Prostate cancer and Antiandrogen – part 2

Prostate cancer and Antiandrogen – part 2

Discussion about Antiandrogen and prostate

As reported in the literature, detection rates of prostate cancer have increased during recent years, and varied between 4.5/100000, and 111.6/ 100000 (12, 13) . In the management of prostate cancer -dependent on the general status of the patient, and disease stage- radical prostatectomy, radiotherapy, brachytherapy, antiandrogen are conventional treatment modalities. After androgen dependency of prostate cancer was revealed years ago, ADT started to be  used in the urology practice for the treatment of the patients with locally advanced, and advanced stage PCa for more than 70 years (14). Basic rationale in ADT is to lower testosterone concentrations down to castration levels. In multiple number of studies it has been clearly shown that hormone- dependent prostate cancer regressed using this approach, and clinically significant outcomes have been achieved (11, 7). However this treatment method for prostate cancer at the same time decreases levels of testosterone which plays a basic role in physiologic, biochemical, and structural integrity of erection with ensuing erectile dysfunction.

Following sexual stimuli, relaxation of sinusoids, and compression of subtunical venules (venous occlusion) play fundamental roles in the mechanism of erection, and maintain erectile state (15).  Testosterone deficiency  enhances response of penile smooth muscles contained in corpora cavernosa to alpha-adrenergics, and increases apoptosis (16-17,8 ). Accordingly, androgen deficiency alters contents of the trabecular smooth muscles in corpora cavernosa by decreasing its elastin, but increasing its collagen components. These changes impair fibroelastic characteristics of trabecular smooth muscles, and diminish their extracellular matrix all of which adversely effect subtunical occlusion mechanism (8). This outcome has been demonstrated with decrease in elastin content of smooth muscles, and increase in the collagen of corpora cavernosa of medically or surgically castrated rats, and in numerous animal studies (18,19). Similar histopathologic results were detected in our study. In present study especially in group 3 and group 4 the increasing rate of collagen was prominent.  These alterations in penile corpora cavernosa manifest themselves with decrease in arterial blood flow, venous insufficiency, and decreased response of erectile tissue to nervous stimuli (20). As a consequence, standard intracavernosal pressure required for an induction and/or maintenance of a healthy erection can not be achieved. On the contrary, in castrated rats, testosterone administration has reversed these adverse effects (18). As indicated in previous animal studies, testosterone deficiency decreases the levels of NO which is the essential mediator in erection. Besides deficiency or lack of testosterone decreases expression of PDE5 contained in erectile tissues. Also, enzymatic activity of PDE5 increases with administration of testosterone (21, 22). Many clinical studies have demonstrated that testosterone deficiency causes erectile dysfunction, and testosterone replacement therapy regresse, and improves ED symptoms (22, 23).

prostate cancer

 

When we think that erectile functions are dependent on testosterone levels, sexual functions of the patients receiving ADT are more deteriorated when compared with those underwent surgery or radiotherapy (24-26). Accordingly, in a study where cases received (Group I, n=38) and did not receive (Group II, n=94) ADT for 3 months before radical  prostatectomy were compared, at follow-up visits performed at postoperative 6 months venous insufficiency was seen in 60, and 20 % of the patients in Groups I, and II, respectively with a significant intergroup difference. Besides significantly lower IIEF scores were detected in Group I (27). In another study where 482 patients who were known to be potent and followed up with the diagnosis of prostate cancer before treatment with neoadjuvant ADT plus brachytherapy or only brachytherapy were investigated. The patients who received neoadjuvant ADT plus brachytherapy had more deteriorated erectile functions relative to those who had undergone only brachytgerapy (76% vs. 52%, respectively ) (28). Similarly in a study by Fowler et al. rates of ED were found to be 72% (n=298), and 55 % (n=1095) among patients who were (Group I) and were not receiving (Group II) ADT following radical prostatectomy (RP), respectively. In their study pre-RP rates of ED in the these groups were reported to be 23, and 22 %, respectively. Only 2 % of these patients reported that they had achieved, and sustained rigid erections sufficent for the maintenance of their sexual functions. As is understood ADT effects libido of the patients adversely. For instance 69% of PCa patients who received (n=170), and 29% of PCa cases who did not receive (n=888) ADT had complained of being sexually inactive (p< 0.001)(29).  In Prostate Cancer Outcomes Study a total of 416 patients who received ADT were investigated. This study revealed that 69% of the patients who were sexually potent before ADT therapy had lost their potencies after ADT(30). In the same study, sexual functions, and libido were comparable before the treatment in both groups, however in the orchidectomized group sexual dysfunction were relatively more frequent. However intergroup differences as for the outcomes of sexual functions were not statistically significant. When compared with the pretreatment levels, post-treatment incidence rates of erectile dysfunction increased from 35 up to 78 % in the orchidectomized, and from 37.9 up to 73.3 % in the GnRH-treated groups. Besides statistically significantly sexual dysfunction occurred in the GnRH, and orchidectomy groups (38.4, and 25.6%, respectively). With erectile dysfunction, you should consult a doctor, change your lifestyle, diet, and read Ed drugs for the treatment of impotence. Understand the drug is right for you or not, you can learn by reading about Viagra online here, but it is better to consult a doctor.

