Changes of resistance indices after medication in benign prostatic hyperplasia: a prospective study

Background This study aimed to determine the relationship between resistive indices (RIs) and changes in prostate size after medical treatment in patients with benign prostatic hyperplasia (BPH). Methods A total of 86 patients with BPH were included in the study, excluding 42 patients with a total prostate volume (TPV) of <30 cc or taking α1-adrenergic blockers and 5α-reductase inhibitors (5ARI) before study participation. Therefore, the data for 44 patients were analyzed. All patients were treated with α1-adrenergic blockers and 5ARIs. The variables examined were prostate-specific antigen, International Prostate Symptom Score, quality of life score, maximal urinary flow rate, residual urine volume, TPV, transition zone volume, and RIs of the urethral artery and left and right capsular arteries. These variables were assessed at baseline and after 3 and 6 months of treatment. Results The mean TPV was 43.5 ± 10.9 and decreased to 35.2 ± 11.5 and 33.9 ± 9.8 after 3 and 6 months of treatment, respectively (p < 0.001). The mean RI of the urethral artery, right capsular artery, and left capsular artery at pretreatment did not decrease significantly. However, comparing the baseline with 3-month data, TPV at 3 months/TPV at baseline was significantly correlated with RI changes in the left capsular artery (r = 758; P < 0.001). Conclusion In patients with BPH, α1-adrenergic blocker and 5ARI medications for 3 and 6 months did not result in a significant reduction in the RI of the urethral artery and both capsular arteries. Larger scale, prospective studies are needed to evaluate the relationship between TPV and RI reductions.


Introduction
Benign prostatic hyperplasia (BPH) causes moderate-to-severe lower urinary tract symptoms (LUTS) and worsens the quality of life [1][2][3].Transrectal ultrasonography is commonly used in the evaluation of BPH, and the Korean clinical practice guideline also advocates its use [4].Grayscale transrectal ultrasonography is mainly used to measure transition zone volume (TZV) and total prostatic volume (TPV), and color Doppler ultrasound is used to evaluate the structures of the prostate capsular and the urethral arteries [5][6][7].The resistive index (RI), which is defined as the systolic flow velocity minus the diastolic velocity divided by the peak systolic velocity (as determined by color Doppler ultrasound), is useful for the diagnosis and follow-up of BPH [6][7][8][9][10].
Studies have reported that surgical management, such as transurethral resection and transurethral vaporization of the prostate, significantly reduces RIs in patients with BPH [8,11,14,15].a1-Adrenergic block monotherapy has been found to significantly reduce prostate RI [15].Few studies have evaluated the changes in RIs after treatment with a1-adrenergic blocker and 5a-reductase inhibitor (5ARI) in patients with BPH patients.This study assessed the correlation between RIs and prostate volumes after combined treatment with a1-adrenergic blocker and 5ARI in patients with BPH.

