A Focused Review on the Effects of Preoperative 5α-Reductase Inhibitors Treatment in Patients Undergoing Holmium Laser Enucleation of the Prostate: What Do We Know So Far?

Introduction

Holmium laser enucleation of prostate (HoLEP) has been established as an alternative to transurethral resection of prostate (TURP) for the treatment of patients with benign prostatic hyperplasia (BPH) and with long-term results comparable with TURP and open prostatectomy. ¹ A frequently reported criticism of HoLEP is the steep learning curve associated with surgical efficiency. ² Thus, understanding the factors and tissue variables associated with surgical efficiency may assist proper patient selection for surgeons in various levels of experience.

There is observational prejudice among experienced HoLEP surgeons, which preoperative treatment with 5α-reductase inhibitors (5-ARIs) may cause changes in tissue characteristics that could increase the difficulty of procedure. Theoretically, as 5-ARIs increase the fibrosis of the prostate, identifying and maintaining the appropriate plane between adenoma and surgical capsule of the prostate could be more challenging. ³ The aim of this review was to investigate all existing literature with regard to the effects of preoperative 5-ARIs treatment during HoLEP.

Materials and Methods

We performed a literature search of PubMed, Scopus, and Web of Science databases for articles published from inception through to August 2017 (inclusive). The search protocol used was a combination of the following words: “finasteride,” “dutasteride,” “5a-reductase inhibitors,” “enucleation,” and “prostate.” All articles in English language related to the topic were reviewed to provide data on the influence of preoperative 5-ARIs in HoLEP.

Results

The mentioned literature review yielded only seven studies (including two congress abstracts) related to the impact of 5-ARIs on HoLEP. ^{2,4 –9} In all studies, the data were collected retrospectively. Two used retrospective video recording for evaluation of the surgical technique characteristics, one of them for bleeding severity and the other for enucleation difficulty. There was a variation across the included studies, with different percentage of patients receiving 5-ARI treatment, whereas the duration on treatment was either not documented or random. Most studies comment on commonly used variables of surgical efficiency such as enucleation time, morcellation time, operating time, prostate tissue volume resected, enucleation efficiency (enucleated weight/enucleation time), energy, and saline usage (Table 1).

In a retrospective study, El Tayeb et al. included 714 HoLEP patients, 31.1% of whom had been taking 5-ARIs preoperatively. No statistical significance was found in the use of 5-ARIs as a predictor of enucleation and/or morcellation times. A multivariate analysis of the same data found that only the weight of the specimen removed was predictive of the time involved. ⁸ Similar results were obtained by Choo et al. In their retrospective study of 107 patients who underwent HoLEP, the location of bleeding arteries was delineated, marking their number and severity of bleeding. A total of 16.8% of those patients were taking 5-ARIs. There was not any statistical significance between the number of bleeding arteries and/or the severity of overall bleeding and the previous use of 5-ARIs. In this study, univariate analysis showed that an important predictor of bleeding (number of intraoperative bleeding arteries) was the Prostate Specific Antigen level, a history of a preoperative biopsy, and incidental finding of prostate cancer in final pathology analysis. Multivariate analysis, however, found prostate volume to be the only significant parameter. ⁴

Another retrospective study by Kikuchi and coworkers evaluating postoperative infectious complications enrolled 190 patients undergoing HoLEP. Thirty-seven of those, almost 20%, were on dutasteride treatment. After multivariate analysis, the authors found that patients on dutasteride had significantly less postoperative bacteriuria. The authors concluded to the hypothesis that probably because of the reduction of prostatic vascularity and potential less perioperative bleeding, the incidence of postoperative bacteriuria was reduced. The exact mechanism of action, if this observation is true, is yet unknown. ⁵

Placer et al. have assessed the preoperative usage of 5-ARI either finasteride or dutasteride in patients undergoing HoLEP. This nonrandomized study included 250 consecutive patients: 144 receiving 5-ARI for at least 3 months and 106 patients with no treatment. These two groups have been compared in relation to specific surgical parameters to assess for effectiveness and complexity of surgery. The authors did not find any difference in operating time, energy, and saline usage, intraoperative complications, hemoglobin decrease, and hospital stay, and conclude that 5-ARI treatment did not have any effect on HoLEP. The only statistically significant difference between those two groups was the higher prostate volume of the patients who received 5-ARI treatment, which also explains the higher resected volume during HoLEP. ⁶

