Varicocele Is the Root Cause Of

Accepted: 22 January 2018

DOI: 10.1111/and.12992

ORIGINAL ARTICLE

Varicocele is the root cause of BPH: Destruction of the valves in the spermatic veins produces elevated pressure which diverts undiluted testosterone directly from the testes to the prostate

M. Goren1 | Y. Gat1,2

1Interventional Radiology, Laniado Hospital, Netanya, Israel Summary 2Department of Condensed Matter In varicocele, there is venous flow of free testosterone (FT) directly from the testes Physics, Sub Micron Research Weizmann into the prostate. Intraprostatic FT accelerates prostate cell production and prolongs Institute of Science, Rehovot, Israel cell lifespan, leading to the development of BPH. We show that in a large group of Correspondence patients presenting with BPH, bilateral varicocele is found in all patients. A total of Yigal Gat, Interventional Radiology, Laniado Hospital, Netanya, Israel. 901 patients being treated for BPH were evaluated for varicocele. Three diagnostic Email: [email protected] methods were used as follows: physical examination, colour flow Doppler ultrasound and contact liquid crystal thermography. Bilateral varicocele was found in all 901 patients by at least one of three diagnostic methods. Of those subsequently treated by sclerotherapy, prostate volume was reduced in more than 80%, with prostate symptoms improved. A straightforward pathophysiologic connection exists between bilateral varicocele and BPH. The failure of the one-way valves in the internal spermatic veins leads to a cascade of phenomena that are unique to humans, a result of upright posture. The prostate is subjected to an anomalous venous supply of undiluted, bioactive free testosterone. FT, the obligate control hormone of prostate cells, reaches the prostate directly via the venous drainage system in high concentrations, accelerating the rate of cell production and lengthening cell lifespan, resulting in BPH.

KEYWORDS benign prostatic hyperplasia, BPH, internal spermatic vein, varicocele

1 | INTRODUCTION in the abdominal cavity as described in an earlier published work (Gat & Gornish, 2006). In the erect human male, there is a mechanism which overcomes the 2. To divide the overall hydrostatic pressure of the vertical blood problem of moving venous blood from the pelvis towards the heart, column within these veins (which is equivalent to a column of against the downward pull of gravity. The vertically oriented internal 35–40 cm of fluid) into 6–8 separate chambers, with the resulting spermatic veins (ISV’s) have 6–8 one-way valves on the left and 6–7 pressure in the lowest of the chambers not exceeding physiologic on the right. levels which range up to about 4 Torr (mmHg). (Gat, Bachar, These valves have several important functions: Zukerman, & Gornish, 2004) 3. To prevent the downward penetration of potentially toxic waste 1. Moving the venous blood upwards against gravity in the ab- products and blood components to the testes, some of which are sence of an active pump. This function is accomplished by vasoactive (such as efflux of catecholamine pre-cursors from the utilising dynamically changing pressure differences which occur left adrenal gland).