Materials and Methods
This prospective study was performed with the approval of the Institutional Review Board of Dongguk University Gyeongju Hospital (IRB number: 110757-201708-HR-02-10). Informed consent was obtained from all the study participants.
Data were collected from patients diagnosed with BPH and having LUTS.A total of 86 patients were initially considered.Those with an elevated prostate-specific antigen (PSA) level (>4 ng/mL) or abnormal digital rectal examination findings underwent transrectal prostate biopsy to rule out prostate cancer.Two patients were excluded from the study for a TPV of <30 cc.The remaining 84 patients with a TPV of >30 cc were measured at baseline and compared with after 3 and 6 months of combined treatment with a1-adrenergic blocker and 5ARI.PSA levels, IPSSs, QoL scores, Q max values, PVRs, TPVs, TZVs, and RIs of the urethral and left and right capsular arteries were also measured at baseline and compared with after 3 and 6 months of combined treatment with a1adrenergic blocker and 5ARI.TPVs, TZVs, and RIs were measured by three urologists not otherwise involved in the study.An H60 ultrasound system (Samsung Madison, Seoul) equipped with a 6.6-MHz transrectal probe was used to measure TPVs, TZVs, and RIs (Fig. 1).Of the 84 patients, 40 who took a1-adrenergic blockers and 5ARI before the study period were excluded.Therefore, the study cohort consisted of 44 patients.
Descriptive statistics were presented as mean ± standard deviations or medians (interquartile ranges).Q max values and PVRs at baseline and after treatments for 3 and 6 months were compared using the generalized estimating equation.Other clinical data at baseline and after treatment were compared using the generalized linear mixed model.Relationships between RI and TPV changes were analyzed using Spearman's rank correlation coefficients.All pvalues were two sided, and p-values of <0.05 were considered significant.The analysis was conducted using SPSS version 26.0 (SPSS Inc., Chicago, IL).
Fig. 2 demonstrates the RI changes and prostate size over time as a graph.IPSS symptom scores, QoL scores, and TPV exhibited significant changes after 6 months of treatment and between 3 and 6 months.Q max values were changed significantly after 3 months of treatment.Other clinical variables did not exhibit significant changes posttreatment.
Table 3 summarizes the correlation coefficients between the RI and prostate volumeerelated variables.The baseline and 3-month values were compared and showed TPV at 3 months/TPV at baseline was significantly correlated with RI changes of the left capsular artery (r ¼ 758; P < 0.001).However, no correlation was observed between the RI of the urethral and right capsular arteries and TPV at 3 months/TPV at baseline.

