The following keywords were used to search PubMed and Web of Science databases for literature published before February 2023: ((“Marion`s disease” [title]) or (“primary bladder neck obstruction” [title]) or (“fibroelastosis of the bladder neck” [title]) or (“primary bladder outlet obstruction” [title]) or (“primary bladder neck dysfunction” [title]) or (“bladder neck” [title]) or (“wall of the bladder neck” [title]) or (“internal vesical sphincter” [title]) or (“functional bladder neck obstruction” [title]) or (“bladder neck dyssynergia” [title]) or (bladder neck hypertrophia [title]) or (“dysfunctional bladder neck” [title]” or (“smooth muscle dyssynergia” [title] or (“proximal urethral obstruction” [title]). Several search filters were used during the search including the language and the time filters to include all the types of articles published in English language in the last 20 years. Generally, the search revealed 136 records. After the removal of non referred articles to PBNO and duplicates, the records were screened by the title and abstract to identify all the articles of real interest. Overall, 0 clinical studies were identified (ClinicalTraisl.gov; International Clinical Trials Registry Platform ICTRP of WHO). Publications with small case series or case reports that dealed with no hypotheses were sorted out. We excluded papers regarding PBNO in females and children. Other 27 articles dealing with historical aspects and technological background of PBNO were additionally discussed. We excluded all the papers regarding embriologycal theories on bladder neck dysfuction. In this setting, the current review focuses particularly on the evaluation of physiopathological changes of the BN and its new hypotheses.
Pathophysiology Of Primary Bladder Neck Obstruction (Pbno) – Historical Findings And New Theories
Initially, Marion focused 1933 on structural changes at the BN by fibrous narrowing and hyperplasia [4]. Leadbetter and Leadbetter assumed in 1959 that a remodeling of the BN in nonmuscular connective tissue results in obstructed BN by hypertrophic musculus sphincter vesicae, fibrous contracture and postinflammatoric processes [5]. Turner-Warwick described in 1973 inefficient BN opening due to an abnormal morphologic arrangement of the bladder musculature (detrusor/trigonal) [14]. Awad suggested in 1976 a neurological dysfunction of the sympathic nervous system with a kind of detrusor-sphincter-dyssynergia [15]. Yalla found in 1977 striated muscle components of the urethral sphincter involving the BN and supposed a dysfunction by as an anatomical anomaly or dysfunction of the BN [16]. To date, however, no concrete cause of the PBNO could be justified. Even if PBNO is a frequent condition, several hypotheses have been formulated on its pathogenesis but none of those has reached a good reliability on clinical practice [17]. There is the hypothesis of an impaired dissolution of the BN mesenchyme during foetal life, others sustained the non compliance of BN musculature; more recent theories support an increase in the density of Neuropeptide Y immunoreactive nerves, stating PBNO is more a functional illness linked to pelvic floor dyssynergia than a structural issue [18].
Over the last 20 years, chronic inflammation has been proposed as a prominent role in the pathogenesis of LUTS and BPH. Although almost all surgical BPH histological specimens show chronic inflammatory infiltrates, most of these patients have neither clinical signs of infection nor any correlation with bacterial or other foreign antigenstherefore an hypotesisis of an autoimmune disease has been proposed [19–22]. The recent literature on this specific pathogenesis theory of PBNO supports two pathogenetic mechanisms: the inflammatory and the non-inflammatory pathways.
Inflammatory Pathway
Compared to patients with typical LUTS related to BPH, PBNO patients are younger, have a lower body mass indexes, lower comorbidity scores, and lower PSA, but worse IPSS scores and smaller prostate volumes [23]. Urodynamicaly, several degrees of urinary obstruction with adequate detrusor function were detected and very often they reported a history of previous or current prostatic inflammation, with a failed treatment. Endoscopically, the features considered suggestive of PBNOare internal urethral sphincter hypercontraction and complete lack of elasticity in the absence of urethral strictures, posterior urethral valves, inflammatory lesions, or foreign bodies [23]. In our opinion the PBNO should be always considered throughout the diagnostic work-up of men presenting with LUTS, especially in the context of younger patients with more severe LUTS, including urethrocystoscopy and video urodynamic assessment with voiding cysto-urethrogram [7].
Several publications let assume that PBNO could be also induced by inflammatory processes. It is well known that there is a relationship between prostatic inflammation and LUTS and that physician-diagnosed prostatitis was associated with a 2.4-fold increase in the likelihood of a later diagnosed BPH. Men with a history of prostatitis were also more likely to receive treatment for BPH compared with men without prostatitis. A diagnosis of prostatitis may be an early marker for later development of BPH [24].
Interestingly, analysing 30 periurethral tissues derived from whole prostates samples (prostate cancer specimen), Cantiello found that 70% had an important periurethral inflammatory infiltration. They found significant differences in terms of severity of IPSS, high collagenic deposition in patients with periurethral inflammation compared with patients without. They speculated that the periurethral fibrosis secondary to inflammation could cause LUTS through decreased urethral flexibility while compromising the ability of the prostatic urethra to enlarge and adequately accommodate urinary flow during micturition [25].
