Prostate cancer: a newly discovered route for testosterone to reach the prostate: treatment by super-selective intraprostatic androgen deprivation


Prostate cancer: a newly discovered route for testosterone to reach the prostate: treatment by super-selective intraprostatic androgen deprivation

UroToday.com - Varicocele has only recently been shown to be a bilateral disease, the primary cause for male infertility and low testosterone level. It has now for the first time been discovered to be the cause of enlargement of the prostate and for the development of prostatic cancer as well. Also, for the first time in the published medical literature, it has been proven that super-selective venography and sclerotherapy (Gat Goren Technique) may reverse early localized prostate cancer and reduce prostate volume in benign prostate hyperplasia (BPH).

These prostate pathologies develop when the testicular venous drainage system ceases to function due to the destruction of the one way valves in the internal spermatic veins (bilateral varicocele). This phenomenon increases rapidly with age due to an excessive hydrostatic pressure that is exerted on the one-way valves of the vertically oriented Internal Spermatic Veins (ISV) a phenomenon that exists only in human males due to their erect, bipedal posture.

The malfunction of these valves produces elevated hydrostatic pressure in the venous drainage of the male reproductive system, some six times greater than normal. This condition leads to a unique biological phenomenon in the human body--venous blood flows retrograde (against the normal direction of flow) from the higher pressures in the testicular venous drainage system to the lower pressures in the prostate drainage system. Free testosterone levels in this venous blood are found to be markedly elevated, with an extremely high concentration of some 130 times the serum level.

After the treatment that we propose below, FT reaches the prostate only via the prostate artery in normal physiologic concentration (0.7 % of the abnormal levels before treatment). The treatment resumes the normal physiologic conditions in the prostate; the only supply of FT to the prostate arrives now, normally, only via the prostate artery. Prostate cells are then no longer subject to over stimulation by the testosterone that enters directly from the testes via the testicular and prostate drainage systems.

The process of evolution from normal prostate cells to prostate cancer cells

The "bathing" of the prostate cells in the extremely high concentrations of FT that we have found under the pathologic conditions of varicocele acts as a constant and overwhelming stress on those genes regulated by FT. In the cell nucleus, those genes are now continually bombarded by AR-ligands in concentrations nearly two orders of magnitude above physiologic in intensity and in frequency. These drive the nuclear apparatus for gene transcription and replication of the next cell generation at a much higher rate of production than it was designed for. Under these abnormal conditions which are hostile to normal production of DNA for the next generation, the precision of the production and the assembly processes of the DNA nucleotides (approximately 4-5x109 nucleotides, and in exact order) is disrupted and this promotes cell mutation in the proliferating prostate cells.

The result is an increasing number of errors on the one hand and insufficiency of error detection and correction in the cell nuclei on the other hand. These persistent circumstances of overwhelming stress on the DNA (and RNA) replication and transcription machineries by the drive of huge FT concentration may lead, with time, to the production of hyperplasic prostate cells and later to mutant prostate cells with a progressive mode in its malignant potential 'from generation to generation,' due to errors in production and insufficiency in the errors' detection and correction apparatuses.

This concatenation of pathologic processes in the male pelvic venous system has been found to cause BPH and later, prostate cancer. Using a variation of our technique for bilateral varicocele sclerotherapy, we have shown in our series of patients that prostatic enlargement can be reversed, and localized prostate cancer can be eliminated.

Our non-surgical treatment stops the flooding of the prostate gland by high concentrations of free testosterone which has been documented in patients with bilateral varicocele.

We would like to stress two of our conclusions based on a molecular biology analysis of malignant mutations in cells.

(1) There is a limited window of opportunity to treat early prostate cancer effectively by this method.

(2) Treating prostate cancer by ADT (androgen deprivation therapy) without stopping the influx of testosterone via the testicular and prostate drainage systems, directly from the testes to the prostate, risks earlier production of aggressive prostate cancer cells, namely, 'androgen independent prostate cancer' (AIPC).

Taller stature is associated with an increased risk for prostate cancer and more aggressive disease.

Our explanation and findings of the pathophysiology as described in our study reveal that the pace of the destruction of the one-way valves, leading to PCa, depends on the vein's vertical height - h. A derivative of Pascal and Newton's principles show that the hydrostatic pressure, P, exerted on the valves is P=ρ ´ h. (where ρ is the specific weight of the blood).

On the basis of this physical hydrodynamic explanation, we are led to predict that taller men are at a higher risk to develop PCa earlier. Since the height of the internal spermatic veins determines the likelihood of the one-way valves wearing out, it should be expected that taller men, whose internal spermatic veins are exposed to higher hydrostatic pressures, should have a higher risk of developing PCa earlier and this indeed was the conclusion of a recently published comprehensive study (Zuccolo et al., 2008).

Why do patients with PCa have lower serum Testosterone?

