Benign Prostatic Hyperplasia: Long-Term Follow-Up of Prostate Volume Reduction After Sclerotherapy of the Internal Spermatic Veins

Accepted: 10 June 2017

DOI: 10.1111/and.12870

ORIGINAL ARTICLE

Benign Prostatic Hyperplasia: Long-term follow-up of prostate volume reduction after sclerotherapy of the internal spermatic veins

Y. Gat1,2 | M. Goren1

1Andrology-Interventional Radiology Maynei Hayeshua Medical Center, B’nei B’rak, Israel Summary 2Department of Physics, Sub Micron The purpose was to examine the results of bilateral percutaneous sclerotherapy of the Research, Weizmann Institute of Science, internal spermatic veins on prostate volume and prostatic symptoms. We previously Rehovot, Israel showed that destruction of one-way valves in the internal spermatic veins (varicocele) Correspondence elevates hydrostatic pressure in the vertical testicular venous drainage system in the Yigal Gat, M.D. PhD. Department of Physics, Sub Micron Research, Weizmann Institute of erect human. This diverts free testosterone (FT) flow at high concentrations directly Science, Rehovot, Israel. from the testes into the prostate. High intraprostatic FT prolongs prostate cell life and Email: [email protected] increases cell proliferation rate—synergistic effects resulting in increased cell population (BPH). Treatment by interventional radiology (or microsurgery) techniques eliminates this diversion of FT flow to the prostate and reverses these pathologic processes. A total of 206 BPH patients with varicocele underwent bilateral sclerotherapy of the ISV. Of these, 81.5% exhibited significantly reduced prostate volume and improvement in prostatic symptoms (measured by IPSS scores) during follow-up period of 12 to over 24 months. 8% went on to require surgery despite mild post-treatment improvement (TURP). The use of prostate medications along with the treatment may have a combined positive effect. Very large prostate volume and large residual volume may limit degree of improvement. It is concluded that effective treatment of varicocele restores normal supply of testosterone to the prostate solely via its arterial supply, resulting in significant decrease of prostate volume and prostatic symptoms. The procedure is safe with only minor transient side effects.

KEYWORDS benign prostatic hyperplasia, gat-goren technique, internal spermatic vein, interventional radiology, varicocele

1 | INTRODUCTION The extant medical literature on the prostate reveals a biological paradox: while serum FT levels decrease with age, the incidence of Benign prostate hyperplasia (BPH) is the most common benign neo- BPH increases with age. plasm in ageing men, affecting almost 75% of men in the seventh Our previously published work has resolved this enigma, showing decade. The cause of BPH has not been fully elucidated. Free testos- that venous valve destruction and insufficiency in the internal sper- terone is the controller of the prostate cell. High intraprostatic concen- matic veins, a phenomenon that increases rapidly with age, is critical tration of free testosterone accelerates cell proliferation and prolongs in the development of BPH (Gat, Gornish, Heiblum, & Joshua, 2008). cell life (Chatterjee, 2003; Feldman & Feldman, 2001). Low intrapros- It has been shown that the destruction of the one-way valves in tatic concentration of FT decreases the rate of production of new cells the internal spermatic veins (varicocele) increases remarkably with age and shortens their survival (Isaacs, 1984; Huggins & Stevens, 1940). (Canales et al., 2005; Levinger, Gornish, Gat, & Bachar, 2007). This

