In recent European guidelines on chronic pelvic pain syndrome (CPPS) and the upgraded terminology [1], CPPS became chronic primary pelvic pain syndrome (CPPPS) and BPS/IC became primary bladder pain syndrome (PBPS), according to the International Association for the Study of Pain classification system [2]. CPPPS is a symptomatic diagnosis excluding pathology and confusable diseases [1]. As defined by the ICS, the PBPS includes bladders with and without Hunner lesions (HL) that present with pain during filling and at least one bladder symptom (e.g., urgency, frequency, nocturia, emptying) [1]. HL show profound submucosal inflammation and epithelial denudation in the bladder by cystoscopy and differ pathologically from non-HL PBPS [3, 4]. ESSIC (International Society for the Study of BPS) developed a classification system differentiating different phenotypes based on cystoscopy with hydrodistension and biopsy [5]. The guidelines on PBPS describe the presence or absence of HL as the only universally accepted phenotype today [4]. Glomerulations are no longer a diagnostic sign of PBPS having no diagnostic, prognostic or therapeutic significance but may still be relevant for research purposes [6]. The abandoning of glomerulations for diagnosis implies that patients with PBPS symptoms remain without a good indication for diagnosis, which results in consulting multiple specialists [7]. Various extravesical causes of pelvic pain, such as endometriosis or pelvic organ prolapse (POP), may cause secondary bladder symptoms. Any such associated secondary bladder dysfunction may partly be attributed to possible mechanisms of neuronal crosstalk and central sensitization. Posterior fornix syndrome (PFS) is one of many causes of pelvic pain that may result in secondary bladder dysfunction as a consequence of weak uterosacral ligaments (USLs). We examined the hypothesis that, at least in some women, the originating cause of PBPS is not in the urothelium but is located outside the bladder, in damaged USLs, leading to a loss of visceral plexus (VP) support.

We evaluated the PFS concept in toto: symptom co-occurrence, pathogenesis, testing by a speculum or other, and cure/improvement by USL repair, for consistency with the Ueda criteria for BPS/IC, with regard to diagnosis, pathogenesis and cure. Ueda et al., in 2021, stated: “Despite the tremendous medical advances made by developing many testing modalities and biomarkers, there can be no successful treatment in the absence of an accurate diagnosis. Thus, there can be no bright future for BPS/IC without these 3 steps: (1) understanding the symptoms, (2) detecting abnormal findings in or outside the bladder, and (3) verifying that the abnormality is the cause of the symptoms [8]. BPS/IC is a symptom complex with no apparent cause. Without anatomically-defined causal abnormality, pain is related to the bladder as a primary bladder pain syndrome (PBPS/IC) by definition, not science (there may be causes not yet defined or discovered). In this context, where chronic pelvic pain (“CPPPS”) plus urinary symptoms (“PBPS”) are demonstrated by scientifically-validated data to have an established causal relationship (for example a positive speculum test (Fig. 1), followed by surgical cure of USLs, as described later in this paper), the bladder pain syndrome [1, 2] must be considered as possibly secondary to weak USLs. Far from clarifying BPS/IC, the new definitions [1, 2] only serve to further confuse a confusing subject. We critically examine PFS according to the UEDA criteria, 1–3 below. The starting and end points of this paper are the questions, “Is BPS/IC one and the same as PFS”? If so, “To what extent?”

With reference to the diagnostic algorithm (Fig. 2), the symptoms within the rectangle identify co-occurring PFS symptoms which are caused by lax or weak USLs. Symptoms relevant to BPS/IC are addressed separately below.

Though pain and urgency can originate from lax USLs, their nervous pathways may differ. Pain originates from mechanically unsupported VPs (Fig. 1), while urgency originates from mechanically unsupported urothelial stretch receptors “N” (Fig. 1).