Fibbi in a large review on the role of the prostate as an immunocompetent organ, considered the presence of a bacterial and non-infectious chronic prostatitis the initiating and inciting factors leading to tissue hyperproliferation. This change might be facilitated via the antigen-presenting capacity of prostatic stromal cells, which are to induce and sustain intraglandular immune responses. They supported the idea that the inflammation-induced damage of the prostatic tissue represents a chronic process of wound healing which activates hyperproliferative programmes resulting in BPH nodules and collagen deposition [26].
Robert highligthed that deep analyses of the inflammatory infiltrates has shown a wide spectrum of antigen-presenting cells, involved in the manteinance of the sterility of the genital environment [27]. However, immune cells could also release cytokines and growth factors that recruit other cells that promote the growth of epithelial and stromal prostatic cells, with an unavoidable prostate volume enlargement and prostatic urethra compression [28].
PBNO-affected patients present symptoms which can be confounded with prostatitis, potentially leading to chronic pelvic pain [6] supporting our idea that PBNO can be a consequence of previous prostatic inflammation. However, there is still a debate on the reversibility of the inflammation linked to reversible causes. Wong examined stability of the newly synthesized collagen in bacterial-induced prostatic inflammation and the reversibility of fibrosis and collagen content after resolution of infection and inflammation. Generating inflammation by injecting E.coli into prostates of mice the authors found the half-life of newly synthesized collagen to be significantly shorter in infected/inflamed prostates than in controls. Moreover authors found antibiotic treatment to reverse collagenic deposition, supporting that fibrosis linked to infectious disease is a reversible process [29]. Moreover, Kim demonstrated that profound epithelial mesenchimal transition is observed in lipopolysaccharide induced prostatitis and that the natural HIF-1α inhibitors ascorbate and curcumin were capable to attenuate prostate enlargement both in vivo and in vitro [30].
Prostatitis is known to be a frequently misdiagnosed condition, as young men who are affected by it, mostly for shaming reasons, don’t seek urological counselling. A sperm culture or Meares Stamey tests are rarely prescribed, and a proper antibiotic or anti-infammatory treatment is rarely proposed. We hypotesized that the presence of all these conditions justify the persistence of a chronic inflammatory intraprostatic status. This lastly represents the promoter of progressive collagenic deposition and decrease of elastic system fibers that determine a sudden and long-term bladder outlet obstruction (due to a more rigid or less elastic BN and prostatic urethra that becomes more difficult to bend or compress) and LUTS progression [31–33].
In other terms we speculate on the possibility that the same inflammatory patterns that have been previously described for BPH development and BOO onset should be taken in consideration for the ethiopathogenetic explanation of PBNO (Fig. 1).
The clinical value of these observations consists of a correct and precise diagnostic framework especially in young people referring pelvic pain, voiding and storage LUTS despite their small prostate volumes. The proper diagnosis could provide a tempestive treatment proposal that can stop illness progression or in same cases reverse inflammation and collagenic deposition, limiting the risk of future obstruction and symtomatic progression.
Non-inflammatory pathways
The data on other, non-inflammatory possible causes of PBNO, are scarse and weak. Like Yalla [16], Billis [34] demonstrated significantly more skeletal striated muscle fibers in TURP resection fragments of the BN in PBNO patients than patients with typical symptomatic BPH. In PBNO patients the fibers were thick, prominent, hypertrophied, and frequently in a parallel distribution; whereas BPH patients showed discrete, thin, and transversally or longitudinally cut fibers. They assumed that in PBNO there is a persistence of the cranial part of the skeletal urethral sphincter, which may interfere in the complex process of voiding, and that may explain why those patients did not have their symptoms relieved with alpha-blocker therapy. According to Yalla and Billis, Zago and Camarota hypothized in a case series a possible role of unbalanced biomechanics of the pelvis on the urethral and vesical sphincter activity by an unknown postural orthopaedic condition with pelvic torsion that causes hypercontraction on the pelvic floor and interfering with the normal micturition [35–36]. Camerota et al. found out that PBNO patients have a high prevalence (76%) of myofascial or articular, mostly nociceptive pain across different regions as a relevant component. They postulated that an interplay of peripheral inflammation, postural imbalance and chronic pain could induce nociceptor activation and sympathetic nervous system hyperactivation which in turn leads to a bladder sphincter dysfunction [35–36] (Fig. 1). Hruz described in 60% of patients with diagnosis of category IIIb chronic pelvic pain syndrome a BN hypertrophy as the primary cause of their symptomatology [37].
Hinata described a correlation between increased prostate volume due to BPH and an increase of collagen fibers and degeneration of muscle bundles in the BN. By progression of prostatic hyperplasia the BN muscles were progressively affected by fibrosis with fragmentation of the smooth muscle sphincter vesicae [38] .
Bolton proved that BN shows a physiological variability around its circumference with a uniform response to noradrenaline of whole circumference, significantly stronger response to alpha-adrenergic agonists compared with cholinergic agonists in the posterior part, where as the anterior part had no significant differential response to these [39]. However, alpha-1-blocker just only have a variable success 30–60% in PBNO. Unfortunately most of these studies are small, uncontrolled and non-randomized, non-placebo-controlled with no consistent type or dosage of drug.