FIGURE 1 ISV anatomy with physiologic venous pressures. Prostatic venous blood flows through prostate venous plexus of Santorini (PVP), vesicular vein (VV), internal iliac vein (Int.I), common iliac vein (CI) and inferior vena cava (IVC). Testicular venous blood mainly via ISV, with distribution to: deferential vein (DV), scrotal vein (SV) and cremasteric vein (CV). Testicular venous blood via DV flows to VV (common drainage to prostate and DV), meeting blood from VP. Both flow jointly to Int.I, CI then into IVC pathology creates a cascade of pathophysiological effects leading to is a physical connection between the testicular and the prostatic ve- BPH (Figures 1 and 2). nous drainage systems. This connection exists at the meeting point The destruction of the one-way valves occurs on both the left and between the deferential vein arriving from the testes, and periprostatic the right sides. (Comhaire, Kunnen, & Nahoum, 1981; Gat, Bachar, venous plexus (and Santorini plexus) arriving from the prostate gland Zuckerman & Gornish, 2004). Disappearance of the one-way valves (Pierrepoint, Davies, Millington, & John, 1975; Wishahi, 1992). These leads to a vertical column of blood which produces, according to two vessels join and flow into the vesicular vein. The elevated venous Pascal’s principle, hydrostatic pressure in the internal spermatic veins pressure in the deferential vein exceeds the lower pressure in the vesic- that is 7–8 times normal on the left side and six times normal on the ular plexus and in the peri-prostatic venous plexus producing a pressure right (Gat, et al., 2006; Streeter, 1971). That leads to a pathologic gradient between the testicular and the prostatic drainage systems. The change of flow direction of FT-rich blood that is not yet fully diluted to venous pressure difference between the testicular (high pressure) and the prostate gland as described in our previous study (Gat et al., 2008). the prostatic (low pressure) drainage systems causes diversion in the This high pressure is propagated through all connecting vessels flow direction from the deferential vein to the prostate venous drainage according to the principle of communicating vessels, a derivative of system. The free testosterone-rich testicular venous blood in the defer- Bernoulli’s Law of Conservation of Fluid Energy (Streeter, 1971). There ential vein flows directly to the prostate gland. This influx, under elevated GAT and GOREN | 3 of 8

FIGURE 2 Anatomy of testicular and prostatic venous drainage in Varicocele Figure 2. Loss of one-way valves causes: (i) loss of mechanism to elevate venous blood upwards against gravity; (ii) increased hydrostatic pressures in testicular drainage system (six to eight times physiologic). Elevated pressure propagated to all interconnected vessels, including deferential vein (DV). Testicular venous blood flows along pressure gradient from testes, directly to prostate (obeying Bernoulli’s principle of “communicating vessels”), via testicular-prostate venous drainage systems, carrying undiluted and unbound high concentrations of FT hydrostatic pressures, widens the diameter of the deferential vein and route as we have directly demonstrated in venographic images ob- the periprostatic plexus (Figure 2). This phenomenon has been demon- tained during the interventional radiology procedure (Figure 3). It is to strated by ultrasound in varicocele (Sakamoto & Ogawa, 2008). The be noted that under these circumstances, the prostate gland receives widened deferential vein allows an increase in the rate of flow accord- testosterone from two sources: the physiologic supply via the prostatic ing to Hagen-Poiseuille (Streeter, 1971) enabling these three horizontal arteries, and the pathologic supply of free testosterone via the venous vessels—deferential, cremasteric and scrotal veins—to contain the blood system. This pathologic condition is a unique phenomenon only in the volume that is unable to flow via ISVs without its competent valves. erect human body. Elevated intraprostatic free testosterone has two This free testosterone-rich blood arrives directly to the prostate synergistic effects; on the one hand, it increases the rate of cell prolif- before it has undergone full volumetric dilution (Gat, Joshua & Gornish, eration (Feldman & Feldman, 2001), and, on the other hand, prolongs 2009; Gat et al., 2008; Jarow, Chen, Trentacoste, & Zirkin, 2001; cell life (Chatterjee, 2003). These two factors lead to the development Strunk, Meier, Schild, & Rauch, 2015). Extremely high concentration of BPH by the progressive increase in the prostate cell population. of free testosterone, more than 100 times the systemic serum concen- The treatment we devised is therapeutic occlusion of the ISVs, in- tration, flows directly into the prostate, via this previously unknown cluding all vertically oriented collaterals, each of which contributes to 4 of 8 | GAT and GOREN

