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The prostate, an androgen-regulated exocrine gland, is an integral part of the male reproductive system which has an essential function in sperm survival and motility in its long hostile route to meet and fertilise the egg in the Fallopian tube. Testosterone is known to be the key, obligatory regulator of the prostate that promotes the development and progression of prostate cancer (PCa). Yet, the pathophysiological mechanism of PCa remains unclear and its causal relation to serum testosterone has not been established. Here, we report on the discovery of a previously unrecognized route of flow of free testosterone (FT), at a concentration of 130 times the physiological levels, reaching the prostate via the testicular and prostate venous drainage systems, bypassing the systemic circulation. This condition results from the malfunction of the vertically oriented testicular venous drainage system in humans, a phenomenon with a prevalence that increases rapidly with age, which causes deviation of the testicular venous flow from its normal route. Early results of an interventional radiological procedure, super-selective intraprostatic androgen deprivation therapy are discussed. This treatment has resulted in decrease in prostate volume, and serum PSA, with disappearance of cancerous cells on repeat biopsies in five of six patients. Some of the unresolved biological enigmatic questions associated with PCa are discussed. We conclude that pathological flow of FT from the testes directly to the prostate in an extremely high concentration via the testicular-prostate venous drainage systems was identified may explain the mechanism for the development of PCa. We suggest a time-window for eradication of localised, androgen-sensitive, PCa cells. We anticipate that this treatment may retard, stop or even reverse the development of the disease. A mechanism for the evolution of PCa is discussed.

Background Age‐dependent increase in the incidence of benign prostatic hyperplasia (BPH) and prostate cancer (PCa) are both related to cell proliferation and survival controlled by intraprostatic free testosterone (FT) concentration. Paradoxically, BPH and PCa occur as circulating testosterone levels decrease, so any possible relationship between testosterone levels and development of BPH and PCa remains obscure. Results In BPH the enlarging prostate is exposed to high testosterone levels arriving directly from the testes at concentrations about hundredfold higher than systemic FT. This occurs because venous blood from the testes is diverted into the prostate due to the elevated hydrostatic pressure of blood in the internal spermatic veins (ISVs). Elevated pressure is caused by the destruction of one‐way valves (clinically detected as varicocele), a unique phenomenon related to human erect posture. While standing, human males are ISVs vertically oriented, resulting in high intraluminal hydrostatic pressures—a phenomenon not found in quadrupeds. In this communication, we demonstrate the fluid mechanics' phenomena at the basis of varicocele leading to prostate pathology. Conclusions So far, varicocele has been studied mostly for its etiologic role in male infertility and, thus, for its effects on the testes. It is becoming clear that varicocele is a major etiologic factor in BPH and likely also in PCa. Restoring normal testicular venous pressure by treatment of the abnormal ISV's in varicocele has been shown to avert the flow from the prostate with the effect of reducing prostate volume, alleviating symptoms of BPH, and increasing concentrations of circulating FT.

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