Correlation of prostatic morphological parameters and clinical progression in aging Chinese men with benign prostatic hyperplasia: Results from a cross‐sectional study

Our study aimed to investigate the correlation of prostatic morphological parameters and benign prostatic hyperplasia (BPH) clinical progression in aging Chinese men.


| INTRODUCTION
Benign prostatic hyperplasia (BPH) is indisputable and a common benign disease among aging males, which has a worldwide prevalence of over 50% in men aged 60 years or older and as high as 88% in men up to 80 years of age. 1,2 As people age, BPH has become an important global public health concern. Though BPH is not a life-threatening disease, it is associated with serious morbidities, including depression, an increased risk of falls, and impaired quality of life (QoL). [3][4][5] BPH is also a slowly progressive disease. If left untreated, lower urinary tract symptoms (LUTS) will get severer and serious complications, such as hematuria, recurrent urinary tract infection (UTI), bladder stones, bladder diverticulum, acute urinary retention (AUR), and even renal insufficiency and failure can occur, which may be attributed to the disease progression 6 and require BPH-related surgical interventions. 7 Recent data suggest that adverse events of BPH have either increased or persisted in hospitalized patients over the past decade. 8 Surgical interventions, including minimally invasive treatment, are usually performed to alleviate symptoms and decrease disease progression in BPH patients who have developed BPH-related complications. 9 However, surgery-associated morbidities, including blood loss, sexual dysfunction, instrumentassociated injury, and even the resultant economic burden, and so forth emerge out to be real considerations.
A few trials have investigated to elucidate patients' characteristics that portend worse prognoses and discovered that incidence of BPH clinical progression increased with aging, increased body mass index (BMI), post-void residual urine volume (PVR), prostate-specific antigen (PSA) levels and total prostate volume (PV), decreased maximum urinary flow rate (Qmax), and aggravated severity of LUTS. [10][11][12] However, none of these trials studied the correlation of prostatic morphological parameters and BPH clinical progression, and the relationship was still unclear.
Moreover, China is a rapidly aging society. According to the sixth national population census in 2010, 13.26% of the Chinese population was older than 60 years. 13 And this percentage is estimated to reach to 16.7% in 2020. 14 Population aging has been a challenge for healthcare systems in China because BPH is one of the most common diseases in advanced-aged males and has high annual healthcare costs. 15,16 Thus, knowledge of the clinical and demographic factors are of great importance, especially for Chinese BPH patients. It may provide seasonable and reasonable management before progression occurs.
From these viewpoints, we have investigated the correlation of prostatic morphological parameters and clinical progression in patients with BPH in our hospital, with the goal of helping clinicians to better understand the relevant factors of BPH clinical progression, and to make the most optimized clinical strategies for BPH management.

| Study design and patient selection
This was a retrospectively observational cross-sectional study conducted on patients diagnosed with BPH in our hospital. All of those objects corresponded to the following conditions 17,18 : (1) digital rectal examination (DRE) and transrectal ultrasound (TRUS) proved the existence of benign prostatic enlargement (BPE) and (2) a systematic prostate biopsy was applied to patients with total PSA (tPSA) of over 4.0 ng/ml, and no malignant components were found.

| Assessments
Nocturnal voiding frequency was a substitute for LUTS severity in this study because nocturia is a highly prevalent and easy-tomeasure symptom, and also one of the most bothersome components in men with LUTS/BPH. 19,20 Nocturia was defined by the International Continence Society as urinating one or more times a night. 21 BPH-related complications assessed in this study included hydronephrosis, AUR, bladder stone, and bladder diverticulum, surrogating the clinical progression of BPH. 6 Hydronephrosis had to be secondary to BPH and was assessed as any pelvicalyceal or ureteral dilation observed on radiographic reports of renal ultrasonography.
AUR referred to a severe complication of BPH characterized by a sudden and painful inability to void voluntarily. 22 Bladder stone and QIAN ET AL.
| 479 bladder diverticulum should also be secondary to BPH and confirmed by radiographic reports of ultrasonography of the urinary system.
Details of the assessment of prostatic morphology have been previously published. 23,24 The ultrasound machine made by Siemens sequoia 512 (EV8C4-S, frequency 3-8 MHz) was used to estimate PV (ml), TZV (ml), and IPP (mm). Measurements of the PV and TZV were calculated using the prostate ellipsoid formula (height × width × length × π/6). TZI was calculated by dividing TZV by PV. 25 Considering the practical clinical significance, TZI was presented as TZI (%) when used as a continuous variable to incorporate into the logistic regression model. 26 PV were divided into <30 ml, 30-60 ml and >60 ml subgroups, TZV < 15 ml, 15-30 ml and >30 ml subgroups, TZI < 0.5, 0.5-0.7 and >0.7 subgroups, and IPP < 5 mm, 5-10 mm and >10 mm subgroups, respectively, according to the commonly chosen clinical grouping strategies, 10,27,28 to fit the clinical practice and extrapolate the results to clinical application.
The fasting serum level of tPSA was analyzed by using Hybritech calibrated Access tPSA assays. 23 Since tPSA could be impacted by recent catheterization in patients with AUR, it was detected 1 week after catheter removal in these patients. BMI was calculated by dividing the body weight (kg) by the square of height (m 2 ).

| Statistical analysis
All statistics were performed using PASW Statistics 22.0 (IBM Corp.).
Continuous variables were expressed as mean ± standard deviation (SD). The intergroup differences were tested using the analysis of variance (ANOVA). Categorical variables were expressed as frequency (percentage). The intergroup differences were tested using the χ 2 test. Multiple imputations (SPSS-based EM method) were used to deal with the problem of missing data. Univariate and multivariate logistic regression analyses were used to investigate the relevant factors of BPH clinical progression. Variables that changed the effect value by more than 10% were incorporated into the adjusted models. 29 Statistical significance was defined as p < .05.

