The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective

Background: The etiology of benign prostatic hyperplasia and prostate cancer are unknown, with ageing being the greatness risk factor. Methods: This new perspective evaluates the available interdisciplinary evidence regarding prostate ageing in terms of the cell biology of regulation and homeostasis, which could explain the timeline of evolutionary cancer biology as degenerative, inflammatory and neoplasm progressions in these multifactorial and heterogeneous prostatic diseases. Results: This prostate ageing degeneration hypothesis encompasses the testosterone-vascular-inflamm-ageing triad, along with the cell biology regulation of amyloidosis and autophagy within an evolutionary tumorigenesis microenvironment. Conclusions: An understanding of these biological processes of prostate ageing can provide potential strategies for early prevention and could contribute to maintaining quality of life for the ageing individual along with substantial medical cost savings.

Benign prostatic hyperplasia is a major health care expenditure in Australia, and this is trending upwards from $5.3million in 2011 to $35.2million in 2018 [18]. Data from the Australian Institute of Health and Welfare predicted that by 2020, 21 out of 100,000 Australian men will die from prostate cancer [19].
This new perspective and overview analyses and evaluates the biological aspects in the accrued interdisciplinary evidence for prostate ageing degeneration, which could provide us with answers to the etiology and pathophysiology genesis mechanisms. These include testosterone ageing, vascular ageing and inflamm-ageing along with amyloidosis and autophagy in cell regulation and homeostasis, as molecular and cellular evidence of prostate ageing in a degenerative multifactorial heterogeneous disease. These new insights into the early evolution of benign prostatic hyperplasia and prostate cancer would allow us to develop strategies for early prevention and maintaining quality of life for the ageing individual along with substantial medical cost savings.

Testosterone-Vascular-Inflamm-Ageing Triad
The hallmark of testosterone-ageing is declining testosterone levels with age > 40 years, which is clearly demonstrated by the Massachusetts Male Aging Study [20,21]. Testosterone has been shown to regulate the nitric oxide-cyclic guanosine monophosphate pathway and testosterone deficiency is known to induce endothelial dysfunction [22,23], especially with ageing [24]. A preliminary study suggested a family history of prostate cancer may prostatitis cases showed more signs of prostatic inflammatory aggregates and prominent positive periodic acid-Schiff protein when compared to semen obtained by ejaculation; suggesting the total ejaculate of prostatitis patients contains only a minimal amount of prostate secretions [148]. Regular resistance training exercises and prostatic massage can also reduce the level of proinflammatory markers and improve PSA levels in men with prostate cancer [149].
A 78-year-old man with an enlarged prostate and urinary symptoms who was treated with 10 prostatic-massages combined with antibiotics showed symptom improvement, with the trans rectal ultrasound documenting a reduction in the prostate volume by 52% (63 g to 30 g) [150]. Citric acid secretion studies in 25 men with enlarged prostates, who were given 10 sessions of prostatic massage over 3 to 4 weeks, showed that the hypertrophy receded in almost all cases [151]. Other studies showed symptom improvement for chronic prostatitis, acute urinary retention and lower urinary tract symptoms in patients with repetitive prostatic massage, and with or without antibiotics [152][153][154][155]. The presence of intraluminal inclusions in the prostate cancer tissues promotes remodeling with disruption of the glands' secretory cycle and drainage function, leading to mechanical trauma, chronic inflammation, and fibrosis development [156]. The prostate corpora amylacea depositions are often a few millimeters in diameter, and can constitute up to a third of the bulk weight of the prostate gland [126].

Autophagy
Amyloidosis is countered by autophagy and the ubiquitin proteasome system, both of which are major degradation pathways for many disease-associated protein aggregates [105,157]. Autophagy it is a natural regulatory mechanism of the cell that eliminates unnecessary and dysfunctional cellular components to maintain homeostasis [158] and in response to cellular stress [159,160].
Experimental data support a model where autophagy induction as a cytoprotective response promotes cell survival under hypoxia in human prostate stromal cells [161], and decreased autophagy flux in the prostate gland may be implicated in benign prostatic hyperplasia [162]. One of the pivotal contributions of autophagy in immunity is the cell's autonomous control of inflammation, which represents an anti-inflammatory mechanism [163]. Two natural compounds, oleanolic acid and ursolic acid in low doses, inhibit benign prostatic hyperplasia cell growth by inducing autophagy and reducing the IL-8-axis inflammatory expression in benign prostatic hyperplasia epithelial cells [164]. Autophagy deactivation is associated with severe prostatic inflammation in patients with lower urinary tract symptoms and benign prostatic hyperplasia [165].
The regulatory dynamic of autophagy in cancer metastasis is multifaceted as it plays a suppressive role in early tumors or a promoting role in late stage tumors [86,87,166,167]. Using a histiocytic lymphoma cell line U937 under oxidative stress and DNA damage conditions, it was found that experimental autophagy inhibition induces high cytotoxicity while autophagy induction reduces genotoxicity [159]. Aurora-A kinase over-expression was significantly higher in human prostate cancer specimens than in benign prostatic hyperplasia, and data suggest that aurora-A kinase plays an important role in the suppression of autophagy, which in turn prevents autophagy-induced apoptosis in prostate cancer [168]. Autophagy is deregulated in ageing and human disease [169].