their ISVs for the treatment of BPH at our institution. These patients were originally diagnosed with BPH and had been followed in urology Tip catheter in right ISV clinics. Inclusion criteria included patients with BPH and age above 40 years. Exclusion criteria were patients with urinary tract infection, acute urinary retention, sensitivity to iodine, renal insufficiency and patients with coagulopathy. Bilateral varicocele was demonstrated in all patients. Varicocele was assessed by physical examination, ultrasound colour-flow Doppler Bladder and contact thermography, using a flexible liquid crystal thermostrip: Varicoscreen® (FertiPro, Beernem, Belgium).This is a clinical diagnostic ISV tool considered the most accurate and sensitive for detection of bilateral and subclinical varicocele, especially on the right side, where it is difficult to detect clinically (Comhaire, Monteyne, & Kunnen, 1976; Gat, Chakraborty, Zukerman, & Gornish, 2005; Kunnen & Comhaire, 1992). Catheter All patients underwent abdominal ultrasound of kidneys, liver, Prostate prostate and bladder in their outpatient clinic setting. Prostate volume measurement was performed by abdominal ultrasound, using the de- Prostate capsular region vice’s proprietary prostate volume algorithm calculated by measuring the prostate in three orthogonal planes. The formulation for calculation PP is as follows. Prostate Volume = 4/3*π*D1/2*D2/2*D3/2, where D1, D2, D3, are the height, width, depth diameters in orthogonal planes of the prostate gland reflected on the screen in abdominal examination. FIGURE 3 Venographic anatomy in the prostatic and perineal Written informed consent of the subjects was obtained. Patients region as seen during right ISV venography Figure 3. Pathologic were told the details of other available BPH treatment options. They retrograde flow seen from tip of catheter (upper left corner), in were informed of possible side effects and complications including: pelvic portion of right ISV. In varicocele, hydrostatic pressure in testicular venous drainage system is higher than in prostate drainage hematoma at the site of intervention, infection, reaction to the con- system. So testicular venous blood flows along pressure gradient trast media, allergic reaction to any of the medications used, bleeding from pampiniform plexus (PP) via the deferential vein and Santorini’s and technical failure. plexus pathologically into prostate. This appears as iodinated contrast A full-patient history, medical examination and medications were material “blush” of the prostate gland capsular region (Long arrows). recorded in all patients. The IPSS questionnaire (International Prostate The contrast material here opacifying prostate capsule replicates the Symptom Score), which is considered an effective tool for evaluat- venous blood from testes in which FT, undiluted and not yet bound to SHBG, at concentration up to 130 times above physiologic levels, ing BPH symptoms and classifying the severity of lower urinary tract bypassing the systemic blood circulation symptoms, was available for 177 patients. Blood tests carried out included the following: PSA, complete blood count, hormonal profile, the elevated hydrostatic pressure that maintains the pathologic con- liver and renal functions and coagulation factors. Percutaneous se- dition. This method of treatment is based on work published in 1976 lective venography and sclerotherapy of impaired ISVs and all associ- by Comhaire and Kunnen on treatment of varicocele in male infertility. ated vertical bypasses and retroperitoneal collaterals were performed, (Comhaire & Kunnen, 1976). Effective treatment can be achieved as an using a technique developed by us (Gat & Gornish, 2006), and based interventional radiology procedure or using microsurgical techniques. on the original work described by Comhaire and Kunnen in 1992. In 2008, our group published our preliminary favourable results The procedure was performed by an experienced interventional with BPH patients who were treated and followed for 6 months (Gat radiologist using a digital fluoroscopic imaging with a 45/90 degree et al., 2008). tilt table as described in detail by Gat, et al. (2008). Catheterisation of The aim of this study is to evaluate this treatment method in a the renal veins and internal spermatic veins was performed through large group of patients, to confirm our earlier prediction and to report a vascular sheath via the femoral vein using local anaesthesia. Digital long-term results. venograms of the internal spermatic veins were obtained during tilt- ing of the table with feet down to facilitate imaging of the entire vein and to visualise collateral veins and retroperitoneal interconnections. 2 | PATIENTS AND METHODS Sclerotherapy of the internal spermatic veins was performed in a step- wise fashion, while the inguinal portion of the vein was compressed This retrospective study was approved by our institutional ethics to stop flow and prevent testicular reflux. At each stage of the occlu- committee. We evaluated 206 patients, 41–84 years old (mean age of sion, a repeat imaging study of the internal spermatic vein was carried 61.7 ± 10.0), who underwent bilateral percutaneous sclerotherapy of out to confirm caudal occlusion of the vessel and to visualise any still GAT and GOREN | 5 of 8 patent collaterals (some of which only appear after the main vein has 120 been occluded). This is continued until only a stump of the main inter- Mean PV nal spermatic vein remains, and no reflux is seen via collaterals. A renal 100 venogram, with the patient semi-erect, is also performed to look for