Potosky et al. reported incidence rates of ED in the groups who received and did not receive ADT for one year as 80, and 30 %, respectively(30). In another study, sexually active patients who were receiving LHRH agonists were evaluated, and the researchers reported that frequency, quality, duration of sexual intercourses, and rijidity of nocturnal erections had been adversely, and significantly affected from ADT(31). As understood from literature information only less than 20 % of the patients under ADT are maintaining their sexual activities (32-34). Nearly half of the patients who discontinued ADT can achieve relatively more satisfactory erections, only a small minority of the patients could recover their sexual activities after months.

Widespread use of maximal androgen blockade in the treatment of metastatic prostate cancer is already acknowledged. Accordingly, in a research clinical a total of 250 cases with prostate cancer were followed up for 9 months. In this study the effect of combination therapy (flutamide and leuprolide)  on sexual functions was investigated (35). In this study after a follow-up period of 9 months, only 13% of the patients had maintained their sexually active lives. In addition, following 9 months of therapy, for 2 years the patients had not received ADT, and during this period 53% of the patients had been sexually active, and sexual functions of all patients improved. On the other hand, improvements in sexual functions still remained below baseline levels. Only 15% of the patients who maintained their sexual functions under ADT indicated that they had achieved satisfactory erections (35). In our study the decrease rate of intracevernosal pressure was prominent in combined group compared to group 2 and group 4.

It is known that as a standard approach ADT is used together with RT in locally advanced or advanced stage prostate cancer (36). This combination treatment exerts adverse effects on sexual functions10. Kushnir et al. investigated 213 patients diagnosed as prostate cancer in two groups. Accordingly, 143 patients who had received RT+ADT treatment were compared with 70 patients who had undergone RT. They demonstrated that sexual functions, and hormonal values in the RT+ADT group significantly decreased when compared with RT monotherapy group (P < 0.0001). The first year post ADT and EBRT poses the greatest risk to sexual function and a continued decline may be expected. However, 26% of men can be expected to maintain their sexual functions at 5 years (37). Testosterone insufficiency can be seen as a long-term effect of radiotherapy (38-40).

In a study where a total of 395 patients who received ADT with the diagnosis of prostate cancer were investigated as for their sexual functions, after an average of 87.4 months of follow-up ED was detected in 14.4 % (n=57) of the cases. Seventy percent (n=40) of them was reported as newly-onset ED. About 33-80 % of these patients had responded to medical treatment, and 44% of them received PDE5Is. In multivariate analysis of these cases <70 years of age, and DM were found to be associated with post-ADT ED(41).   In another study, demonstrated that androgen deprivation impaired relaxation effect of sildenafil which was restored with testosterone treatment in rats (42). Since for optimal response of cavernosal tissue to PDE5I treatment, androgen is a must, and sildenafil has a decreased effectiveness in cases with androgen deprivation.45. A placebo-controlled cross-over trial (43) in patients treated with EBRT and neo-adjuvant or concurrent ADT found that the effect of sildenafil was significant (p = 0.009) vs. placebo. However, only 21% of patients had a treatment-specific response, and improved during sildenafil treatment, but not during the crossed-over placebo phase(43).

According to these results it can be concluded that the negative effect of isolated LH-RH agonist treatment on cavernosal tissues is less compared to orchidectomy and combined treatment. Probably the use of sildenafil citrate will be more useful in this group of patients.

 

Ethics Committee Approval: Ethics committee approval was received for this study from the ethics committee.

Peer-review: Externally peer-reviewed.

Author contributions: Concept – F.F.; Design – F.F.; Supervision – F.F., F.E.; Resource – F.F., F.E.; Materials – F.F., F.E., F.M., B.S.P. ; Data Collection and/or Processing – F.F, F.G.; Analysis and/or Interpretation – F.F.,  F.E.; Literature Search – F.F.; Writing – F.F., F.E.; Critical Reviews – F.F., F.E.

Conflict of Interest: No conflict of interest was declared by the authors.

Financial Disclosure: The authors declared that this study has received no financial support.

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By Dr. Ravi Mootha, M.D. On: May 22, 2019 at 10:01:19