The largest retrospective study included in our analysis is by Monn et al., which enrolled 960 patients and reached a similar conclusion. In this study, the authors tried to find preoperative predictors of enucleation and morcellation efficiency in patients undergoing HoLEP. They did find that reduction of operating time was related to prostate volume, tissue quality (tough prostatic tissue termed as beach balls), previous history of urinary tract infection, and surgeons' experience. In their analysis, they included patients also receiving 5-ARIs and report that despite a trend toward faster enucleation time in those patients on 5-ARI treatment, this has not reached statistical significance. Morcellation time, however, was slightly reduced in these patients, which is somehow controversial considering that in theory 5-ARI treatment could increase the fibrous content in the prostate, resulting in more difficult morcellation because of the quality of tissue enucleated. The authors do accept the fact that this could be a random effect because of multiple variables resulting in this observation. In addition, the use of 5-ARI was not associated with any reduction in bleeding. ²

Warner and colleagues calculated the average enucleation rate (or enucleation efficiency = enucleated weight/enucleation time) in 176 patients undergoing HoLEP. Patients separated into four groups: those with no medical treatment (Group A), with a-blocker (Group B), 5-ARI alone (Group C), and combination treatment with a-blocker and 5-ARI (Group D). Further analysis of the population in two cohorts (Group A + B and Group C+D) to evaluate the tissue-specific effects of 5-ARIs revealed a trend toward higher enucleation rate for the latter cohort (0.91 vs 0.63 g/minutes), which did not reach statistical significance. No statistically significant difference was found in the complication rate between the two cohorts. ⁹

Factors that could influence the degree of difficulty in maintaining the correct plane between the surgical capsule and the prostatic adenoma were investigated in a very interesting article from Sato and coworkers in Japan. Age at the time of surgery, history of acute urinary retention, preoperative dutasteride treatment for 3 months, pre-existing urinary tract infection or bladder stones, clean intermittent catheterizations, indwelling urinary catheter, TURP, and prostate hyperthermia therapy were the factors included in the analysis. The authors used newly defined criteria to assess the difficulty in enucleating the adenoma from the surgical capsule, using retrospective video recording from the operation. Three evaluators, blinded to patient information, classified enucleation difficulty into four grades. The classification was based on the proportion of the adenoma surface that could be enucleated easily, with a clear view of the surface and without making an incision through the tissue between the adenoma and capsule, with the exception of incisions in the mucus layer or those made to reach the capsule: grade I difficulty, ≥75% of the surface; grade II, ≥50% of the surface; grade III, ≥25% of the surface; and grade IV, <25% of the surface. The higher the grade, the more difficult the enucleation. Before this, the evaluators graded 20 operations not included in the study and the grading was identical in 18 operations. The authors found that preoperative dutasteride treatment was the only contributing factor influencing the difficulty in dissecting the surgical capsule. Surgical time, weight of the resected prostate, and resection efficiency were not affected, leading to the assumption that surgeons with a certain level of skill can overcome this difficulty, which does not directly translate into reduction of surgical efficiency. There was also a statistical difference in postoperative drop in hemoglobin levels between the two groups in favor of dutasteride arm. However, the drop in hemoglobin in both groups was minimal, arising to a mean 0.6 g/dL in the nondutasteride group compared with 0.3 g/dL in the dutasteride group (p = 0.03). ⁷

Discussion

5-ARIs block the conversion in the prostatic stroma cells of testosterone into its active form, dihydrotestosterone. Through this action, 5-ARIs decrease the activity of androgen-controlled growth factors that are responsible for angiogenesis and vascularization. ¹⁰ Given the above, they can theoretically reduce operative prostatic bleeding. And indeed, this has been proven in many randomized studies evaluating the role of preoperative 5-ARIs in reducing blood loss in classic monopolar TURP. ^{11 –13} Busetto et al. also studied the influence of 8-week course with dutasteride in bipolar TURP (B-TURP). They found that dutasteride could reduce operative, perioperative bleeding and prostate vascularity (using the molecular markers for vascular endothelial growth factor [VEGF] and CD34), but only in patients with large prostates (≥50 mL) who underwent B-TURP. ¹⁰ Similarly, dutasteride reduced perioperative blood loss in a retrospective study, including patients who underwent open prostatectomy. ¹⁴

In contrast, long-term treatment with 5-ARIs does increase the risk of fibrosis of prostate. ¹⁵ Enatsu et al. have shown with histopathology that the fibrotic changes in the prostate and penis were higher in rats receiving dutasteride than the control group. ³ Kim and colleagues compared with Elisa the transforming growth factor-β (TGF-β) concentration in TURP specimens, between men receiving 5-ARIs preoperatively for at least 1 year and men without prior treatment. TGF-β signaling pathway plays the most important role in the fibrotic process. TGF-β was significantly increased in the first group, meaning that at least long-time treatment with 5-ARIs increases prostatic fibrosis. ¹⁵ On top of that, 5-ARIs reduce prostate volume by causing regression of the soft glandular element of the gland, resulting in a greater percentage of the fibromuscular stromal element. ⁸