Evolutionary Tumorigenesis Microenvironment
Evolutionary theory dictates that natural selection is the survival of fittest in the changing environment [170,171]. The prostate ageing degeneration process provides a point of cross-talk between the testosterone-vascular-inflamm-ageing triad, amyloidosis and autophagy, within a prostate stagnation tumorigenesis microenvironment [172]. Together, this tumorigenesis microenvironment and evolutionary biology forms the "evolutionary tumorigenesis microenvironment model", which could explain the local ecology [173] of degenerative, inflammatory and neoplasm progressions of prostatic diseases, which can span over at least three decades [174]. This could account for a "linear timeline evolutionary pressure" proportionate to gradual natural selection as a slow mutational wave [175] for the emergence of cell subsets' (distinct phenotypes) survival [176][177][178][179][180][181][182][183][184][185][186], in adapting to the increasingly changing prostate pathophysiology microenvironment [57,58,179,[187][188][189][190][191][192]. It also aligns well with the natural progression of the disease and symptom severity during the course of the ageing prostate. Hypoxia localised prostate cancer is associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres [191].

Prevention
This prostate ageing degeneration hypothesis postulates that this triad of testosterone, vascular and inflamm-ageing results in conjoining nitric oxide down-regulating, vascular/endothelial dysfunction and inflammation, with the induction of amyloidosis and autophagy. These are the key etiology and pathophysiology contributors to the prostatic diseases within the evolutionary tumorigenesis microenvironment. It provides a framework for integrating new evidence into a comprehensive concept of a timeline of evolutionary cancer biology of prostate ageing as degenerative, inflammatory and neoplasm progressions of the diseases, for at least a 30 years period ( Figure 1). This is a testable hypothesis where biomarkers panel sets can be used to chart the course and range of the ageing degeneration processes.
The future paradigm shift involves an emphasis on prevention as early maintenance of healthy vascular function is necessary to preserve cell function, homeostasis and regulation [166,193], thus prolonging the function of the prostate gland, and delaying/avoiding late stage amyloidosis and autophagy dysregulation [86][87][88][89][90]. Other, potential strategies for ameliorating these biological processes of endothelial dysfunction, oxidative stress and inflammation [221][222][223] could be developed. These should also be complemented consistently with a healthy diet and lifestyle [224][225][226][227]. The future paradigm shift involves an emphasis on prevention as early maintenance of healthy vascular function is necessary to preserve cell function, homeostasis and regulation [166,193], thus prolonging the function of the prostate gland, and delaying/avoiding late stage amyloidosis and autophagy dysregulation [86][87][88][89][90]. Other, potential strategies for ameliorating these biological processes of endothelial dysfunction, oxidative stress and inflammation [221][222][223] could be developed. These should also be complemented consistently with a healthy diet and lifestyle [224][225][226][227].
The key in preventive medicine is to prevent the disease from developing by catching or stopping it early; in this case between the fifth (40s) and before the seventh (60s) decade of life [228][229][230]. A potential three-pronged approach can be explored: Testosterone replacement therapy: long term replacement therapy should be considered to maintain the vascular function; this is a topic of importance that is discussed below as it is an integral part of the prostate ageing degeneration hypothesis.
Prostate stagnation: a standard operating procedure using a patented prostate device US8182503B2 could be developed for regular periodic home use for prostate-rectal drainage [155,247,248], in order to modulate the prostate-stagnation tumorigenesis inflammatory microenvironment [139,249]; this is yet to be fully investigated.
Testosterone replacement therapy has been mired in controversy since its introduction in the 1930s up until to the present day [250][251][252][253][254]. Similarly, findings from the Women's Health Initiative trial of continuous conjugated equine estrogens alone reported two years later, which suggested prevention of coronary heart disease in women who began hormone replacement therapy at age < 60 years and an overall reduction in breast cancer, were largely ignored [255]. This highlights the "window of opportunity and timing" hypothesis, in which the age of starting hormone replacement therapy affects its risk [256] and with "yin-yang" roles [257]. Nitric oxide is one of the most well studied and recognized female estrogen-induced vasodilators [258][259][260][261].  The key in preventive medicine is to prevent the disease from developing by catching or stopping it early; in this case between the fifth (40s) and before the seventh (60s) decade of life [228][229][230]. A potential three-pronged approach can be explored: Testosterone replacement therapy: long term replacement therapy should be considered to maintain the vascular function; this is a topic of importance that is discussed below as it is an integral part of the prostate ageing degeneration hypothesis.