flow upwards against gravity and prevent downward flow. Their 1.1 | Normal flow pattern of free testosterone destruction starts in the second decade, and an additional 15% to the prostate of men suffer from this disease with each subsequent decade. The blood that drains the testes and flows upward in the ISV’s with (Levinger, Gornish, Gat, & Bachar, 2007) It is our erect posture the assistance of the one-way valves, carries with it free testoster- and the vertical ISVs that exert a hydrostatic pressure overload one. As this blood leaves the testes, its concentration of FT is ex- on the valves leading to their incompetence. tremely high in comparison with the systemic circulation. The ISV Varicocele is not seen in quadruped mammals—the horizontally blood enters the systemic circulation on the left at the renal vein and oriented ISV’s in quadripeds do not have and do not need valves. The on the right (in 93% of patients) at the IVC. It is diluted volumetri- average hydrostatic pressures in their ISV’s systems remain around cally by a factor of nearly 100 (Jarwo, Chen, Trentacoste, & Zirkin, zero Torr. 2001; Walsh, 2002). In addition, protein binding to sex hormone- binding globulin (SHBG) inactivates nearly 99% of the FT (Feldman 1.3.1 | The damage caused by ISV valves’ failure & Feldman, 2001), and the free testosterone, now at physiologic levels, will reach the prostate via its arterial supply, having been diluted The elevated hydrostatic pressures produced by failure of the functionally by three orders of magnitude. valves in the ISV and their tributaries are propagated directly to all the venous structures that directly connect to them in compliance with Bernoulli’s principle of communicating vessels. Because there 1.2 | The control functions of FT in the prostate cell are no venous valves in the subinguinal testicular venous struc- FT is the obligate controller of prostatic cells. It regulates prolifera- tures or in the pelvic venous plexus, this entire venous pool is sub- tion, differentiation, cell maintenance, cell survival and apoptosis jected to the elevated hydrostatic pressures that occur in the ISVs (Isaacs, 1984). Under physiologic conditions in which FT supply to in varicocele. Normally, the pressures in the prostatic veins are the prostate is solely via the prostatic arteries, a “steady state” is low (around 4 Torr), but slightly higher than the pressures in the established between the rates of cell proliferation and cell death, pelvic venous plexus, so the direction of flow is out of the pros- and the gland’s volume remains normal. Elevated intraprostatic tate and towards the internal iliac veins and IVC. Under the condi- levels of FT increase the rate of cell proliferation and prolong cell tions created by varicocele, the pressure in the deferential vein survival, increasing the cell population and thus enlarging the gland. (DV) is some eight times above that in the prostatic venous plexus. (Chatterjee, 2003; Feldman & Feldman, 2001) Therefore, the direction of venous flow from the deferential vein divides into two flows. One, as usual, flows towards the IVC by way of the iliac veins. The second is diverted towards the prostate 1.2.1 | Varicocele gland where the extant venous pressure is lower (Gat, Gornish, Varicocele occurs when the valves in the vertically oriented ISV’s Heiblum & Joshua,2008; Gat, Joshua, Gornish, 2009). The pres- deteriorate, then malfunction and disappear as a result of incremen- sure gradient between the DV (which is at a higher venous pres- tal damage. Gravitational force produces elevated hydrostatic pressure) to the lower pressure prostatic venous system drives free sure in the vertically oriented ISVs. Elevated hydraulic stress on the testosterone-rich blood from the testes via the DV and Santorini delicate valve leaflets over time exceeds their elastic strength. (Gat venous plexus into the prostate. This, in essence, creates a highly & Gornish, 2006). Damage occurs to the one way valves of the ISVs abnormal flow phenomenon, unique in humans, in which an organ progressively from about the end of puberty until about the age of receives blood supply anomalously via its venous system. Under 75 years. This progressive valve failure begins at the lowest valve, the conditions which obtain in varicocele, the prostate gland is which is intermittently exposed to the highest hydrostatic pressure supplied with testosterone from two sources: and proceeds upwards, with the upper valves being the last to be affected. As the valves deteriorate and eventually resorb, a vertical 1. The physiologic supply from the prostatic artery. This is vol- column of blood (up to 35 cm on the right and 45 cm on the left) is umetrically diluted testosterone which is also bound to sex established in the ISV and its tributaries. That hydrostatic pressure hormone-binding globulin (SBHG), and reaches the prostate is propagated within the entire ISV system, down to the testes and in the appropriate, normal concentration. into the pelvic fossa venous plexus (Santorini), according to the law 2. The pathologic supply from the prostate venous system of free of communicating vessels (Bernoulli’s Principle). It can reach 27 Torr testosterone in very high uncontrolled concentration directly (mmHg) on the right and 33 Torr on the left, that is, 6-8 times normal. from the testes via the DV, via the Santorini plexus, the peripros- tatic plexus and directly into the prostate gland.

