dutasteride and Body-Weight

To evaluate the effects of dutasteride on the expression of angiogenesis markers in rat and human prostates.. Eight-week-old male Sprague-Dawley rats were divided into three groups of six each according to dutasteride dose, including the control group (regular diet), 2.5 mg group (2.5 mg/kg dutasteride) and 5.0 mg group (5.0 mg/kg dutasteride). A total of 41 patients awaiting transurethral resection of the prostate (TURP) were divided into two groups: 20 patients received no medication and 21 received 0.5 mg dutasteride daily for 2-4 weeks until TURP.. At 2 weeks, dutasteride effected a significant decrease in body weight and prostate weight compared with the control rat group. Analysis by reverse transcription-polymerase chain reaction and Western blot revealed that hypoxia-inducible factor-1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression was lower in the dutasteride-treated groups than in the control group, except for HIF-1alpha protein. HIF-1alpha and VEGF expression was similar in the 2.5 mg and 5.0 mg groups. Human prostate tissues demonstrated homogeneous staining of HIF-1alpha and VEGF with regard to extent, intensity and intracellular location in both groups. There was no significant difference in microvessel density between the two groups.. The expression of HIF-1alpha and VEGF in rat prostates is suppressed by dutasteride. However, less than 4 weeks of dutasteride administration does not suppress the expression of HIF-1alpha, VEGF and microvessel density in human prostate tissue. Further clinical investigation with dutasteride including a larger, placebo-controlled study is warranted to establish the mechanism and duration of dutasteride.

Topics: Aged; Aged, 80 and over; Animals; Antigens, CD34; Azasteroids; Blood Loss, Surgical; Body Weight; Dutasteride; Enzyme Inhibitors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Male; Microvessels; Middle Aged; Models, Animal; Neovascularization, Physiologic; Organ Size; Prostate; Rats; Rats, Sprague-Dawley; Transurethral Resection of Prostate; Vascular Endothelial Growth Factor A

The prostate cancer prevention trial (PCPT) and Reduction by dutasteride of Prostate Cancer Events (REDUCE) trial found that 5α-reductase (5αR) inhibitors finasteride and dutasteride respectively, decreased prostate cancer prevalence but also increased the incidence of high-grade tumors. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have high 5αR1 and low 5αR2 expression. Because finasteride inhibits only 5αR2, we hypothesized that it would not be as efficacious in preventing prostate cancer development and/or progression in C57BL/6 TRAMP x FVB mice as dutasteride, which inhibits both 5αR1 and 5αR2.. Six-week-old C57BL/6 TRAMP x FVB male mice were randomized to AIN93G control or pre- and post- finasteride and dutasteride diet (83.3 mg drug/kg diet) groups (n =30-33) that began at 6 and 12 weeks of age, respectively, and were terminated at 20 weeks of age. The pre- and post- finasteride and dutasteride groups were designed to test the preventive and therapeutic efficacy of the drugs, respectively. Final body weights, genitourinary tract weights, and genitourinary tract weights as percentage of body weights were significantly decreased in the Pre- and Post-dutasteride groups compared with the control. The Post-dutasteride group showed the greatest inhibition of prostatic intraepithelial neoplasia progression and prostate cancer development. Surprisingly, the Post-dutasteride group showed improved outcomes compared with the Pre-dutasteride group, which had increased incidence of high-grade carcinoma as the most common and most severe lesions in a majority of prostate lobes. Consistent with our hypothesis, we found little benefit from the finasteride diets, and they increased the incidence of high-grade carcinoma.. Our findings have commonalities with previously reported PCPT, REDUCE, and the Reduction by dutasteride of Clinical Progression Events in Expectant Management (REDEEM) trial results. Our results may support the therapeutic use of dutasteride, but not finasteride, for therapeutic or preventive use.