Prostate stagnation: a standard operating procedure using a patented prostate device US8182503B2 could be developed for regular periodic home use for prostate-rectal drainage [155,247,248], in order to modulate the prostate-stagnation tumorigenesis inflammatory microenvironment [139,249]; this is yet to be fully investigated.
Testosterone replacement therapy has been mired in controversy since its introduction in the 1930s up until to the present day [250][251][252][253][254]. Similarly, findings from the Women's Health Initiative trial of continuous conjugated equine estrogens alone reported two years later, which suggested prevention of coronary heart disease in women who began hormone replacement therapy at age < 60 years and an overall reduction in breast cancer, were largely ignored [255]. This highlights the "window of opportunity and timing" hypothesis, in which the age of starting hormone replacement therapy affects its risk [256] and with "yin-yang" roles [257]. Nitric oxide is one of the most well studied and recognized female estrogen-induced vasodilators [258][259][260][261].
Important health problems in men such as type 2 diabetes, insulin resistance, erectile dysfunction, benign prostatic hyperplasia and depression have been shown to share common pathological processes, such as endothelial dysfunction and inflammation [262], and in numerous testosterone-related concomitant disease and comorbidities . Men with low testosterone levels exhibit increases in cardiovascular disease risk markers [286], micro vascular dysfunction [274,287] and these are associated with higher prostate cancer aggressiveness [288]. Both aggressive and metastatic prostate cancer are influenced by metabolic alterations and cardiovascular disease [289], and the progression in hormone naïve prostate carcinomas correlates with low numbers of vascular vessels [290]. In human surgical specimens, there is evidence that local atherosclerosis of the prostatic artery is significantly associated with prostate size [291]. The use of nicorandil, a nitrate derivative to increase the blood flow, reduces the development of prostatic hyperplasia [292]. Sclerotherapy of the internal spermatic veins restores normal supply of testosterone to the prostate solely via its arterial supply, resulting in a significant decrease in prostatic volume and symptoms [293]. Findings from a study suggest that endothelial dysfunction is associated with lower urinary tract symptoms in men [274]. Experimental testosterone deprivation orchiectomy studies showed induced changes to the prostate of rats, and testosterone replacement therapy was effective in reversing such alterations [294]. In two 60-day studies, canine orchiectomy lowered prostate vascularisation [295] and blood volume [296].
Erectile dysfunction is associated with prostate cancer incidence [297] and vascular function. Sleep fragmentation, benign prostate obstruction and nocturnal frequency could decrease sleep-related erections, reflecting the patient's relevant erectile function [298]. Long term testosterone therapy improves long term blood circulation of penile arteries, penile length and girth, erectile function, and nocturnal penile tumescence and duration [299]. Low androgen status decreased the nitric oxide production and impaired erectile function of rats [300] and electrical penile erection stimulation in mice induced angiogenesis, cell survival and proliferation, and anti-fibrosis signaling pathways [301].
A collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, found no risk association [310]. In cancer, the two-concentration (biphasic) hypothesis of nitric oxide has determined that low levels of nitric oxide are cancer promoting, while high levels of nitric oxide are protective against cancer [311][312][313][314]. The acquisition of hypoxia-induced malignant phenotypes in tumor cells is impeded by nitric oxide activation of cyclic guanosine monophosphate signaling [315]. Nitric oxide promotes apoptosis and inhibits autophagy in human liver cancer cells [316]. In autophagy, tripartite motif 36 expression is increased in response to androgen and has a prostate cancer suppressive role [317][318][319]. Loss of testosterone impairs anti-tumor neutrophil function [320].

Conclusions
The disease criteria used by the World Health Organization were applies to human biological ageing and it has been found that aging fits the ICD-11 criteria and can be considered a disease; it is included in the extension code for "Ageing-related" (XT9T) in the "Causality" section of the ICD-11 [333].
Tissue degeneration and loss of organ function are features of ageing; conversely, cancer is a state of sustained cellular proliferation and the gain of new functions [42].
Therefore, the most advantageous and best chance strategy is early preventive intervention before tissue damage sets in, and to maintain the vascular function of the ageing prostate gland for as long as possible. Could early, long term testosterone replacement therapy be the Achilles' heel of prostate cancer? A large preventive trial is warranted to discover the answers to this important question.