP (r=0.12, p=0.032) in all subjects. These data firstly indicated that metabolic syndrome was as a risk factor for developing BPH, secondly revealed that the transabdominal ultrasonography was able to use as the standard clinical tool for the useful assessment of prostatic size in daily medical health examinations. Key Words Benign Prostatic Hyperplasia, Prostatic Anteroposterior Size, Metabolic Syndrome, Transabdominal Ultrasonography, Japanese Healthy Males. INTRODUCTION Benign prostatic hyperplasia (BPH) was the most common benign disease in men over forty years of age. Lower urinary tract symptoms associated with BPH usually consisted of voiding dysfunctions such as a weak stream and residual sensation, and filling dysfunctions such as pollakisuria and urgent micturition. Although BPH and prostatic adenocarcinoma might be unrelated etiologically, they were the major Received: May 30, Address; Asahi Medical Clinic, , Hakuraku, Kanagawaku, Yokohama City, Kanagawa, Japan. TEL: , FAX: , asahicc basil.ocn.ne.jp 2Address; Yokohama Rosai Hospital, 3211, Kozukue, Kohokuku, Yokohama City, Kanagawa, Japan. TEL: , FAX: neoplasms affecting the human prostate and their frequent occurrence together had several clinical implications. Prostatic cancer was currently common in patients with BPH. Therefore, the simple, non-invasive method for prostatic diseases was very important for the medical health examinations. Many procedures have ever been used for predicting the degree of BPH, such as urethrocystoscopy, cystourethrography and transrectal ultrasonography. But their techniques have not widely used as the standard clinical tool for the medical health examinations. Recently, Watanabe et al. reported that transabdominal ultrasonography was useful as a screening test for evaluating the prostatic size.~1' However, it has not been clear whether transabdominal ultrasonography is simply useful method in medical health examination. On the other hand, it was well known that metabolic syndrome based on insulin resistance or hyperinsulinemia was closely associated with established risk factors for BPH.[21-[4] The metabolic syndrome consisted of the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease, including overall obesity, visceral obesity, dyslipidemia, hyperglycemia, and hypertension.[5]-[7] The older males, especially with hypertension frequently demonstrated BPH.[8], [9] Furthermore, the association of obesity, diabetes mellitus, hypertriglycedemia, and hypertension with insulin resistance has been well recognized.[10], [11] It has also been reported that the patients with fatty liver disease was associated with metabolic syndrome.[12], [13] However, the relationship between BPH and the metabolic syndrome based on insulin resistance and/or hyperinsulinemia in the non-obese and normo-lipidemic adults has not been fully understood. Therefore, we investigated the relationship between BPH and various metabolic factors including serum lipids, hypertension, fatty liver, impaired glucose tolerance and insulin resistance by use of a simple, non-invasive method of transabdominal ultrasonography in order to clarify the effects of metabolic syndrome on BPH in healthy males. MATERIALS AND METHODS The subjects of this study were 333 Japanese men who underwent medical examinations in our medical center. They all had no history of diabetes mellitus, BPH and they had not 12

2 IIzuKA et al.: Metabolic Syndrome as a Risk Factor for Developing Benign Prostatic Hyperplasia 475 received any medications affecting BPH signs, blood glucose, blood pressure (BP) and plasma lipids. All subjects were studied in the morning. They were also analysis using the StatView: 5 software package. A probability value of less than 0.05 was considered significance. to indicate statistical asked to refrain from smoking or using caffeine-containing beverages before the visit and had been fasting overnight. Systolic and diastolic blood pressure (S-BP, D-BP) were determined by use of automatic blood pressure monitor BP- 203RV (Nippon Colin Co: Tokyo) after a rest of 15 minutes. Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in meters) squared. Blood samples were drawn from an antecubital vein after a 12-hour fast to determine the fasting plasma glucose (FPG), fasting plasma insulin (FIRI) and fasting plasma lipids and the other laboratory data. FPG and FIRI were measured by an enzymatic method and by enzyme immunoassay using IRI Kit (Abbott Japan Co. LTD., Japan), respectively. Plasma prostate-special antigen (PSA) was measured by chemiluminescent immunoassay using Architect: Total PSA Kit (Abbott Japan Co. LTD., Japan). Laboratory data were measured with HITACHI 717-OS Automatic analyzer (Hitachi Co. Tokyo, Japan). Insulin resistance (HOMA-IR)[14] and pancreas ƒàcell function (HOMA-3)[14] were calculated using a homeostasis model based on the following formula: HOMA-IR=FIRI (U/ml) ~FPG (mmol/ml)/22.5, HOMA- 3 = 20 ~ FIRI (U/ml) I (FPG (mmol/ml) - 3.5). Prostatic size was measured from the transabdominal ultrasonographic estimates of the anteroposterior, transverse and sagittal dimensions for a prostate ellipsoid shape. Maximum diameters were used for each measurement. A convex probe (5.20 MHz) equipped an EUB-6500 (Hitachi, Tokyo, Japan) was used to perform transabdominal ultrasonography. Both prostatic volume and bladder volume were calculated using the following formula: Prostatic volume (cm3) = [Anteroposterior size (mm) ~ Transverse size (mm) ~ Sagittal size (mm) ~ RESULT 1) Clinical characteristics in all subjects Clinical characteristics in all subjects were showed in Table 1. As shown in Table1, the age was mean 45.3 yrs old in the smaller group and mean yrs old in the larger group (p< vs smaller group), and both S-BP and D-BP levels were significantly higher in the larger group than those in the smaller group; mean S-BP (121 mmhg in the smaller group, 127 mmhg in the larger group: p<0.05 ), D-BP (76 mmhg, 79 mmhg: p<0.01). The levels of FIRI and BMI were significantly higher in the larger group than those in the smaller group, however FPG and plasma HbA 1 c levels were not different in two groups; FIRI (6.89 ƒêu/l, 7.75 ƒêu/l: p<0.01), BMI (23.4 kg/m2, 23.9 kg/m2: p<0.05). 2) HOMA-IR, HOMA-R, PSA, Prostatic size and I-PSS in all subjects HOMA-IR, HOMA-f3, PSA, prostatic size, bladder size, I-PSS, QOL score, filling score and voiding score in all subjects were shown in Table 2. As shown in Table 2, the volume, prostatic anteroposterior size, transverse size, sagittal size of the prostate and the bladder, I-PSS, QOL score, filling score and voiding score were significantly higher in the larger group than those in the smaller group. And HOMA-IR and HOMA-~3 levels were significantly lower in the smaller group than those in the larger group; HOMA-IR (1.74, 1.97: p<0.0001), HOMA-ƒÀ (70, 1, 74.5: p<0.01). Furthermore, PSA level was higher in the larger group than that in the Table 1 Clinical characteristics in all male subjects. (4ƒÎ/3) ~ (1/2)3] =1000 Bladder volume (cm3) = [Anteroposterior size (mm) ~ Transverse size (mm) ~ Sagittal size (mm) ~ (4it/3) ~ (112)3] =1000 All subjects were divided to two groups according to the prostatic anteroposterior size; 146 subjects in the smaller group ( Anteroposterior size <28.0 mm, mean size; 23.0 mm, mean age; 45.3 yrs) and 187 subjects in the larger group (Anteroposterior size 28.0 mm, mean size; 32.1 mm, mean age; 51.3 yrs), respectively. BPH symptom severity were determined by the International Prostate Symptom Score (I-PSS: total score: 35 points). As to urological symptoms, the filling score of BPH was measured with the total score of the questions 2, 4 and 7 on I- PSS (total score: 15 points) and the voiding score of BPH was measured with the total score of the questions 1, 3, 5 and 6 in I-PSS (total score: 20 points). Quality of life score was determined by the QOL score (total score: 6 points). Results were expressed as the mean±sd. Linear correlation coefficient and unpaired t-test were used for statistical *p<0.05, **p<0.01, ***p<0.001 vs Larger group, Mean }S.D. 13

3 476 HEP., Vol. 33, No. 4, 2006 smaller group (0.81 ng/ml, 1.27 ng/ml: p<0.001), however, the specific gravity and ph levels in urinalysis were not different among two groups. 3) Relationship between HOMA-IR and the prostatic various sizes in all subjects Relationships between HOMA-IR and the prostatic volume, transverse size, anteroposterior size, sagittal size were shown in Fig. 1. As shown in Fig. 1, the prostatic anteroposterior size was significantly and positively related with HOMA-IR (r=0.14; p=0.027), however the prostatic volume, transverse size and sagittal size were not related with HOMA-IR. 4) Relationship between the prostatic anteroposterior size and clinical data in all subjects As shown in Fig. 2, there was a significantly positive relationship between the prostatic anteroposterior size and BMI (r=0.10, p=0.0498), S-BP (r=0.11, p=0.0459) and D-BP (r=0.12, p=0.032), age (r=0.31, p<0.0001) in all subjects. Table 2 HOMA-IR, HOMA-R, PSA, prostatic volume, prostatic size, bladder volume, bladder size and I-PSS score in all male subjects. *p<0.05, **p<0.01, ***p<0.001 vs Larger group, Mean±S.D. Fig. 1 Relationship between prostatic anterioposterior size, transverse size, sagittal size values and HOMA-IR in all subjects. 14