1.3 | A unique phenomenon It should be noted here that the above observations of patho- It should be pointed out here that varicocele is a unique phenom- logical backflow from the testes directly to the prostate are not enon which only occurs in bipedal human males. The function of hypothetical. This pathologic backflow can be and is observed the one-way valves in the ISV’s is to enable and assist venous directly during venographic examinations of the ISV’s which are GOREN and GAT | 3 of 5 performed during treatment. After effective occlusion of the ISVs at open surgery, as they are so small and are collapsed. Initially, these and all associated vertically oriented bypasses, the control veno- tiny veins provide assistance to the failing ISV system by capillary grams demonstrate that this pathologic backflow towards the flow upwards according to Laplace’s principle of “capillary force.” prostate gland ceases since the pressure gradient between the (Streeter, 1971a,b) At some point, as these vessels dilate under the testicular-prostatic drainage systems that exists in varicocele is persisting elevated pressures, the widened vessels lose their “capil- eliminated. The prostate then receives the testosterone its cells lary force” and can no longer support flow against gravity. Each one need only via the arterial supply at normal, physiologic concentra- of these tiny veins, undetectable by physical examination and even by tions only about 1% of those that occur in varicocele. direct surgical inspection, will propagate the abnormal pressures in the ISV drainage system (according to Pascal’s principle) into the pelvic fossa as they do not have valves. Despite their small size, these 2 | PATIENTS AND METHODS widened collateral vessels contribute to the same elevated hydrostatic pressure with the same effect as the abnormal pressures in the Beginning in 2009 and over the course of 7 years, 901 patients were larger veins do (Pascal), and therefore, they need to be eliminated for seen in our clinic for BPH. These patients ranged in age from 33 any treatment to be effective (hence the efficacy of microsurgery, in to 81 years, with a mean age of 60 years. The patients all reported addition to the nonsurgical interventional radiology technique which symptoms compatible with BPH, with IPSS scores varying from 3 to we have used). Using only physical examination, a large portion of 35 (mean score 19.3; median score 19.7). The patients were examined the patients with ISV valvular insufficiency on the right side will es- using three modalities: physical examination; contact thermography cape diagnosis and will not have treatment. (Varicoscreen ®); and colour flow Doppler ultrasound. Of those modalities, only thermography can reliably detect subclinical varicocele. 4.2 | The difficulty in the diagnosis of right- sided varicocele

