Metabolic syndrome-related factors as possible targets for lower urinary tract symptoms in Korean males

Abstract Introduction A positive association between benign prostate hyperplasia (BPH)/lower urinary tract symptoms (LUTS) and metabolic syndrome (MetS) was reported in several studies, but studies from Asia often showed conflicting results. Materials and methods Medical records were obtained from a health promotion center database between 2021 and 2022. Men without a history of treatment for LUTS were evaluated using the International Prostate Symptom Score (IPSS), Overactive Bladder Symptom Score (OABSS), transrectal ultrasonography. Results Of 1345 individuals, 603 (44.8%) had MetS. Older age, higher IPSS values, higher prevalence rates of BPH and overactive bladder, higher triiodothyronine, and lower testosterone and sex-hormone binding globulin were observed in individuals with MetS than in individuals without MetS. The severity of LUTS significantly increased in the individuals with MetS (p = .002). In individuals with MetS, age, HbA1c, and cerebrovascular disease (CVD) were associated with IPSS. For OABSS, age, HbA1c, thyroid-stimulating hormone (TSH), coronary artery occlusive disease, and CVD were identified as predictors. Conclusions We confirmed the positive correlation between MetS and BPH/LUTS in Korean. Factors including TSH and atherosclerosis affected LUTS in individuals with MetS. These findings suggested a potential role of thyroid hormones and atherosclerosis in the etiology and treatment of BPH/LUTS in patients with MetS.


Introduction
Lower urinary tract symptoms (LUTS), which can include weak urinary stream, urgency, urinary frequency, nocturia, and incomplete voiding, are common in the elderly population and commonly result from benign prostatic hyperplasia (BPH) [1,2].BPH is a chronic, progressive disease influenced by endocrine factors such as androgens and estrogens, growth factors, and other causes.Among men over the age of 40 years, about 50% will develop BPH, and 30-50% of those will have LUTS.These findings suggested that BPH/LUTS is related to underlying mechanisms and pathophysiological cofactors of more than a single cause [3,4].
Several studies have presented a positive correlation between metabolic syndrome (MetS) and BPH/LUTS.It has been suggested that MetS may lead to intraprostatic inflammation and exacerbate BPH [5,6].However, the mechanism between MetS and BPH/LUTS is unclear, and a three-hit hypothesis was suggested.The first hit is a prostatic inflammation induced by infection; the inflammation could be sustained or exacerbated by altered metabolism, particularly hypercholesterolemia (second hit).The third hit is hypogonadism or hyperestrogenism.The combined action of the three hits may result in prostate remodeling and further prostate enlargement [7].Additionally, thyroid dysfunction had a major impact on all components of MetS, and recent studies showed that free thyroxine (FT4) was related to BPH/LUTS [8,9].Another study reported that nonalcoholic fatty liver disease (NAFLD) was associated with BPH and LUTS while NAFLD is regarded as a hepatic feature of MetS [10,11].
Most US and European population-based studies demonstrated a positive association between MetS and LUTS, but Asian-population based studies often show contrasting results [12][13][14].Thus, we investigated the relationship between MetS and BPH/LUTS in the Korean population needing further evaluation and identified the effects of several MetSrelated factors on BPH/LUTS.