| Demographics and clinical characteristics
A total of 1038 patients were reviewed. Of this cohort, 86 patients had missing data in BMI. Multiple imputations were used to generate new data and process the missing data, and no statistical differences were found between the original and the interpolated data (Table S1). Recorded clinical and demographic characteristics of all men and those subgroups divided upon specific prostatic measurements are shown in Tables 1 and 2. Prostatic morphological parameters were positively associated with age, tPSA, and nocturia (Table 2). These factors should be considered as potential confounders when estimating the correlation of prostatic measurements and BPH clinical progression.     Table 1).

| Overall incidence of BPH clinical progression
Results of ANOVA showed that the cumulative incidence of BPH-related complications was positively associated with prostatic morphology (all p < .001). Patients with a greater prostate size had a higher probability of BPH clinical progression, especially the occurrence of AUR and hydronephrosis ( Table 2). showed that additional adjustment for the confounding variables did not significantly reduce the ORs for the association between the prostatic morphological parameters and BPH clinical progression.

| PV
Multivariate logistic regression analysis confirmed that a PV of >60 ml (adjusted OR: 2.485, 95% CI: 1.559-3.960) was associated with a significantly higher possibility of BPH progression relative to that of subjects with PV < 30 ml (p < .001). But there was no statistical difference in BPH progression between patients with a PV of <30 ml and those with PV of 30-60 ml (p = .108) ( Table 4).  BPH has been defined as enlargement of the prostate gland caused by a benign overgrowth of chiefly glandular tissue and tends to obstruct urination by constricting the urethra, which was also used in our research. However, there are still some patients without enlargement of the prostate, but suffering from LUTS in clinical settings. In our study, we found that 122 (11.75%) patients had a PV < 30 ml. Foo's team proposed that clinical BPH is not BPE, but an adenoma/adenomata irrespective of size, which causes bladder outlet obstruction (BOO), and the site of adenoma/adenomata determines the degree of obstruction. 36,37 This can explain to some extent that why a small prostate can also cause BOO and induce LUTS. Unfortunately, we did not record the descriptions of the prostate adenoma/adenomata in this study, which needed to be borne in mind in future research.

| TZV
Clinical progression of BPH is mainly referred to severer LUTS with serious complications, such as hematuria, recurrent UTI, bladder stones, bladder diverticulum, AUR, and even renal insufficiency and failure. 6 The trial of Medical Therapy of Prostatic Symptoms However, when we used the simplified BPH clinical progression model, the cumulative incidence of disease progression was much higher (63.68%). But intriguingly, this result was in accordance with the Chinese habit of a delayed doctor visit until the symptoms become severe. In this study, the mean (SD) age of these first hospital visiting BPH patients was 70.61 ± 9.11 years, which was much elder than in others' reports, 10,40 confirming this special phenomenon from the other aspect. But actually, this simplified model needs to be validated by further larger-scale and better-designed studies conducted in multicenter before extrapolating the present findings to patients with BPH presenting in real life.
Nocturia is a highly prevalent and easy-to-measure bladder storage symptom, and also one of the most bothersome components in men with LUTS/BPH. 19,20 Frequently voiding twice or more per night can have a substantial impact on an individual's QoL, with sleep disruption leading to chronic fatigue, increased risk of falls and fractures, as well as mortality. 41,42 Therefore, nocturia is widely used to evaluate the severity of LUTS. 43 In China, it is impractical to systemically evaluate the LUTS severity of patients in their first outpatient or emergency visiting using PVR, Qmax, IPSS, or other index scores in most situations because of the imbalance in patient-clinician ratio and the inspection-related economic burden, especially at primary hospitals. And as an attempt to make our work more broadly applicable by creating a simplified model with easily measured factors, we used nocturnal voiding frequency as the life, in clinical settings. Consequently, further larger-scale prospective and better-designed studies would be helpful.
In brief, prostatic morphological parameters are significantly associated with BPH clinical progression. Patients with larger prostatic morphological parameters are more easily to progress. Utilizing these parameters permits the estimation of individual patient risk for clinical progression. Novel clinical decision strategies based on our results will allow urologists to weigh patient-specific benefits against possible risks of adverse effects for a given patient, which will be helpful in developing more cost-effective treatment strategies for BPH management. But our results need to be further validated before extrapolating in clinical application.

ACKNOWLEDGMENTS
The authors appreciate Dr. Weiming Wang, Dr. Liang Zhang, and other colleagues in Xinhua Hospital for data collection. We also gratefully acknowledge the contributions of Dr. Yunkai Zhu and Dr.
Yaqing Chen (Department of Ultrasonography, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University) for their excellent technical assistance in the ultrasound examinations.

CONFLICT OF INTERESTS
The authors declare that there are no conflict of interests.

ETHICS STATEMENT
All procedures performed in this study were in accordance with the ethical standards of the Ethics Committee of Xinhua Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

AUTHOR CONTRIBUTIONS
Subo Qian: study design, data collection and management, data analysis, manuscript writing, and editing. Shun Zhang: study design, data collection, data analysis, manuscript writing and editing. Weimin Xia: data collection and data analysis. Ding Xu: data collection and data analysis. Jun Qi: manuscript editing and supervision. Haibo Shen: study design, data analysis, manuscript editing, and supervision. Yu Wu: study design, data collection and management, data analysis, manuscript editing, and supervision.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author, Yu Wu, upon reasonable request.