3 | RESULTS On the right, there is no reflux in the ISV during Valsalva manoeuvre, which is the basis for the diagnosis of this condition both on physical In every one of the 901 patients, varicocele could be detected by examination and by colour flow Doppler study. The reason for this at least one of the three modalities. Two hundred and forty-four of follows: these patients underwent venography in the course of subsequent The right ISV usually drains into the IVC, in which the intravascu- sclerotherapy treatment of the ISV’s. Bilateral varicocele was found lar pressures range from +5 to −5 Torr. The venous pressures in the in 242 of these. In two patients, varicocele was only demonstrated ISV are always physiologically higher than those in the IVC (around venographically on the left; the right ISV could not be cannulated +10 Torr). Valsalva manoeuvre will not promote reflux. In about 60% and examined. of patients, the uppermost orifice valve in the right ISV is competent. Prolonged Valsalva will distend the IVC and compress the ISV orifice which enters it an angle of less than 90 degrees. (Furthermore, if 4 | DISCUSSION flow in the IVC would be reduced or stopped by a prolonged Valsalva manoeuvre, IVC flow to the heart would be restricted, and the pa- 4.1 | Difficulties in the diagnosis of varicocele tient would faint.) Under normal anatomic conditions, the venous It is well known that the hydraulic conditions which exist in the tes- pressure in the ISVs will always be greater than in the IVC. Only ticular venous system make the diagnosis of varicocele a difficult in 5%–6% of patients, in whom the right ISV drains into the right one, especially on the right side. On physical examination, the reflux renal vein, might reflux be elicited on physical examination or on ul- of blood during Valsalva manoeuvre generates a subtle impulse in trasound as it does on the left side. Most of the cases of right ISV the scrotal veins. This subjective finding is only detected once the valvular insufficiency (varicocele) are therefore missed on clinical affected veins have sufficiently dilated from the effects of the loss examination. (Gat et al., 2006a) of the one-way valves. Its sensitivity is limited by both operator- Contact thermography (CT) is a sensitive detector of varicocele dependent and pathophysiologic factors and is not a reliable de- on the right and also for all subclinical varicoceles, as it relies on tector of insufficiency of the ISV valves in its earlier stages. This is heat conductivity. In cases of valvular insufficiency, thermography referred to as “subclinical” varicocele in the urologic literature. But, detects the presence of the warmer venous blood from the intra- even small, undetected vertical bypasses create the same elevated abdominal portion of the ISV (around 37 degrees Celsius, as opposed hydrostatic pressure as larger vessels, according to Pascal’s principle to scrotal venous blood temperatures of 33–34 degrees Celsius) as it (Streeter, 1971a,b) reaches the scrotum. (Gat et al., 2004) From venographic studies, we know that in many, if not most, It should be noted that in 60% of patients, there are inter- cases of varicocele, there are many retroperitoneal collateral veins testicular venous connections which, in cases of varicocele, would in the pelvic and abdominal portions of the ISVs. These are only tens allow elevated venous pressures to be propagated from one side to of microns in diameter and are not detectable by ultrasound and not the other even in cases of unilateral reflux. 4 of 5 | GOREN and GAT

have bilateral varicocele. In two patients, unilateral (left) varicocele 4.3 | Implications of our observations for was found. These results confirm the findings predicted by the prostate disease application of straightforward physical principles, fluid mechanics Support for our results is seen in the recently published work of and the inherent strength of biological structures (the veins and Strunk and co-workers and the more recent review by Rauch. They their valves). have published a series of 30 patients who had ISV venography In humans, given their erect posture, the elevated hydrostatic and sclerotherapy for BPH. These patients had not been previously pressures that are present within the vertically oriented ISV’s diagnosed with varicocele on clinical studies and all were found to gradually deteriorate the one-way valves in these vessels. The re- have bilateral ISV valvular insufficiency at venography. (Rauch & sult is bilateral varicocele, with the venous pressures in the testic- Strunk, 2017; Strunk, Meier, Schild, & Rauch, 2015) ular drainage system raised over six times normal. Venous efflux Our observations give new life to the pioneering work of Huggins from the testes, rich in free testosterone, is diverted directly into and Hodges over 70 years ago. In 1940, they had made the observa- the prostate via the existing testicular-prostatic venous connection that long exposure of the prostate to high testosterone concen- tions (according to Bernoulli’s principle of communicating vessels). tration leads to BPH (Huggins & Stevens, 1940). Their observations The high concentrations of intraprostatic free testosterone accel- remained an enigma for over 60 years. It was not understood how it erate the rate of prostate cell production, and prolong cell life, could be that serum testosterone decreases with age, while the in- these two synergistic factors increase prostate cell population, cidence of BPH increases with age. The pathophysiologic conditions leading to BPH. we describe in detail above explain the mechanism behind their original observations. The high concentration of FT arrives the prostate ORCID directly from the testes via the “back door,” that is, via the venous drainage system, by retrograde backflow. This is all a result of the M. Goren http://orcid.org/0000-0001-6236-2494 increased hydrostatic pressure in the testicular venous drainage sys- Y. Gat http://orcid.org/0000-0003-3525-4724 tem that is produced when the one-way valves are destroyed in the vertically oriented ISVs. Huggins and Hodges went on to receive the Nobel prize for REFERENCES their discovery that elevated concentration of intraprostatic Chatterjee, B. (2003). 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