in mL 80 additional internal spermatic vein orifices. The treatment is performed as an ambulatory procedure, using local anaesthesia and can be taken

volume 60 from 1:30 to 2:30 hours. Following this outpatient procedure, patients were released after 30 to 60 minutes of rest and after receiving in- Vertical Line = Rang e 40 Prostate structions for proper homecare and recommendations to return to normal activity after 24 hrs. 20 Those patients who were receiving medications to reduce prostate symptoms were told to continue their use in the follow-up period. 0 Pre- 6 Months 12 Months 24 + Months During the more than 24 month follow-up period, patients were asked treatment (N = 124) (N = 112) (N = 80) to complete the IPSS questionnaire. Prostate volume measurements (N = 206) by abdominal ultrasonography were performed in each patient several CHART 1 Prostate Volume change during Follow-up (from times during the follow-up period (generally every 6–9 months). Table 1)

2.1 | Statistical analysis IPSS Scores These patients had pre- and post-procedural prostate volume and IPSS 25 IPSS Scores scores and were followed up. The results of prostate volume changes 20 and IPSS score were subjected to statistical analysis. Wilcoxon rank test was used to assess baseline versus post-procedural changes in 15 measured parameters because of the wide range of prostate volumes 10 in the patient population. 5

0 3 | RESULTS PRE-TREATMENT 3 Months (No. = 104) 6 Months (No. = 116)12 Months (No. = 84) (No.= 206) : Pre-treatment: 7.7 The results are summarised in Table 1 and displayed graphically on 3 Months 7.5 6 Months 7.4 Chart 1 and 2. 12 Months 7.7

