Prostate cancer? You dumb f***, it is actually proven scientifically that it does nothing to prostate cancer and it actually increases the risk in developing a more stronger and more aggressive prostate cancer you uneducated analphabetic ape, that's why the FDA didn't even approve it as a prostate cancer treatment. Do your research you dumb f*** before talking, you think your so intelligent for mimicking transgender regimes and for reading a couple of studies online that you actually don't understand sh*t from them... It's really unbelievable how dumb you are, besides the fact that in all the times spent on the internet your not even capable of writing 2 correct sentences in English, dumb f***! Prostate cancer lmao, what a retard damn. And even if it's raises the free TEST it does not mean that you get more DHT you retard because inhibiting the enzyme that actually converts it does not permit it, it just converts the free TEST to Estrogen you dumb f***, that's where the Gyno and some of the sexual sides come from, uneducated sh*t expert that you are.. So much time spent here and on the internet and you don't know the basics on which this drugs act and work, daaaaaaaamn what a retarded f*** you are!
The Dark Side of 5α-Reductase Inhibitors' Therapy: Sexual Dysfunction, High Gleason Grade Prostate Cancer and Depression
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4064044/
5α-RIs therapy contributes to high Gleason grade PCa
The premise put forth by Huggins (1941) suggested that PCa is androgen-dependent and androgen deprivation results in tumor shrinkage [
56]. Androgen-dependency of PCa is predictable because tumor cells are derived from normal prostate cells, which retain expression of the androgen receptor (AR). Androgen deprivation therapy (ADT) of PCa initially results in tumor regression, but the cancer often relapses into androgen-independent cancer within 18-24 months and tumors no longer require androgens for growth [
5,
6].
Because conversion of T to 5α-DHT is a critical pathway in normal prostate growth and function, inhibition of 5α-R activity in the prostate results in a reduction of intraprostatic 5α-DHT levels and a decrease in prostate growth and size [
57]. There is no evidence that T or 5α-DHT causes initiation, promotion or development of PCa [
5,
6,
58,
59]. This hypothesis was further supported by the recent study of Muller et al. [
59] in which patients enrolled in the Placebo arm of the REDUCE trial [
13] showed no association between baseline total T nor 5α-DHT and PCa. The authors concluded that "
baseline serum T
and 5α-DHT
levels were unrelated to prostate cancer detection or grade" [
13,
59]. This raises the question-how could 5α-RIs be useful as chemo-preventative agents if PCa development is unrelated to T or 5α-DHT? As stated by Walsh (2010) in the FDA panel discussion in 2010, "
No clinical benefit has been demonstrated in patients with prostate cancer treated with PROSCAR" [
16]. In addition, the potential reduction in the incidence of PCa in the general population with the use of these agents may not exceed 10%, which is not statistically significant [
16]. Furthermore, the documented increase in Gleason high-grade PCa tumors in response to treatment with these agents proves that these drugs do not prevent development and growth of PCa; they merely prevent biopsies due to reduction in prostate volume. Most importantly, if 5α-RIs indeed prevent PCa development, then how come they are not approved for treatment of PCa?
As suggested by Crawford et al. [
60], Justman [
61], and Walsh [
62,
63] four important points need to be considered before the decision is made to use 5α-RIs for chemo-prevention of PCa. These are: (1) 5α-RIs do not prevent PCa development and therefore, these drugs have no significant effect on reducing the real risk of metastatic PCa in men; (2) 5α-RIs reduce the risk of detecting low-grade tumors, but do not increase survival or reduced mortality [
17]; (3) if these drugs indeed chemo-prevent PCa, then why aren't they used in the treatment of PCa?; and (4) to reduce the overall risk of PCa in the population, 5α-RIs as chemo-preventative agents must be entirely free of any side effects [
60,
61,
62,
63]. Theoret et al. [
15] reported that even after re-evaluation of the data from the PCPT [
14] and the REDUCE trial [
13] with the revised Gleason scoring system, these drugs were shown to increase the incidence of Gleason high-grade PCa tumors. The authors concluded that "
the trade-off inherent in using a 5αRI
for prostate cancer prevention is the acceptance of one additional high-grade cancer in order to avert three to four potentially clinically relevant low-grade cancers" [
15]. Put more simply, when using 5α-RIs as chemo-preventive agents - the risks outweigh the benefits.