Materials and methods
This study was approved by the institutional review board (IRB) of our institution (IRB number: 3-2020-0236).The requirement for informed consent was waived as the study was based on retrospective, anonymous patient data and did not involve patient intervention or the use of human tissue samples.Medical records were reviewed from a health promotion center database of male patients who underwent medical examinations between March 2021 and February 2022.Data collected included age, body mass index (BMI), medical history, blood laboratory test results, prostate volume (PV), prostate-specific antigen (PSA), International Prostate Symptom Score (IPSS), and Overactive Bladder Symptom Score (OABSS) results.
To avoid selection bias, only patients with the first visit to our hospital for medical examination who underwent both transrectal ultrasonography (TRUS) and abdominal ultrasonography simultaneously were enrolled in the study.TRUS is recommended for patients over 40 years of age.Based on medical history, patients with a history of medical or surgical treatment for prostate disease, pyuria in urine analysis, uncontrolled diabetes mellitus (DM), bladder carcinoma, and those who had undergone lower abdominal surgery were excluded.
MetS was defined according to modified National Cholesterol Education Program Adult Treatment Panel III criteria.MetS is diagnosed when three or more of the following five criteria are met: waist circumference � 90 cm (male), systolic blood pressure � 130 mmHg or diastolic blood pressure � 85 mmHg or drug treatment for hypertension (HTN), triglyceride (TG) level � 150 mg/dL or drug treatment for elevated TG, highdensity lipoprotein cholesterol (HDL-C) level � 40 mg/dl (male) or drug treatment for low HDL-C, and fasting blood glucose � 100 mg/dl or drug treatment for elevated glucose [15].
IPSS is based on the answers to seven questions concerning urinary symptoms and one regarding the quality of life.The answers are assigned points from 0 to 5. The total score ranges from 0 to 35 (asymptomatic to very symptomatic).Total IPSS values were categorized as mild (scores 0-7), moderate (scores 8- 19), and severe (scores 20-35) LUTS.OABSS consists of four symptoms (daytime frequency, nocturia, urgency, and urge incontinence), and the total score is obtained as the sum of the four symptom scores.Overactive bladder (OAB) diagnosis was defined as an OABSS � 3 with an urgency score of � 2. PV was calculated using the prostate ellipsoid formula (height � width � length � p/6) from TRUS data.BPH was defined by PV � 30 cm 3 [16].Fatty liver disease was diagnosed and stratified in severity based on known standard criteria according to the level of hepatic tissue hyperechogenicity, a discrepancy between the liver and right kidney, and visibility of the vascular structures [17].
Continuous variables are expressed as median (interquartile ranges), whereas categorical variables are reported as the number of occurrences and frequency.Baseline characteristics were compared using the Chi-Squared test for categorical data and Student's t-test for continuous data.Multiple linear regression analysis with forward stepwise procedures was used to identify predictors for LUTS after identifying the factors by simple linear regression analysis.The level of significance was set at .05 in all analyses.All statistical analyses were performed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA).

Results
Of 1345 individuals, 603 (44.8%) had MetS.The baseline characteristics of the individuals with and without MetS are shown in Table 1.Older age, higher total IPSS values, larger PV, higher prevalence rates of BPH and fatty liver, higher triiodothyronine (T3), and lower testosterone and sex-hormone binding globulin (SHBG) were observed in individuals with MetS than in those without MetS.The prevalence of OAB was significantly higher in individuals with MetS than in those without MetS (16.6% vs. 23.9%,p ¼ .001).The severity of LUTS significantly increased in the individuals with MetS: 48.9% vs. 54.7% for moderate and 7.1% vs. 10.3% for severe LUTS (p ¼ .002).The severity of fatty liver also increased in the individuals with MetS: 16.6% vs. 39.5% for moderate to severe fatty liver (p < .001).PSA, free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were not different between both groups. In