No significant complications were reported during the procedure CHART 2 IPSS Scores during follow-up (from Table 1) or throughout the follow-up period. Testicular discomfort for up to three days occurred in nine patients (4.3%), and mild, transient urti- Prior to treatment, the mean prostate volume was 66.2 ± 37.8 ml. caria was noted during and immediately after the procedure in 7 (3.4%) The mean baseline IPSS–BPH symptom score was 19.8 ± 7.7. patients. These resolved spontaneously and without consequences. Improvement in either prostate volume and or in IPSS was observed in 81.5% of the patients. (Table 1) At 6-month post-treatment, mean prostate volume stood at 57.9 ± 34.0 ml (N = 129), which fur- TABLE 1 Prostate volume and IPSS BPH scores for 206 patients ther decreased to 50.2 ± 29.1 ml among the 112 patients evaluated N Mean (SD) p Value at 12 months following the procedure (Table 1). The 80 patients as- Age (years) 206 61.7 ± 10.0 sessed at least 24-month post-treatment demonstrated a mean pros- Prostate volume (ml) tate volume of 45.8 ± 23.8. The IPSS scores submitted by the patients Pre-treatment 206 66.2 ± 37.8 improved within the first 3 months of treatment, reaching a mean score of 12.4 ± 7.5, and further improved to 11.4 ± 7.3 and 10.6 ± 7.5 6 months post-treatment 129 57.9 ± 34.0 <<.001 within six and 12 months of treatment, respectively, decreased from 12 months post-treatment 112 50.2 ± 29.1 <<.001 the baseline score of 19.8 ± 7.7. 24 months plus 80 45.8 ± 23.8 <<.001 post-treatment PSA levels before and after treatment demonstrated a minor decrease (from an average of 3.9 to an average of 3.8). The PSA levels IPSS – BPH symptom score were subjected to the Wilcoxon rank test and the differences in the Pre-treatment 177 19.8 ± 7.7 PSA levels before and after treatment were found to be not statisti- 3 months post-treatment 104 12.4 ± 7.5 <<.001 cally significant. 6 months post-treatment 116 11.4 ± 7.3 <<.001 Sixteen patients underwent TURP in the follow-up period 12 months post-treatment 84 10.6 ± 7.5 <<.001 after the treatment. In those patients, two or more of the following 6 of 8 | GAT and GOREN accompanying medical problems had been observed before the treat- After our treatment, the free testosterone reaches the prostate ment: Enlarged prostate volume above 120 ml; post-void residual in normal concentration solely via the physiologic route (the prostate bladder volume more than 130 ml; thickened bladder wall, chronic artery, Figure 4). That concentration is calculated at <1% of its levels prostatitis; previous urinary retention and enlarged median lobe. before occlusion of the internal spermatic veins. The treatment of the We have made the following preliminary observation regarding a root cause of BPH, as proposed here, restores the physiologic levels small subgroup of our patients (10) who had been already been using of intraprostatic free testosterone and hence restores the normal ratio prostate medications (5 α reductase inhibitors) before undergoing of new cell production and cell death. Gradually, the excess number the procedure and stopped their use after their procedure. In these of prostate cells will decrease at a biological pace determined by the patients, there was a temporary reversal of the improvement of their normal ratio of cell proliferation to cell death. prostatic symptoms that they had experienced after their treatment. Our results have recently been supported in an independent study. This temporary reversal disappeared upon re-introducing the medi- Strunk et al. (2015) conducted a randomised study of 30 patients re- cations. Continued follow-up of these patients showed that their cently published, who were treated for BPH using this technique. They post-procedure improvement continued. also demonstrated reversal of flow direction in the prostatic venous drainage system in their patients. In their discussion, they also re- garded the successful treatment to have eliminated this reversal of 4 | DISCUSSION flow. All 30 patients had bilateral varicocele. Among them, 16 patients who were under follow-up for 6 months have reported significant im- Our present work confirms the predictions we made in research which provement in IPSS score and in quality of life. we initially carried out in 2008. At that time we first described the Our work is a retrospective study, without a parallel control mechanism that causes BPH and the treatment we developed which group under follow-up. While ostensibly, that might be considered a reverses it. Using a much larger number of subjects (206) and longer “weakness” of our study, it should be recalled that prostate volume follow-up in the present study, we have strengthened the clinical evi- persistently and significantly increases with age, and IPSS (and qual- dence which further supports our original prediction. ity of life) deteriorates. Thus, without treatment, prostate glands are The treatment reduced prostate volume by 13.6% after 6 months, expected to increase in size over time. In the seminal study (Berry, by 24.2% and 30% after 12, 24 months and above, respectively, with Coffey, Walsh, & Ewing, 1984), the researchers reported the preva- significant improvement in lower urinary tract symptoms. Clinical im- lence and growth rate of human benign prostatic hyperplasia with age provement was observed in 81.5% of treated patients, with no compli- by combining and analysing data from 10 independent studies con- cations and only minimal incidence of transient side effects. taining more than 1,000 prostates. The results: The doubling time of We have previously noted that the destruction of the valves in the prostate volume is 4.5 years between the ages of 31–50 and 10 years internal spermatic veins is a phenomenon unique to humans resulting between the ages of 51–70. from their bipedal erect posture. In our previous studies, we found that There are six additional preliminary observations of our patient co- as a consequence of destruction of the one-way valves in the inter- hort which slowed or limited the response to treatment: nal spermatic veins (varicocele) the prostate gland is subjected to free testosterone at serum concentrations of more than 100 times normal 1. Prostate volume more than 120 ml. (Gat et al., 2009) and actually receives a dual supply of testosterone: 2. Residual bladder volume over 130 ml. the physiologic supply via the prostatic arteries and an abnormal, 3. Patients with IPPS higher than 24. unique venous supply via the prostatic veins because of the patho- 4. Patients with enlarged median lobe. physiologic mechanism we have described. 5. A clinical history of chronic prostatitis. By completely occluding the abnormal internal spermatic veins, 6. A clinical history of urinary retention with previous need for including the associated network of vertically oriented collaterals catheterisation. and venous bypasses, which is accomplished using the treatment method we have described, the elevated hydrostatic pressure in the We also note, anecdotally, that the use of 5 alpha reductase inhib- testicular venous system is no longer exists (Figure 4). As a result, the itors may have a salutory effect on the overall improvement seen after intravascular pressures in the testicular and prostatic venous drain- undergoing the treatment. age systems equilibrate, venous back-pressure from the deferential As noted by Huggins and Hodges in their landmark work of the vein to the prostate is eliminated, and free testosterone no longer early 1940’s, “All known types of adult prostatic epithelium undergo flows into the prostate via the deferential vein (Gat et al., 2008). atrophy when androgenic hormones are greatly reduced in amount or Thus, the treatment prevents the supply of FT from the vein to the inactivated” (Huggins & Hodges, 1941). Their observation was further prostate. The direction of blood flow in the deferential vein becomes proven to be therapeutically beneficial when they showed drastic re- physiologic, that is, only towards the inferior vena cava (where the duction of prostate volume of patients with BPH in response to bi- pressures range from −5 to 0 mmHg), via the vesicular venous plexus, lateral orchiectomy (Huggins & Stevens, 1940). Several other workers the internal iliac and thence to the common iliac veins, along the have confirmed this in prostate disease: reducing the level of intrapros- pressure gradient. tatic androgen leads to partial and transient involution of established GAT and GOREN | 7 of 8