4 IIzuKA et al.: Metabolic Syndrome as a Risk Factor for Developing Benign Prostatic Hyperplasia 477 Fig. 2 Relationship between prostatic anterioposterior size values and Systolic BP, Diastolic BP, BMI, age values in all subjects. Furthermore, the prostatic anteroposterior size was significantly and positively related with plasma creatinine (r=0.12, p=0.0304) DISCUSSION and blood platelet (r=0.17, p=0.0027). This study firstly revealed that there were a significantly positive relationship between the prostatic anteroposterior size and various factors of metabolic syndrome, such as insulin resistance, S-BP, D-BP and BMI, secondly demonstrated that the transabdominal ultrasonography was able to use as the standard clinical tool for the useful assessment of prostatic size in daily medical examinations. Its important merit was that it was a simple, non-invasive method for medical health examination. Watanabe et al, firstly reported that transabdominal ultrasonography was useful as a screening test for evaluating, and the parameter of horizontal shape (the ratio of the anteroposterior vs transverse dimension) of the prostate made an assessment of the degree of BPH in 51 patients with lower urinary tract symptoms.[1] There has not been other report that BPH was diagnosed by use of transabdominal ultrasonography. And, this study firstly demonstrated that transabdominal ultrasonography was the most useful method for diagnosing BPH in healthy men. The other ratio parameter of transrectal ultrasonography has been reported as transitional zone index; the ratio between transitional zone volume and prostate volume.[15] According to transitional zone index,~151 maximum urine flow rate and I-PSS worsen as transitional zone index increases. However, this study showed that the parameter of horizontal shape (the ratio of the anteroposterior vs transverse dimension) did not related with BPH, only the anteroposterior dimension of the prostate was significantly related with I-PSS and the factors of metabolic syndrome. The difference resulted from that all subjects were not clinically diagnosed as BPH or the anteroposterior size of the prostate might partially reflect the transitional zone index. In this study, lower urinary tract symptoms measured by I- PSS including the total score and the filling or voiding scores on I-PSS was significantly and positively related with age, especially 50 yrs and over 50 yrs. Interestingly, the score of I- PSS and metabolic syndrome factors including S-BP, D-BP, HOMA-IR and HOMA-ƒÀ significantly became worse as the age was increasing. The PSA level, the prostatic volume and various the prostatic sizes were higher in the larger group than those in the smaller group. However, only the anteroposterior size of the prostate was significantly related with HOMA-IR, BMI and BP. In healthy subjects without BPH, the horizontal ratio of the prostate was not different from that in patients with BPH, however the anteroposterior size of the prostate might be an important predictor for developing BPH. According to the classification aged 50 years old, the anteroposterior size of the prostate was significantly related with systolic- and diastolic-bp in men over 50 years old (n=114; r=0.14, r=0.18). Therefore, when we examined some subject over 50 years old having over 28 mm in the anteroposterior size of the prostate, or having over 5 points in I-PSS total score, we should consider that he would suffer from BPH and should be followed by the best way to rule out BPH. On the other hand, it was well established that the prevalence of BPH and diabetes increases with age.[5]-[7] Many studies reported that insulin resistance and/or hyperinsulinemia were conditions known to be associated with obesity, 15

