Evaluation of Effectiveness of Antiandrogen Treatments on Cavernosal Tissues – part 1

Evaluation of Effectiveness of Antiandrogen Treatments on Cavernosal Tissues – part 1

Introduction

Prostate cancer is known to be the most frequently encountered cancer type in men excluding skin cancer (1). It has been reported that for example in the year 2012, 1.1 million men were diagnosed as prostate cancer, and 70 % of them occurred in developing countries (2).  Besides prostate cancer-related mortality rates rank second after lung cancer (3). That would remove all stagnation in the blood channels of the penis is very helpful drug Viagra, but to treat cancer of the prostate need other methods of treatment and mandatory medical supervision of Oncology and urologist.

Despite, raising awareness about prostate cancer  (PCa) , availability of diagnostic methods which detect prostate cancer at an early stage, routine clinical use of PSA,  nearly 20% of prostate cancer cases can be still in the advanced or metastatic stage of the disease at the diagnosis (4). Androgen deprivation treatment (ADT) is a well known standard approach in metastatic prostate cancer. Apart from this, ADT can be applied in recurrent cases following primary definitive treatment of PCa or locally advanced prostate cancer. Androgen deprivation treatment can be implemented as orchidectomy, use of luteinizing hormone-releasing hormon (LHRH) agonists (ie. leuprolide, goserelin, triptorelin and histrelin) or gonadotrophin-releasing hormon (GnRH) antagonists (ie. degarelix). Conventionally, antiandrogens as bicalutamide, and nilutamide have been added to these treatment modalities. Among them GnRH agonists effect basophilic cells are found in the anterior lobe of pituitary, and stimulate gonadotropins known FSH (follicle stimulating hormone), and LH (luteinizing hormone) with resultant production of testosterone. However use of GnRH agonists for prolonged periods of time downregulates pituitary GnRH receptors with resultant suppression of the release of gonadotropins. As a natural consequence of this mechanism, serum testosterone levels decrease (5-7). Here, antiandrogens bind androgen receptors, and block the effects of endogenous androgens at receptor level. Thus GnRH agonists cause complete androgen blockade, when they are used in combination (5, 6, 8).

Antiandrogen Treatments on Cavernosal Tissues

ADT can cause multiple number of side effects including decrease in libido, diabetes mellitus, decrease in muscle tonus, changes in body mass index, osteoporosis, hot flushes, changes in lipid profile, and memory, gynecomastia, and sexual dysfunction (9-11).  In this study the effectiveness of orchidectomy, and use of LHRH agonists on cavernosal tissues has been evaluated.

Material and Methods

Forty-two male Wistar-Albino rats, weighing 200–250 g each, were used in this study. The rats were handled in the laboratory according to institutional guidelines as well as the Guide for Care and Use of Laboratory Animals of the National Research Council. All procedures were realized in compliance with the provisions of 1986 Strasbourg Universal Declaration on Animal Welfare, and the approval of Ethics Committee (HADYEK 89) was obtained. They were kept in a temperature controlled room (20–23 ºC), on a 12 h light/dark cycle with food (commercial rat chow) and fresh water available adlibitum. Forty-two rats were equally randomized into 4 groups. Rats were anesthesized with ketamine (50 mg/kg), and Group 1(n=11)  was assigned as the control group. Group 2 (n=10) received only antiandrogen (LH-RH agonist goserelin (3.6 mg depot) at daily doses of 100 µg/rat/sc for 4 weeks. Group 3 (n=11) received oral antiandrogen bicalutamide. Grup 3 received antiandrogen bicalutamide at daily oral doses of 25 mg/kg for 4 weeks, and concurrently 3.6 mg depot formulation of LH-RH agonist goserelin at daily subcutaneous doses of 100 µ/rat. In Group 4(n=10), the rats were fixed in supine position. After cleansing the operation site with sterile povidone-iodine solution, through scrotal incision both testes were surgically dissected away from surrounding tissues, and liberated. After ligation of both spermatic cords with 2/0 silk sutures, testes were taken out, and the incision was closed. Four weeks after surgery, The intracavernosal pressure(ICP) was measured using a 25-gauge needle inserted into the left crus of the penis connected to polyethylene tubing filled with heparin. The ICP were measured using a data acquisition system (BIOPAC MP 45 SYSTEM-USA ). The ICP, obtained by electronic averaging, were continuously recorded and displayed and stored using a Dell personal computer. For cavernosal nerve stimulation, the bladder and prostate were exposed through a midline abdominal incision. The cavernosal nerve was identified posterolaterally to the prostate on one side, and a stainless steel bipolar stimulating electrode was placed on the nerve. The cavernosal nerve was stimulated with square wave pulses at a frequency of 16 Hz, voltage of 2.5V , 5V, 7.5V and 10V and pulse width of 5 ms for a duration of 30 seconds using a STN 0211 Nerve Stimulator. Then, under general anesthesia, penectomy was performed. Afterwards, blood samples were drawn from systemic circulation, and cervical dislocation was carried out.

Biochemical evaluation

Blood samples were collected by centrifugation and sera were stored at -80 ° C until biochemical examination. Testosterone levels were studied with the Enzyme Linked ImmunoSorbent Assay (Organon Teknika Reader 230S, Austria) from all samples. Serum testosterone levels were studied using Cayman (Cayman Chemical Company, MI, USA) kits.

Histopathological Evaluation

Penectomy materials fixed in 10% formaldehyde solution were sampled, and after tissue follow-up procedures, they were embedded in paraffin blocks, and blocked. Sections prepared from paraffin blocks were stained with Masson’s trichrome dye. Sections from all groups were evaluated as for their collagen density on a scale extending from (+) to (++++). In the evaluation of smooth muscle/collagen ratio, density of collagen content of tissues was graded based on the percentage of areas stained as follows:  10-30% (+), 31-50%  (++), 51-70% (+++), and 71-100 % (++++) (Figure 1).

Statistical methods

Descriptive analyses were performed to gather information about general characteristics of the groups. In the evaluation of continuous variables for their fitness to normal distribution, Kolmogorov-Smirnov test was used. In intergroup comparisons normality of distribution was evaluated using ANOVA test. Data about continuous variables were expressed as mean ± standard deviation. P values less than 0.05 were considered to be statistically significant Calculations were performed using commercially available statistical software programs. (IBM SPSS Statistics 20, SPSS inc., an IBM Co., Somers, NY, USA)

Results

In intergroup comparisons between the control group (Group 1) , and all other groups (Groups 2, 3, and 4), it has been revealed that cavernosal pressures decreased markedly in response to all different electrical stimuli delivered, however drop in cavernosal pressure was statistically significant when 7.5, and 10 volts were applied (p =0.005, p<0.001). All pairwise comparisons between all other groups did not demonstrate the presence of any significant pressure gradient(Table 1).

In histopathological evaluation, tissue collagen density was found to be increased in other groups relative to the control group.  In Groups 3, and 4, 4+ collagen densities were more diffuse when compared with Groups 1, and 2. While in Group 2 which received only LH-RH agonists +4 density was not seen with resultant lesser destructive changes(Table 2).

In biochemical evaluation, there was no significant difference in testosterone level between groups 2, 3 and 4. Read the rest of the article in the second part.

References

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4.      Albrecht WCollette LFava C, et al. Intermittent maximal androgen blockade in patients with metastatic prostate cancer: an EORTC feasibility study. Eur Urol. 2003; 44: 505-11.

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By Dr. Ravi Mootha, M.D. On: May 22, 2019 at 04:20:13