Benign Prostatic Hyperplasia- what do we know?

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madman

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Abstract

OBJECTIVES
Benign prostatic hyperplasia (BPH) is a prevalent disease with significant health and economic impacts on individuals and health organizations across the world, whilst the cause/initiation of the disease process has still not been fully determined.

METHODS
This review presents historical and contemporary hypotheses on the pathogenesis of benign prostatic hyperplasia, with the potential implications in regards to current medical therapies.

RESULTS
In BPH, pathways involving androgens, oestrogens, insulin, inflammation, proliferative reawakening, stem cells, and telomerase have been hypothesized in the pathogenesis of the disease. A number of pathways first described over 40 years ago have been first rebuked and then have come back into favor. A system of an inflammatory process within the prostate, which leads to growth factor production, stem cell activation, and cellular proliferation encompasses a number of pathways and is currently in vogue. This review also highlights the physiology of the prostate cell subpopulations and how this may account for the delay/failure in treatment response for certain medical therapies.

CONCLUSION
BPH is an important disease, of which the pathogenesis is not fully understood that impacts the effectiveness of medical therapies. These impacts patients, with further research potentially highlighting novel therapeutic avenues.



Benign prostatic hyperplasia, commonly known as BPH, results in benign enlargement of the prostate gland, due to unregulated hyperplastic growth of either the epithelial and fibromuscular tissues of the transition zone and periurethral area (1). Despite many years of scientific study, there is still no basis for the hyperplasia, which restricts attempts to devise new treatments.





Pathophysiology of BPH

Genetics/hereditary factors

Androgens

Oestrogens

Insulin

Growth factors/ inflammation

Androgen receptor and growth factors

Role of chronic inflammation

Reawakening hypothesis

Stem cells

Role of telomerase





Implications for current treatment modalities

A surgical approach via prostate tissue resection, vaporization or enucleation remains the gold standard of treatment for the benign prostatic obstruction of the urethra, normally for severe symptoms or disease complications. Surgery is not without risk, with the main problems being infection, incontinence, ejaculatory dysfunction and impotence. Minimal invasive procedures are an emerging treatment arm for BPH. Patients within this arm normally have symptoms that are not responding to medical therapies but do not wish to undergo invasive surgical procedures or are not medically fit to undergo them, however not completely risk-free, with reports of urinary retention, urge incontinence, and pelvic pain post-procedure for all methods (79).

Due to these risks, with milder symptoms, medical therapy is the first option. The treatment involves either as a monotherapy or as a combination of alpha-blockers and 5ARIs. Both of these treatments have been recommended for over 20 years (80).

Alpha-blockers such Tamsulosin and Alfuzosin, act on the smooth muscle within the prostatic urethra, relaxing it, enabling better flow of urine.
5-ARIs such as Finasteride and Dutasteride inhibits the conversion of testosterone to dihydrotestosterone and decreases the impact of androgen receptor (AR) on cell proliferation. The combination of these two groups together has been shown to improve overall symptoms (81).

There are however problems with both treatments. Alpha-blockers do not treat any area of disease initiation/causation, so after 2 years of treatment, their efficacy can be seen to decrease (82). They also have side effects such as postural hypertension and retrograde ejaculation.

5-Alpha reductase inhibitors clinically take a substantial time to show effect, normally 6 to 9 months. The reasons for this are discussed above, which include; the overall dependence of BPH on androgens, the targeting of the wrong “driver” cell population, and the independence of growth factor release in chronic inflammation seen in BPH (figure 1). Furthermore, the activation of the nuclear factor-kappa B pathway by inflammation induces overexpression of androgen receptor variant type 7. This AR variant is associated with increased disease severity and provides a mechanism for patient resistance to 5-ARI treatment (83).

Added to this, they have a significant side effect profile of erectile dysfunction, decreased libido, and decreased ejaculate volume (84). Also, their use in men with BPH with undetectable cancers has been brought into perspective by some negative outcomes in the REDUCE and PCPT trials in the USA (85). Based on this data, any underlying high-grade prostate cancer (in addition to BPH) would be likely to progress faster to a malignant and fatal disease, as a result of this treatment for non-fatal BPH by 5ARIs. There is also some evidence that long-term use of 5aR inhibitors can have significant side effects for men. These include the loss of sexual function, neurological and psychological problems, sometimes persisting even after the treatment has been stopped (86).








Conclusion

With years of research into the pathological process of BPH, we are still far from having a definite answer for the initiating and maintaining factor(s) for this disease.
Current treatment has not changed for a number of years, despite the fact that the mechanism of the disease has yet to be proven and there is a lengthy delay seen in clinical benefit from treatment. As highlighted above, this disease will most likely impose a significant burden on patients and healthcare services in the future, so new research into finding the driving factor(s) behind this common and neglected disease to discover new treatment avenues is imperative.
 

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Screenshot (1927).png

Figure 1: Multiple consequences of an external Growth stimulus on pre-hyperplastic tissues in the prostate. Inhibition of either the original stimulus or the secondary messenger growth factors (or hormones) would provide a novel and effective treatment for BPH.
 
Screenshot (1928).png

Figure 2: Adapted from Ficarra et al 2014. The self-perpetuating cycle of inflammation and how it can lead to hyperplasia and BPH (47).
 
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