European Urology

1.1. NOS/NO levels decreased in the prostate and penile smooth muscle

This hypothesis attempts to explain the link by a proposed reduced production of nitrinergic innervation and nitric oxide synthase (NOS)/nitric oxide (NO) in the pelvis, including both the penis and prostate. It is known that NOS/NO production in the prostate is reduced in BPH (transition zone) when compared to normal prostate tissue. This theory closely follows that which explains the molecular mechanism of ED and links these two diseases into a single unifying concept. It logically follows that prostate tissue levels of NOS/NO are reduced in BPH progression, reducing prostatic tone relaxation. This proposed reduction in NOS isoforms results in an altered neurogenic influence on voiding function that is recognised as progressive BPH or LUTS. This theory is supported by limited evidence in which BPH tissue nicotinamide adenine dinucleotide phosphate staining and NOS immunohistochemistry show a qualitative decrease in the otherwise dense nitrinergic innervation of glandular epithelium, fibromuscular stroma, and blood vessels. Unlike the well-developed penile model, the role of NOS and its products are not well characterised in the prostate. This hypothesis is based on a limited number of studies that depend largely on immunohistochemistry. Although these data have several methodologic flaws, the concept does have a consistent appeal [5].

The NOS/NO theory is further supported by the characterisation and functional relevance of cyclic nucleotide PDE isoenzymes of the human prostate. The most common PDEs noted in prostate tissue were PDE type 4 and PDE type 5. The functional relevance of these PDE isoenzymes is noted in the relaxing effect of nonspecific PDE inhibitors (papaverine), as well as the effect of specific PDE inhibitors (sildenafil). Of more interest to this study is the recognition that Northern and RNA dot blots for PDE11A gene expression noted its presence in testes, skeletal muscle, and the prostate. Type 11A protein abundance was greatest in prostate compared to other organs.

1.2. Effects of autonomic hyperactivity on LUTS, prostate growth, and ED

Our laboratory identified the relation of autonomic neural input to the prostate as providing an environment that induced rat prostatic growth; absence of this input results in regression of the gland [6]. These findings were supported by additional animal studies using a strain of spontaneously hypertensive rats that develop increased autonomic activity, prostate hyperplasia, and erectile dysfunction [7]. The improvement in erectile function after brief aggressive treatment may be related to improvement in structurally based vascular resistance within the penis and the decrease in responsiveness of α₁-adrenoceptor-mediated erectolytic signalling. This putative explanation is attractive because it links established clinical physiologic findings of LUTS, BPH, and ED with an established basic science support. It remains unclear whether the increase in LUTS or ED is the result of a central increase in sensitivity to peripheral signals or a consequence of an alteration in the function of the bladder/penis itself that generates increased central activation. The various animal models suggesting a role between autonomic nervous system (ANS) overactivity and increased prostate growth is further supported by epidemiologic investigations linking the clinical diagnosis of BPH with increased autonomic tone [8]. Autonomic hyperactivity or increased ANS activity is significantly associated with the signs and symptoms of BPH. This has implications for understanding the pathophysiology of BPH, prostate growth, ED, and BPH progression. The ANS is known to be intimately involved in the mechanisms of voiding. We also described the quantitative relation between ANS tone and the subjective experience of dysfunctional voiding [9], suggesting the ANS acts as mediator that can modulate voiding symptoms or ED or both about their anatomically designated baseline, perhaps in part under the influence of central, mood-related factors. Similarly, autonomic hyperactivity or increased sympathetic tone is a known regulator of smooth muscle relaxation and penile reactivity.

1.3. Pelvic ischaemia as a mechanism for LUTS and ED

An additional theory relating both ED and LUTS is diffuse atherosclerosis of prostate, penis, and bladder [10]. Major risks for this include hypertension, smoking, hypercholesterolaemia and diabetes, all which similarly affect ED. Animal models mimicking pelvic ischaemia and hypercholesterolaemia show a striking similarity in the smooth muscle alterations of the detrusor and corporal smooth muscle. There are several potential mechanisms for this, including hypoxia induced overexpression of transforming growth factor-β1 and altered prostanoid production. Understanding how this could adversely affect penile smooth muscle function is consistent with our current understanding of the penile pro-erectile response. The relevant mechanism explaining the bladder effects may be very similar with an associated bladder ischaemia (bladder outlet obstruction or pelvic vascular disease), inducing the same smooth muscle loss with replacement of collagen deposition and fibrosis as well as loss of compliance, hyperactivity, and impaired contractility.