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
[53], and in numerous testosterone-related concomitant disease and comorbidities
[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76]. Men with low testosterone levels exhibit increases in cardiovascular disease risk markers
[77], micro vascular dysfunction
[65][78] and these are associated with higher prostate cancer aggressiveness
[79]. Both aggressive and metastatic prostate cancer are influenced by metabolic alterations and cardiovascular disease
[80], and the progression in hormone naïve prostate carcinomas correlates with low numbers of vascular vessels
[81]. In human surgical specimens, there is evidence that local atherosclerosis of the prostatic artery is significantly associated with prostate size
[82]. The use of nicorandil, a nitrate derivative to increase the blood flow, reduces the development of prostatic hyperplasia
[83]. 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
[84]. Findings from a study suggest that endothelial dysfunction is associated with lower urinary tract symptoms in men
[65]. Experimental testosterone deprivation orchiectomy studies showed induced changes to the prostate of rats, and testosterone replacement therapy was effective in reversing such alterations
[85]. In two 60-day studies, canine orchiectomy lowered prostate vascularisation
[86] and blood volume
[87].
Erectile dysfunction is associated with prostate cancer incidence
[88] and vascular function. Sleep fragmentation, benign prostate obstruction and nocturnal frequency could decrease sleep-related erections, reflecting the patient’s relevant erectile function
[89]. Long term testosterone therapy improves long term blood circulation of penile arteries, penile length and girth, erectile function, and nocturnal penile tumescence and duration
[90]. Low androgen status decreased the nitric oxide production and impaired erectile function of rats
[91] and electrical penile erection stimulation in mice induced angiogenesis, cell survival and proliferation, and anti-fibrosis signaling pathways
[92].
Nitric oxide serves many biological functions
[93][94][95]; ageing is frequently associated with
l-arginine deficiency
[96][97] and with the menopausal transition in women
[98], as a substrate for nitric oxide synthase. Both oral
l-citrulline and/or
l-arginine supplementation increases nitric oxide bioavailability levels in plasma and tissue
[30][31][32][33][34][99]. L-arginine restores doxorubicin-induced vascular dysfunction in cancer treatments by attenuating vascular nitric oxide release and apoptosis
[20]. Emerging evidence suggests that increasing nitric oxide bioavailability or endothelial nitric oxide synthase activity activates telomerase and delays endothelial cell senescence
[100].
A collaborative analysis of the worldwide data on endogenous hormones and prostate cancer risk, found no risk association
[101]. 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
[102][103][104][105]. The acquisition of hypoxia-induced malignant phenotypes in tumor cells is impeded by nitric oxide activation of cyclic guanosine monophosphate signaling
[106]. Nitric oxide promotes apoptosis and inhibits autophagy in human liver cancer cells
[107]. In autophagy, tripartite motif 36 expression is increased in response to androgen and has a prostate cancer suppressive role
[108][109][110]. Loss of testosterone impairs anti-tumor neutrophil function
[111].
Testosterone replacement therapy itself is able to reduce endothelial dysfunction, oxidative stress and inflammation
[112][113][114][115][116][117][118][119][120][121], and is used as treatment for lower urinary tract symptoms and erectile dysfunction
[90][122][123][124][125].
3. 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
[126].
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
[127].
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.