Discussion
The present study revealed that combined treatment with a1adrenergic blocker and 5ARI did not reduce RIs in patients with BPH.However, TPV at 3 months/TPV at baseline was significantly correlated with RI changes of the left capsular artery.Testosterone and dihydrotestosterone promote growth in the stromal and epithelial cells of the prostate gland in BPH [16].This inner growth and the outer prostate capsule surround the prostate gland, increase intraprostatic pressure, and provoke periurethral compression [11,16].A decrease in elasticity and the amount of collagen in the prostatic urethra reduce prostatic urethra compliance and increase resistance to flow [16,17].These two mechanisms exacerbate BOO [16,17].Urethral arteries, which originate from the inferior vesical arterial system, form a right angle and surround the prostate gland through the bladder neck.The capsular arteries originate from the prostatic arteries as they pass along the anterolateral surface of the prostate [7,12].Elevated intraprostatic pressure increases prostate vascular resistance by compressing the blood vessels in the prostate, and RIs provide a measure of this increase in vascular resistance [9,11,13].RIs may be considered as noninvasive measures of BOO severity for this reason [6,9,10,12].a1-Adrenergic blockers loosen smooth muscle tone in the urethra, bladder neck, and prostate gland by inhibiting a1-adrenergic receptors, which predominate in these areas [18].Bulut et al. [15] reported that alfuzosin 10 mg once daily for 3 months decreased the RIs of the prostate and capsular arteries from 0.73 ± 0.1 to 0.70 ± 0.1 (p ¼ 0.0001) in patients with mild-to-moderate LUTS and Q max values of <15 mL/s.Significant RI reductions of prostate capsular arteries after treatment with a1-adrenergic blocker imply that prostate muscle tone may be associated with intraprostatic pressure [15].However, no significant difference was observed between RIs at baseline and after 3 months of treatment in patients with TPVs of !30 cc who had received a combined treatment of a1adrenergic blocker and 5ARI.Previous reports have shown that a1adrenergic blocker monotherapy is most effective at 3 months in BPH with TPVs !30 cc, as determined using IPSSs [19], and 5ARI monotherapy improves symptoms after more than 4e6 months of treatment and reduces TPVs and TZVs continuously until 24 months [20,21].a1-Adrenergic blocker monotherapy exhibited clinical progression in patients as TZVs increased over time [19,20].These findings show that decreases in intraprostatic pressures induced by a1-adrenergic blocker monotherapy were insufficient in these patients.However, doses and types of a1-adrenergic blockers were not unified in these studies, and these two factors may have contributed to this result.
The longitudinal changes in prostate capsular RIs observed in this study were smaller than those reported by other studies that included patients who underwent surgical treatment.Although intraprostatic pressure starts decreasing from 1 month after surgical treatment, the effect of 5ARI treatment on TPV continues for 24 months [8,20,21].Patients were followed after treatment only Table 2 Changes in clinical variables in baseline and after 3 and 6 months' treatment using a1-adrenergic blockers and 5a reductase inhibitors  for 6 months, which was insufficient to observe the effect of 5ARI.Bulut et al. [15], in a comparative study of medical and surgical treatment groups at 3 months, reported that the surgical treatment group showed greater reductions in the RIs of prostate capsular arteries, which suggests a1-adrenergic blocker monotherapyeinduced reductions in RIs of prostate capsular arteries are less than those achieved by surgical treatment [15].A shorter follow-up period and different treatment modalities may explain the observed differences between the RIs of the prostate capsular arteries.
The RIs of urethral arteries did not decrease significantly after the combined treatment with a1-adrenergic blocker and 5ARI in the present study.Tsuru et al. [22] reported that the RIs of urethral arteries were not correlated with TPV, TZV, IPSS, and Q max .RIs of prostate capsular arteries were taken as assessment tools in the majority of studies that have evaluated changes in RIs in BPH after treatment [8,14,15].5ARI reduces TZVs and TPVs [20,21], and the associated gradual decrease in intraprostatic pressure may be associated with decompression of urethral and prostate capsular arteries.
Although RIs of the urethral and right capsular arteries were not significantly correlated, the only significant finding was that TPV at 3 months/TPV at baseline was significantly correlated with RI changes of the left capsular artery.Previous studies demonstrated that TPV was correlated with RI in BPH [8,12].To the best of our knowledge, only a few studies reported the correlation between TPV and RI changes.Considering that the greater the rate of decrease in TPV, the greater the decrease in prostatic pressure, these results may have some significance [9,11,13].Because RI on the opposite side was not correlated with TPV at 3 months/TPV at baseline, further studies are needed to confirm this clinical significance.
This was believed to be the first prospective study to compare the RIs of urethral arteries and left and right capsular arteries at baseline and after 3 and 6 months of combined treatment with a1adrenergic blocker and 5ARI in patients with BPH.The study results demonstrated nonsignificant treatment-induced RI changes in the urethral and both capsular arteries.Approximately 50% of patients had missing values during follow-up periods, which would be one of the reasons that this study demonstrated nonsignificant results.
Also, this study has several limitations.First, the sample size was small.Second, lifestyle factors (e.g., alcohol consumption and cigarette smoking) were not considered, which affect LUTS and vascular diseases [15,[23][24][25].Third, as mentioned earlier, the study period was not long enough to access the effect of 5ARI.Fifth, the study did not contain a control group (e.g., a1-adrenergic blocker alone, 5ARI alone, or a placebo group).

Conclusions
It was shown that the combined treatment with a1-adrenergic blocker and 5ARI for 3 and 6 months did not significantly reduce the RIs of urethral and both left and right capsular arteries in BPH patients with a TPV of !30 cc.Larger scale, prospective studies, including the control group, are required to evaluate the nature of the relationship between TPV reduction and RIs after the combined treatment.

Fig. 2 .
Fig.2.RI and total prostate volume changes at baseline and after 3 and 6 months of treatment using a1-adrenergic blockers and 5a-reductase inhibitors.RI, resistive index.

Table 1
Baseline clinical characteristics

Table 3
Correlation coefficients between the RIs and prostate volumeerelated variables TPV, total prostate volume; TZV, transition zone volume.D.J. Park et al. / Resistance indices in benign prostatic hyperplasia