Discussion
The  [20][21][22].Therefore, we investigated the relationship between MetS and BPH/LUTS in Koreans needing further evaluation.The pathophysiological factors associated with the development and aggravation of BPH/LUTS were investigated in multiple studies.Vignozzi et al. found a correlation between sex hormone changes and BPH in rabbits on a high-fat diet.Receptors for sex steroids were increased in the prostates of rabbits, suggesting that the sensitivity to changing gonadal hormones is upregulated in MetS [23].Consecutively, the authors suggested a three-hit hypothesis.The first hit is a prostatic inflammation induced by an overt, subclinical, bacterial, or viral infection.The second hit is sustained or exacerbated inflammation by altered metabolism, particularly hypercholesterolemia.The third hit is hypogonadism or hyperestrogenism favoring the maintenance of the inflammatory state.The combined action of the three hits may result in prostate remodeling and further prostate enlargement [7].Total testosterone level continuously decreases with age, and the lowest level was observed in males in their 50 s.There is a paradoxical increase in men > 60 years [24,25].Similarly, the increase in MetS with age continues up to the sixth decade; however, a variable prevalence was observed after the sixth or seventh decade [26,27].These findings also suggested a potential relationship with sex hormones, MetS, and BPH.
In the present study, PV was a significant factor for IPSS in all individuals, and age, PSA, and waist circumference were related to PV.It is well known that PV is strongly related to PSA in men with BPH and increases with advanced age [28].A relationship between obesity and PV was clarified in several studies.Fowke et al. found that PV significantly increased as BMI or waist circumference increased in men with a negative prostate biopsy [29].A positive association between PV and waist circumference was also identified in the Korean male population [30], and this relationship was confirmed in our study.Furthermore, patients with MetS had larger PV and higher annual prostate growth rate compared with patients without MetS [31,32].
NAFLD is considered a hepatic feature of MetS and is significantly associated with inflammatory molecules, cytokines, and low testosterone [33,34].Considering the three-hit hypothesis, NAFLD could affect, at least in part or indirectly, the development of BPH.Chung et al. reported that NAFLD was associated with an increased risk of BPH regardless of MetS, and the risk increased incrementally according to NAFLD severity [10].Eren et al. found that NAFLD grade correlated positively with IPSS values, PV and post-voided residual urine volume, whereas there was a negative correlation with maximum urinary flow rate [11].In our study, however, fatty liver was not a predictor of increasing total IPSS and OABSS values regardless of MetS.Since LUTS is caused by various conditions, bothersome LUTS was present in 30-50% Thyroid dysfunction intimately interacts with all components of MetS, and thyroid hormones have a role in cell differentiation, growth, and metabolism.Recent studies showed that free thyroxine (FT4) was significantly related to large PV and high IPSS values [8,9].In our study, higher T3 was observed in individuals with MetS than in those without MetS, and TSH was significantly associated with OABSS in all individuals and in those with MetS.Thus, further studies about thyroid hormones in the relationship and therapeutic potential for BPH/LUTS are needed.
Male OAB is associated with bladder outlet obstruction caused by BPH [35].In a previous study, OAB patients with concomitant BPH/LUTS showed higher OABSS, OABSS subscores, total IPSS values, IPSS subscores, and CVD history than OAB patients without BPH/LUTS [36].The present study found that CVD is significantly associated with total IPSS values in individuals with MetS, and CAOD is significantly related to total IPSS and OABSS values regardless of MetS.These findings suggest a positive correlation between systemic atherosclerosis and the severity of LUTS.Atherosclerosis in the aorta and its branches, especially the iliac arteries, could result in a chronic decrease in blood perfusion to the lower urinary tract, and chronic bladder ischemia is a common cause of LUTS in the elderly [37].Moreover, atherosclerosis is a chronic inflammatory disease characterized by the infiltration of vascular walls by lipids and leukocytes, and MetS is a powerful and prevalent predictor of cardiovascular events [38,39].Cakir et al. reported that patients with BPH and MetS who had tamsulosin plus statin therapy showed more improvement in IPSS values than those who had either tamsulosin or statin therapy [40].Therefore, treatment of MetS components can prevent atherosclerosis and probably LUTS.
There are several limitations to this study.First, the study was designed as a retrospective study conducted at a single institution; thus, our results may not be generalizable.Second, objective evaluation of LUTS was limited because uroflowmetry was not included in the medical examination items of our health promotion center.Third, we only suggested potential therapeutic targets of BPH/LUTS treatment.Further studies are needed to prove the effectiveness of the proposed treatment options on BPH/LUTS.Finally, the analysis was conducted for men only.To determine the effect of MetS on the lower urinary tract, further studies need to be conducted on women and compare these with data from men.
In conclusion, we confirmed the positive correlation between MetS and BPH/LUTS in the Korean population.Factors including TSH and atherosclerosis affected LUTS in individuals with MetS.These findings suggest a potential role of thyroid hormones and atherosclerosis in the etiology and treatment of BPH/LUTS in individuals with MetS diagnosed.Further research is required to find novel pharmacological options whose potential we have proposed.

Table 2 .
Multiple linear regression analysis for IPSS, OABSS, and prostate volume.

Table 3 .
Multiple linear regression analysis for IPSS, OABSS according to metabolic syndrome.