To the Heart K RV RV K

0 mmHg (-5 / +5) IVC ISV Bypasses - treated Bypasses - treated

35 cm 40 cm ISV - treated

Right Left ISV - treated

CI FIGURE 4 ISVs and all their collaterals must be occluded to eliminate elevated venous pressures in varicocele. Figure 4. Int. I Diagrammatic display of the treated ISV 6 mmHg 6 mmHg vessels and their collaterals (shaded in grey). Elevated venous pressure resulting CV VV from failure of valvular system in ISV 6 mmHg 6 mmHg eliminated by occluding main ISV and PP the several possible collaterals, from just PP above the inguinal (groin) region to just DV DV below sites of drainage of the ISV into IVC SV P (on right) and renal vein (on left). Venous VP Santorini pressures in pelvic and inguinal regions T normalise and shunting of FT-rich blood T from testes to prostate via the Santorini venous plexus ceases Testicular Artery

BPH (Isaacs, 1984; Kaplan, Chung, Lee, Scofield, & Te, 2012; Peters FT concentration accelerates prostate cell proliferation and prolongs & Walsh, 1987), and prostate cancer (Feldman & Feldman, 2001; cell life. These two synergistic factors increase the number of prostate Huggins & Hodges, 1941; Isaacs, 1984). cells in the prostate gland, leading to BPH. Treating varicocele adequately eliminates the elevated pressure in the testicular venous drainage system and the pathologic expo- 5 | CONCLUSIONS sure of the prostate cells to excess FT flowing via the testicular- prostatic drainage systems. After complete occlusion of the internal The cause of BPH, as demonstrated in our study, is the prolonged spermatic veins and their collaterals, testosterone supply to the exposure of the prostate gland to high concentrations of free testos- prostate reverts to physiologic levels, being supplied via the pros- terone arriving via the testicular-prostatic venous drainage systems tate arteries only. As a result, the pathologic proliferation/apoptosis following destruction of one-way valves in the internal spermatic veins ratio of prostate cells that exists in varicocele patients is reversed (varicocele), a unique phenomenon in the erect posture of the humans. after adequate treatment. The prostate is exposed to high levels of testosterone from the venous The procedure is safe and effective, leading to significant reduc- drainage system beyond that supplied by its arterial supply. Elevated tion of prostate volume and prostate symptoms. 8 of 8 | GAT and GOREN

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