This is not surprising since the recent follow-up data on the PCPT have clearly shown that there are no significant benefits in terms of reducing mortality and increasing survival [
17]. As Ehdaie and Touijer [
64] pointed out, while the medical community is eager to provide early intervention for patients with high prostate specific antigen levels after therapy, it remains critical to weigh the harm of treatments against the uncertain benefits to the patients. It is incumbent that physicians critically evaluate the current evidence and weigh the risks and benefits of such interventions [
64]. Since the PCPT [
14] and REDUCE trials [
13], used PCa incidence as an end point instead of mortality, there is little that one can conclude about the chemo-preventive nature of these agents and their ability to prolong survival and improve quality of life [
65].
Data from a large, long-term Randomized Control Trial (RCT
ARI40005) raised a serious concern regarding the safety of 5α-RIs, dutasteride, because of significant increase in the risk of "cardiac failure" [
13,
66,
67]. As pointed out by Justman [
61] some of the unidentified risks of 5α-RIs may be attributed to the limitations of the clinical trials. For example, these trials had no primary or secondary endpoints to detect cardiovascular events; therefore, some of the events may have been overlooked or underestimated. Moreover, since cardiovascular events were not investigated as part of the primary or secondary endpoint, clinical trial investigators may have had different interpretations and may have not given them serious consideration [
16,
61,
67].
Several studies have attempted to evaluate the efficacy of 5α-RIs in reducing tumor growth in the animal models. Interestingly, the study by Umekita et al. [
68] showed that various PCa tumor cell lines respond differently to androgen treatment. For instance, the tumor cell line, LNCaP 104-R2, when implanted in castrated, nude, male mice continued to grow. However, treatment with TP resulted in tumor regression not tumor growth. Remarkably, treatment with TP together with finasteride resulted in increased tumor growth. These findings suggest that ADT may not necessarily be beneficial for treatment of all forms of PCa and that androgen replacement therapy may be a potential treatment for some forms but not all forms of PCa [
68]. Recently, several small clinical trials have reported using testosterone therapy in patients with localized PCa, after radical prostatectomy or brachytherapy. These studies found positive results based on lack of biochemical recurrence in the treatment arms [
69].
Since PCa is a heterogeneous disease, different tumors possess different metabolic properties. In a study using androgen-insensitive PCa cell lines in an animal model, it was reported that the 5α-RIs, finasteride and dutasteride, did not inhibit tumor incidence or tumor growth suggesting the limited potential benefits of 5α-RIs as chemo-preventive agents in all forms of PCa.
It should be noted that 5α-RIs alter cellular biology with uncertain outcomes. For example, treatment of animals with 5α-RIs resulted in marked increase in the expression of the AR [
70]. The implication of such dysfunctional metabolism may contribute to loss of androgen dependence and to acquisition of high-grade tumors. In addition, Yun et al. [
71] postulated that finasteride increases expression of hemoxygenase-1 and other related factors in PCa cell lines (PC-3). The authors suggested that finasteride-induced alteration in gene expression may be in part responsible for finasteride-induced high grade prostate tumors [
71]. It is not surprising that Theoret et al. [
15] reported a significantly number of high grade tumors (
Fig. 4), with finasteride and dutasteride in the data from the PCPT [
14] and REDUCE trials [
13] respectively, even after using the revised Gleason scoring system [
15].
FIG. 4
Relative and absolute risk of prostate cancer according to modified Gleason score (mGS), PCPT and REDUCE trial. 5α-RI, 5α-reductase inhibitors. I bars indicate 95% confidence intervals. Adapted from Theoret MR, et al. N Engl J Med 2011;365:97-9, with permission of Massachusetts Medical Society [15].
The overwhelmingly negative decision by the FDA panel of scientists and medical experts [16] speaks volumes and raises a significant concern about the safety and the efficacy of these drugs as chemo-preventive agents for PCa, given that they elicit many serious adverse side effects [16]. With the postmarketing increase in reported adverse events, the FDA has mandated a revision to the labeling for all 5α-RIs [16]. The labeling changes included a warning of increased sexual dysfunction, depression, and increased risk of high-grade PCa.