Lower serum testosterone is found in patients with PCa (Morgentaler et al., 1996) and is even lower with more aggressive disease (Hoffman et al., 2000). Studies have shown that varicocele reduces serum FT level (Comhaire and Vermeulen, 1975). This occurs since the elevated hydrostatic pressure in the internal spermatic veins exceeds the intratesticular arteriolar pressure, leading to hypoxia in the testicular micro-circulation and ischemic changes in the Leydig cells, resulting in decreased FT production (Gat et al., 2004, 2005).

Under these conditions, PCa and decreased serum FT levels both derive from the same underlying cause, namely, destruction of the one-way valves in the internal spermatic veins.

Persistent elevated intra-prostatic androgen concentrations after ADT. Is it possible?

This enigmatic phenomenon has been described in patients undergoing ADT by several recent studies (Page, 2006; Mostaghel, 2007; Visakorpi, 1995), and can also be clearly understood based on our findings.

ADT reduces the testicular FT production to about 4% of its normal capacity, thus achieving castrated serum levels (Huhtaniemi et al., 1987; 1985). Despite this, based on our findings, calculations show that FT continues to arrive in the prostate gland, via the testicular and prostate drainage systems, at a calculated concentration of 5 times (~0.04 x 130 = 5) the normal serum level.

Is there a causal relation between serum testosterone and prostate cancer?

Our assertion may explain why serum concentration of testosterone was found not to be associated with the risk of prostate cancer (Roddam, 2008). Since we showed in our articles (Gat et al. 2008, 2009) by fluid-mechanic analysis of the malfunctioned venous drainage system in the male reproductive system that intra-prostate FT is elevated some 2 orders of magnitude above physiologic serum level, it becomes apparent that serum androgen levels are practically not relevant for the clinical assessment of the effect of ADT on intra-prostate androgen levels and therefore on the status of the disease. It also explains why the low serum levels of FT found in patients treated with ADT do not suppress androgen-dependent gene expression in the prostate tissue (Page, 2006). The present study also explains why FT levels in prostate tissue during ADT are sufficient to activate androgen receptors despite medical castration (Page, 2006; Mostaghel, 2007).

Also, it can be understood why exogenous testosterone replacement therapy does not negatively affect prostatic tissue or its micro-environment (Marks, 2006). All these phenomena can be explained by our findings--that the serum concentration arriving via the prostate artery is negligible compared to the concentration arriving, pathologically, via the 'back-door' (the impaired testicular-prostatic drainage system), as described above.

Androgen in extreme high concentration does reach the prostate gland via the impaired testicular and prostate drainage systems

In our studies, we show the causal relation between testosterone and the evolution of prostate cancer. Huggins and Hodges were correct when they asserted in 1941 that testosterone is the cause of prostate cancer. However, the real 'genotoxic' testosterone is not the physiologic serum testosterone which reaches the prostate via the prostatic artery. Rather, the cause is the free testosterone in high concentrations that reaches the prostate via the 'back-door' through the testicular and prostate venous drainage systems because of faulty one-way valves in the testicular venous drainage system that we have described above, a phenomenon that increases rapidly with age.

About the phenomenon of castration resistant prostate cancer (CRPC)

Androgen deprivation therapy (ADT) is initially effective in treating PCa. However, almost invariably, prostate cancer cells begin to proliferate more rapidly and aggressively and become androgen independent (Chen, 2004; Issacs, 2004; Feldman, 2001), rendering ADT ineffective. How does this happen?

FT arriving via the drainage system is a biologic factor for developing PCa. The initial mutant cell lines are likely to be sensitive to high androgen concentrations and cells of this type reaching the systemic circulation (where its concentration is about 130 times lower), which might produce metastases, are likely not to survive. This would explain why the progress of the disease is very slow.

Inside the prostate, under the above described conditions of extremely high concentration of FT, rarely and coincidentally, a mutant cancerous cell may eventually emerge that can survive in a lower androgen environment. If it reaches the bloodstream, it may implant successfully and produce a viable metastasis.

Importantly, by bypassing the systemic circulation, the FT that reaches the prostate via the 'back-door' is not detected in the peripheral blood; hence the measured serum androgen levels do not reflect the reality of intraprostatic androgen milieu.

When ADT is initiated, the tumors, which consist of androgen sensitive cells that had proliferated before initiation of treatment, regress under ADT, since they cannot survive at that lower level of FT. However, at the same time within the prostate gland, a different scenario occurs. Under ADT, the FT levels arriving via the 'back-door' drop from 130 times to only five times the physiologic level (due to the ADT as explained above). The result is a persistent, overwhelming stress on the cell nuclei caused by the elevated concentrations of FT reaching the prostate directly from the testes. These can be calculated to be four times above physiologic, in spite of the ADT.

These conditions increase the selection pressure for the evolution of cell lines that become progressively more resistant to decreasing levels of androgen, that is, less dependent on extra cellular androgen for survival and proliferation.