5 478 HEP., Vol. 33, No. 4, 2006 hyperglycemia, dyslipidemia, visceral fatty disease and hypertension.[161, [17] Recently, two expert groups; the World Health Organization (WHO) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) have proposed criteria defining what they called the metabolic syndrome based on insulin resistancej16], [17] According to these criteria, the metabolic syndrome was common in older men and would increase in prevalence as age and obesity become more and more. Interestingly, both the metabolic abnormal factors and the prostatic anteroposterior size increased as age became older in this study. The higher level of the prostatic anteroposterior dimension might be an important marker for a cluster of the metabolic syndrome. The mechanism for underlying link between the metabolic syndrome based on insulin resistance and BPH, especially the prostatic anteroposterior hyperplasia has not been clear yet. The present study suggested that the hypertrophic effect of hyperinsulinemia firstly induced an enlarged prostate gland; especially the anteroposterior size of the prostate, and secondly through its sympathoexcitatory effect, the hyperinsulinemia added a dynamic component to the obstructed urinary flow. Thus, the sympathetic nerve system activated by hyperinsulinemia, which acted via alphal-adrenoceptors on vascular and prostatic smooth muscle, played important role in both BPH and hypertension. This mechanism supported the data on the efficacy and tolerability of alphas-adrenoceptor antagonists coming from studies of patients with either hypertension or BPH.[91 It was easy to get the anteroposterior dimension of the prostate by use of transabdominal ultrasonography in daily clinical examination. However we should note that transabdominal ultrasonography showed a limited ability to detect a small prostate with urinary tract obstruction. Although much work needs to be done, the current studies begin to focus attention on the role of BPH in daily health medical examination for men. ACKNOWLEDGEMENTS The authors wish to thank Dr. A. Hamada, Dr. S. Abe in Japan Overseas Healthy Administration Center for clinical advice. This study was supported by Medical Research Grant from Japan Labour Welfare REFERENCES Corporation. [1] Watanabe T, Miyagawa I: New simple method transabdominal ultrasound to assess the degree of benign prostatic obstruction: size and horizontal shape of the prostate. Urology 9: ,2002 [2] Iizuka T, Takano T, Saito J, Soyama A, Ito H, Yamaguchi K, Nishikawa T: Relationship between lower urinary tract symptoms and benign prostatic hyperplasia in type 2 diabetes (Abstract). J Japan Diabetes Society 46 Supplel: 5-246, 2003 [3] Hammarsten J, Hogstedt B: Hyperinsulinaemia as a risk factor for developing benign prostatic hyperplasia. Eur Urology 39: ,2001 [4] Michel MC, Mehlburger L, Schumacher H, Bressel H-U, Goepel M: Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. Urology 163: ,2000 [5] Reaven GM: Role of insulin resistance in human disease. Diabetes 37: ,1988 [6] Haffner SM, Rewers M, D'Agostino R Jr, Selby J, Mykkanen L, Savage P, Tracy R, Saad MF, Howard B: Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the insulin resistance atherosclerosis study. Diabetes Care 22: ,1999 [7] Meigs JB: Epidemiology of the insulin resistance syndrome. Curr Diabetes Reports 3:73-79,2003 [8] Daneshgari F, Crawford ED: Benign prostatic disease. Postgrad Med 93:82-84,1993 [9] Kaplan SA, Kaplan NM: Alpha-blockade: monotherapy for hypertension and benign prostatic hyperplasia. Urology 48: ,1996 [10] Gerich JE: The genetic basis of type 2 diabetes mellitus: Impaired insulin secretion versus impaired insulin sensitivity. Endcr Rev 19: ,1998 [11] Taniguchi A, Nakai Y, Sasaki M, Yoshii S, Hamanaka D, Hatae Y, Kawata M, Yamanouchi K, Okumura T, Tokuyama K, Nagasaka S, Fukushima M: Relationship of regional adiposity to insulin resistance and serum triglyceride levels in nonobese Japanese type 2 diabetes mellitus. Metab 51: ,2002 [12] Silverman JF, Pories WJ, Caro JF: Liver pathology in diabetes mellitus and morbid obesity: clinical pathological, and biochemical considerations. Pathol Annu 24: ,1989 [13] Bouchard C, Despres JP, Mauriege P: Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 14: 72-93,1993 [14] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and Ĉ-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: ,1985 [15] Kaplan SA, TeAE, Pressler LB, Olsson CA: Transitional zone index as a method of assessing benign prostatic hyperplasia: Correlation with symptoms, urine flow and detrusor pressure. J Urol 154: ,1995 [16] Albetti KG, Zimmet PZ: Definition, diagnosis and classitication of diabetes mellitus and its complications. Part 1: diagnosis and classification diabetes mellitus provisional report a WHO consultation. Diabet Med 15: ,1998 [17] Executive Summary of The Third Report of The National Cholesterol Education Orogram (NCEP) Expert Panel on Detection, Education, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III) (no authors listed). JAMA 2585: ,