Topics: 5-alpha Reductase Inhibitors; Animals; Azasteroids; Body Weight; Cholestenone 5 alpha-Reductase; Disease Progression; Dutasteride; Finasteride; Lymph Nodes; Lymphatic Metastasis; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Receptors, Tumor Necrosis Factor, Member 25

5α-reductase 1 (5αR1) and 5α-reductase 2 (5αR2) convert testosterone into the more potent androgen dihydrotestosterone. 5αR2 is the main isoenzyme in normal prostate tissue; however, most prostate tumors have increased 5αR1 and decreased 5αR2 expression. Previously, finasteride (5αR2 inhibitor) treatment begun 3 weeks post-tumor implantation had no effect on Dunning R3327-H rat prostate tumor growth. We believe the tumor compensated for finasteride treatment by increasing tumor 5αR1 expression or activity. We hypothesize that finasteride treatment would not significantly alter tumor growth even if begun before tumor implantation, whereas dutasteride (5αR1 and 5αR2 inhibitor) treatment would decrease tumor growth regardless of whether treatment was initiated before or after tumor implantation.. Sixty 8-week-old male nude mice were randomized to Control, Pre- and Post-Finasteride, and Pre- and Post-Dutasteride (83.3 mg drug/kg diet) diet groups. Pre- and post-groups began their treatment diets 1-2 weeks prior to or 3 weeks after subcutaneous injection of 1×10⁵ WPE1-NA22 human prostate cancer cells, respectively. Tumors were allowed to grow for 22 weeks; tumor areas, body weights, and food intakes were measured weekly. At study's conclusion, prostate and seminal vesicle weights were significantly decreased in all treatment groups versus the control; dutasteride intake significantly decreased seminal vesicle weights compared to finasteride intake. No differences were measured in final tumor areas or tumor weights between groups, likely due to poor tumor growth. In follow-up studies, proliferation of WPE1-NA22 prostate cancer cells and parent line RWPE-1 prostate epithelial cells were unaltered by treatment with testosterone, dihydrotestosterone, or mibolerone, suggesting that these cell lines are not androgen-sensitive.. The lack of response of WPE1-NA22 prostate cancer cells to androgen treatment may explain the inadequate tumor growth observed. Additional studies are needed to determine whether finasteride and dutasteride are effective in decreasing prostate cancer development/growth.

Topics: Animals; Azasteroids; Body Weight; Cell Line, Tumor; Cell Survival; Dihydrotestosterone; Dutasteride; Finasteride; Humans; Male; Mice; Mice, Nude; Prostatic Neoplasms; Rats; Testosterone; Tumor Burden; Xenograft Model Antitumor Assays

The objectives of this study were to investigate whether chlormadinone acetate (CMA, Prostal, CAS 302-22-7) more markedly decreased ventral prostate and seminal vesicle weights and exerted more beneficial effects on intraprostatic androgen levels than dutasteride (DUT, CAS 164656-23-9) in rats. Dose-dependent inhibiting effects on prostate and seminal vesicle enlargement were observed after the 14-day administration of CMA (30, 100 mg/kg/day) and DUT (0.3, 1 mg/kg/day). The prostate atrophy rates calculated as the percentages relative to the vehicle-treated group were 50.5 and 67.9% with 30 and 100 mg/kg CMA and 34.9 and 37.0% with 0.3 and 1 mg/kg DUT, respectively, and the atrophying effect of CMA was significantly greater than that of DUT (p < 0.05). The results of 7-day administration were similar to those of 14-day administration. While CMA dose-dependently and significantly (p < 0.05) reduced the testosterone (T) and dihydrotestosterone (DHT) concentrations in prostate, DUT reduced the DHT concentration but markedly increased the T concentration (20-40 times). Even though it was carried out in rats, this study revealed for the first time that the antiandrogen CMA showed a stronger atrophying effect than the 5alpha-reductase inhibitor DUT on direct comparison. The difference between the atrophying effects of CMA and DUT is considered to be attributed to the present results that CMA reduced the concentrations of both androgens (T and DHT) in prostate but DUT did not, and the fact that CMA has a potent androgen receptor-blocking action but DUT does not.

Topics: 5-alpha Reductase Inhibitors; Androgen Antagonists; Androgens; Animals; Azasteroids; Body Weight; Chlormadinone Acetate; Dutasteride; Male; Organ Size; Prostate; Rats; Rats, Sprague-Dawley; Seminal Vesicles