Prostate Cancer Abstracts 5

© 2011

Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment

            (Gat, Gornish et al. 2008) Download

The prostate is an androgen-regulated exocrine gland producing over 30% of the noncellular components of the semen and promoting optimal conditions for survival and motility of sperm in the vagina. Benign prostate hyperplasia (BPH) is the most common benign neoplasm in men. Its aetiology is not clear, and therefore, current medical treatments are directed towards the symptoms. Though testosterone is known to be the promoter of prostate cell proliferation, no causal relation between serum testosterone levels and BPH has been found. In this study, we propose a novel and tested pathophysiological mechanism for the evolution of BPH and suggest a tested and effective treatment. We found that in all BPH patients, the one-way valves in the vertically oriented internal spermatic veins are destroyed (clinically manifested as varicocele), causing elevated hydrostatic pressure, some 6-fold greater than normal, in the venous drainage of the male reproductive system. The elevated pressure propagates to all interconnected vessels leading to a unique biological phenomenon: venous blood flows retrograde from the higher pressure in the testicular venous drainage system to the low pressure in the prostatic drainage system directly to the prostate (law of communicating vessels). We have found that free testosterone levels in this blood are markedly elevated, with a concentration of some 130-fold above serum level. Consequently, the prostate is exposed to: (i) increased venous pressure that causes hypertrophy; (ii) elevated concentration of free testosterone causing hyperplasia. We have treated 28 BPH patients using a technique that restores normal pressure in the venous drainage in the male reproductive system. The back-pressure and the back-flow of blood from the testicular to the prostate drainage system were eliminated and, consequently, a rapid reduction in prostate volume and a regression of prostate symptoms took place.


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

            (Gat, Joshua et al. 2009) Download

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.

Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa)

            (Giton, de la Taille et al. 2008) Download

Seeking insight into the possible role of estrogens in prostate cancer (PCa) evolution, we assayed serum E2, estrone (E1), and estrone sulfate (E1S) in 349 PCa and 100 benign prostatic hyperplasia (BPH) patients, and in 208 control subjects in the same age range (50-74 years). E1 (pmol/L+/-S.D.) and E1S (nmol/L+/-S.D.) in the PCa and BPH patients (respectively 126.1+/-66.1 and 2.82+/-1.78, and 127.8+/-56.4 and 2.78+/-2.12) were significantly higher than in the controls (113.8+/-47.6 and 2.11+/-0.96). E2 was not significantly different among the PCa, BPH, and control groups. These assays were also carried out in PCa patients after partition by prognosis (PSA, Gleason score (GS), histological stage, and surgical margins (SM)). Significantly higher E1S levels were found in PCa with: PSA>10 ng/L (3.05+/-1.92) versus PSA<or=10 ng/mL (2.60+/-1.55), stage pT3-T4 (2.99+/-1.80) versus pT2 (2.58+/-1.58), and positive (3.26+/-1.95) versus negative margins (2.52+/-1.48). E1 was higher in poor- than in better-prognosis PCa. E2 was significantly higher in PCa with GS>or=4+3 (109.5+/-43.8) versus GS<or=3+4 (100.6+/-36.5) and increased significantly when GS increased from 3+3 to 4+4. Estrogens, especially E1S appeared to be possible markers of PCa progression. Attempting to identify potential sources of E2 in PCa according to prognosis, as well as in BPH, we found a significant correlation coefficient between E1S and E2 (0.266-0.347) in poor-prognosis PCa and no correlation in BPH (0.026) and better-prognosis PCa (0.013-0.104). It is as though during progression of PCa from good to poor prognosis there were a shift in the E1 to E2 metabolic pathway from predominantly oxidative to predominantly reductive.

Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden

            (Stocks, Lukanova et al. 2007) Download

Factors related to insulin resistance have been implicated in prostate cancer development, however, few analytical studies support such an association. We performed a case control study on 392 prostate cancer cases and 392 matched controls nested in a prospective cohort in Northern Sweden. Plasma concentrations of C-peptide, leptin, glycated haemoglobin (HbA1c) and fasting and post-load glucose were analysed and homeostatic model assessment of insulin resistance (HOMA-IR) was calculated. Conditional logistic regression analyses were used to calculate odds ratios (OR) of prostate cancer. High levels of C-peptide, HOMA-IR, leptin and HbA1c were associated with significant decreases in risk of prostate cancer, with ORs for top vs. bottom quartile for C-peptide of 0.59 (95% Confidence Interval [CI], 0.40-0.89; p(trend) = 0.008), HOMA-IR 0.60 (95% CI, 0.38-0.94; p(trend) = 0.03), leptin 0.55 (95% CI, 0.36-0.84; p(trend) = 0.006) and HbA1c 0.56 (95% CI, 0.35-0.91; p(trend) = 0.02). All studied factors were strongly inversely related to risk among men less than 59 years of age at blood sampling, but not among older men, with a significant heterogeneity between the groups for leptin (p(heterogeneity) = 0.006) and fasting glucose (p(heterogeneity) = 0.03). C-peptide and HOMA-IR were strongly inversely related to non-aggressive cancer but were non-significantly positively related to risk of aggressive disease (p(heterogeneity) = 0.007 and 0.01, respectively). Our data suggest that androgens, which are inversely associated with insulin resistance, are important in the early prostate cancer development, whereas insulin resistance related factors may be important for tumour progression.


References

Gat, Y., M. Gornish, et al. (2008). "Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment." Andrologia 40(5): 273-81.

Gat, Y., S. Joshua, et al. (2009). "Prostate cancer: a newly discovered route for testosterone to reach the prostate : Treatment by super-selective intraprostatic androgen deprivation." Andrologia 41(5): 305-15.

Giton, F., A. de la Taille, et al. (2008). "Estrone sulfate (E1S), a prognosis marker for tumor aggressiveness in prostate cancer (PCa)." J Steroid Biochem Mol Biol 109(1-2): 158-67.

Stocks, T., A. Lukanova, et al. (2007). "Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden." Int J Cancer 120(12): 2678-86.