Theoretically, these fibrotic changes can increase the degree of difficulty in identifying and maintaining an appropriate plane on the surgical capsule of the prostate during transurethral enucleation techniques. This plane is vital for proper dissection and hemostasis, so increased fibrosis could cause difficulty in defining it. ⁹ However, the reduction of bleeding during this procedure could contribute on maintaining a clear field with better vision, which could assist the operator completing easier and faster the enucleation part. This has been proven as mentioned before in TURP, but there is also histopathologic evidence in HoLEP as described by Sugie and coworkers who performed an in vivo evaluation of microvessel density (MVD) in prostates with BPH treated with dutasteride. Administration of dutasteride for 7.07 ± 2.46 weeks before HoLEP caused a reduction in MVD in the tissue of patients with BPH, particularly in the bladder neck side. ¹⁶

The mentioned two competing factors, increased fibrosis versus reduction of bleeding during the operation, were the motivation for this review, to find out whether 5-ARIs facilitate or not HoLEP. Despite the poor quality and absence of consistent data in the literature, some conclusions can be drawn. In the studies included in this review, several factors were analyzed as potential surrogate markers of surgical efficiency. These included enucleation and morcellation time, resected prostate volume, enucleation and morcellation efficiency, bleeding, intraoperative complications, hospital stay, and postoperative infections. According to Warner et al., enucleation rate was higher in patients receiving 5-ARIs than those who did not, independent of prostate size. ⁹ Similarly, Monn et al. identified a trend to faster enucleation time in patients on 5-ARI treatment, however, this did not reach to any statistical significant difference. ² The rest of the studies failed to show any significant either positive or negative impact of the preoperative use of 5-ARIs. If we were to define the mentioned surgical parameters as a measure of how 5-ARIs could impact surgical efficiency, it could be stated that we have some evidence (but not strong because of the retrospective and nonrandomized nature of the studies that could introduce bias) that 5-ARIs do not negatively impact significantly the operating surgeon and in fact it might facilitate the enucleation step because of the trend of an improved enucleation rate.

However, this statement must be made with caution especially in the absence of randomized studies. Sato and colleagues made a very important observation. ⁷ Even though surgical efficiency (surgical time, enucleation time, and resected prostate volume) does not show to be impacted by the use of dutasteride, still in their retrospective review of the video recordings of HoLEP operations, it was evident that the enucleation process was graded as more difficult in patients receiving 5-ARIs using a custom-made grading score during the enucleation step. The absence of difference in the surgical efficiency and outcomes most likely results because of the high level of experience in the participating surgeons in the included studies. This is highly likely to be true, as a skilled surgeon is able to orient and identify the surgical capsular plane even in more challenging circumstances. This comes in disagreement with Warner and coworkers wherein the enucleation rate, hence the surgical efficiency, was in fact increased in patients on 5-ARIs. ⁹ The authors in the latter speculate that this could be an effect of potential less bleeding because of the use of 5-ARIs, which could lead to better observation of the operating field or less enucleated adenoma.

The grading of Sato et al. seems easy and reproducible and similar classification scores might be used in the future to be able to compare the results of different studies. Perhaps less experienced surgeons could use this information and be cautious on performing HoLEP in patients on 5-ARIs in the beginning of their learning curve. Certainly, there is still only little evidence in the literature and, therefore, better quality research is required to address the true effects of 5-ARIs in patients undergoing HoLEP. It would also be interesting to investigate the effect of the duration of 5-ARIs before HoLEP and their impact according to the prostate volume, as none of these parameters have been evaluated in the majority of the existing studies. This would be of utmost importance as a possible longer usage may increase fibrosis and may result in different results.

Conclusion

In summary, 5-ARIs treatment has been found to have conflicting results in relation to the effects on HoLEP. It might reduce the postoperative bacteriuria in patients undergoing HoLEP, which theoretically could result in reduced postoperative urinary tract infections. The intraoperative bleeding and the risk of fibrosis are very difficult to be quantified in the degree required to make clear recommendation. There is a trend toward better enucleation rate and reduced morcellation time, but this may also reflect bias of the studies. Well-designed studies, correlating the preoperative duration of 5-ARIs with the enucleation difficulty in similar groups of surgeon experience, might offer better explanation of the actual effect of 5-ARIs.