We can thus make the following assertions: ADT indeed reduces the systemic FT concentration remarkably. However, the reduction of intra-prostatic FT is limited, with FT levels reduced to "only" 4-5 times normal (instead of some 130 times normal). Hence, paradoxically, and contrary to its goal, ADT may accelerate the evolution of more 'aggressive' prostate cancer cells with time. The above reasoning may explain the mechanism by which ADT may actually shorten the time to progression of the disease, as was indeed demonstrated in a recently published study (Ross, 2008).

It is extremely Important to know that while ADT decreases the serum androgen to castrated levels, the intra-prostatic FT level decreases only to 4-5 times above physiologic serum levels. Thus, there is created a greater selection pressure for PCa cells that are external androgen independent.

In the context of cellular 'natural selection' (in an analogy to Charles Darwin's struggle for existence of organisms and species), we would propose that there is an increased probability for highly aggressive mutant cancer cells to be produced inside the prostate after initiation of ADT. It is thus logical to state that under ADT, these potentially malignant, aggressive populations could emerge earlier than would be developed without ADT (Ross et al., 2008).

One of these mutations could produce a particular survival advantage, including the ability to produce its own free testosterone, as has been shown in a recent study (Locke et al., 2008). Such an advantageous mutation to produce FT is entirely possible since these cells, like any somatic cell in the male body, have the genetic information needed to produce FT. If a new mutant cell is produced by chance (an error of production process as described above) without the repressors of FT synthesis, this cell will produce FT on its own.

In this way, prostate cancer cells can become truly independent of extrinsic androgen. These mutants simply are able to provide their own androgens for survival and proliferation. At that juncture, these mutant cells will proliferate preferentially, and dominate a new PCa cell population (Darwin).

The 'Window of opportunity' to eliminate PCa

Since there is a limited 'window of time' for treatment, we suggest that intraprostatic cancerous cells should be eradicated before they develop AIPC while they are still dependent on the highest concentration of FT (and of course before they develop metastases and AIPC). So, we suggest that the first line of treatment should be in localized prostate cancer and directed towards the origin of the problem -- the flow of FT via the drainage system. In light of the above considerations, we would propose that the use of ADT should be a second stage therapy only, after elimination of back-flow to the prostate via the 'back-door'. Elimination of the venous back-flow into the prostate should be performed as early as possible in order to prevent the possibility that prostate cancer cells, with mutationally acquired capacity to produce FT by their own, will be produced.

Suggested treatment:

Super-selective intraProstatic Androgen Deprivation Therapy (SPAD)

Deriving from these observations, the most effective treatment would be to treat the actual cause--eliminating retrograde back-flow from the testes to the prostate. This can be accomplished by occlusion of bilateral ISVs including the network of small vertically oriented venous bypasses and retroperitoneal collateral veins that are almost invariably associated with the impaired ISVs. Since the same pathologic hydrostatic pressure is propagated in each one of these collateral veins as in the larger main ISVs, all these collaterals must be treated as well.

The technique for percutaneous transvenous varicocele treatment was a technique that originally developed by Kunnen [Kunnen and Comhaire, 1992] for the treatment of varicocele in male infertility and recently has been modified as the Gat Goren technique for treatment of impaired venous drainage apparatus in the male reproductive system. This treatment technique for the prostate can be described as Super-selective Intraprostatic Androgen Deprivation Therapy [Gat and Gornish, 2006]

In Summary:

(1) Prostate cancer may develop as a consequence of extreme intraprostatic concentration of free testosterone. This occurs due to the progressive physical deterioration and destruction of the one-way valves in the ISVs, increasing rapidly with age and that produce pathologic high hydrostatic pressure in the testicular venous drainage system. As a result, testicular venous blood is diverted directly to the prostate, by abnormal retrograde back-flow with its excessively high concentration of FT, bypassing the systemic circulation and undetected in the peripheral blood.

(2) Eliminating the pathologic hydrostatic pressure in the testicular venous drainage systems by occlusion of the malfunctioning ISVs, including all the associated venous bypasses and retroperitoneal collaterals, prevents the back-flow of FT rich blood to the prostate and may be effective in eradicating localized PCa cells in the early stages of their development.

(3) Understanding the basis of the known effect of intraprostatic FT on the evolution of the prostate cancer cell population leads us to suggest that there is a limited window of opportunity to effectively treat prostate cancer. ADT alone may thwart the suggested effective treatment measures.

(4) Huggins and Hodges were correct when they asserted in 1941 that testosterone is the cause of prostate cancer. However, it is not the serum testosterone level that reaches the prostate physiologically via the prostatic artery that affects the gland. Rather, the cause is free testosterone in high concentrations that reaches the prostate via the 'back-door' (venous drainage system) because of the impairment in the testicular venous drainage system that we have studied and described above.

1, and M. Gornish, MD1 as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

1. Mayanei Hayeshua Medical Center and Condensed Matter Physics, Weizmann Institute of Science, Israel

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