With reference to Fig. 1, when the quiescent afferent axons sited in VP are stimulated by gravity “G” or muscle movement, they send afferent impulses to the brain, which (wrongly) interprets them as pain from a wound and sends efferent impulses to the end-organ to heal it. Inflammatory cytokines are involved in nerve injury or inflammation-induced central sensitization and develop hyperalgesia/allodynia [27]. Specific cytokines in the spinal cord, dorsal root ganglion (DRG), or injured nerves generate abnormal spontaneous activity from injured nerve fibres or compressed/inflamed DRG neurons [27]. Patients with primary vestibular pain syndrome have a neurogenic plasticity with significantly increased nerve fibres and mast cell counts in the vestibular area [28]. The urothelium in PBPS shows sensory hyperinnervation and increased mast cells and other inflammatory cells [29]. Because the urothelium is much thinner than the vulvar wall, the inflammatory reaction may erode the urothelium to cause a Hunner lesion. Hunner’s lesions occur mainly in older patients between 53 to 65 years of age and represent less than 7% of BPS/IC patients [30]. The prevalence of HL is disparate, ranging from 3.5% to 56% [4]. HL, also present at an older age compared to non-Hunner-PBPS, are associated with a smaller bladder capacity and represent 5%–57% [31]. HL patients are clinically and pathologically distinct from non-HL PBPS patients [3, 4]. A HL is determined with cystoscopy as a local inflammatory reaction and disrupted urothelium or urothelial denudation [4, 32]. A reddened mucosal area with small vessels radiating towards a central scar, splitting at distension, is visualized and usually associated with a waterfall bleeding under hydrodistension, as seen in glomerulations [31]. Biopsies from the inflamed area show inflammatory infiltrates, granulation tissue, detrusor mastocytosis, and fibrin deposits [31, 33, 34].

We hypothesize that sustained traction on the VP results in continuous neuroinflammatory reactions, and the lesion converts in time to collagen 3, and then collagen 1 [35], to form endstage fibrosis.

There is substantial doubt that mast cells are relevant for PBPS and HL as there has not been a significant between the number of mast cells and the clinical symptoms and lesions [6, 36].

BPS/IC symptomatology combined with a PFS might occur with or without a HL, although the mechanism of origin of HL remains unclear.

These studies led to several research questions and discussions between the authors of this paper.

(1) Do HL BPS and non-HL BPS which have classic PFS symptoms [13, 37] have a common origin? If so, what tools could be used to assess this? What would these tools look for – evidence of inflammatory reaction, origins of the urgency, or both–? The origins of urgency are rarely mentioned in previous writings on BPS/IC. Regauer et al. [29] found evidence of sensory hyperinnervation in almost all PBPS patients with HL and without, and in 30% (4 of 13) of patients with OAB and no pain. Is 4 of 13 sufficient to say there is a common histologically relevant origin? If so, what tools could be used to assess this? Ueda et al. [3] recently applied artificial intelligence methods to develop the machine-learning algorithm to detect HL using large-scale unannotated medical images of the bladder mucosa obtained under conventional white light imaging 90% or narrow-band imaging 67%. It seems possible that the same machine learning could be applied to search and quantify specific inflammatory cells, such as leukocytes, macrophages, mast cells, etc.

It has been demonstrated that pain and urgency co-occur and are cured or improved variously, but not always simultaneously, by USL repair [13-17, 19-26, 37] (Fig. 2). Based on this, one could assume that pain and urgency have a common cause, USL laxity, but have very different pathways corresponding with the dorsal column or spinothalamic pathways [51, 52]. Liedl et al. found that urgency (84%), frequency (82%), nocturia (70%), and CPP (78%) had differentincidences (Fig. 2) and different cure rates. Petros et al. [25] and Goeschen et al. [13] also found significantly different incidences of pain and urgency symptoms and different cure rates. With both studies [13, 25], there was equivalent incidence and cure rate for pain and the various bladder dysfunction symptoms, whether the prolapse was minimal (1st or 2nd degree) or major (3rd and 4th degree) [13, 25].

(2) If, as hypothesized in Fig. 1, “bunched” unsupported visceral nerves” are the cause for CPP, it could be predicted that the pain element of PBPS would co-occur in other sites, for example, the vulva (vulvodynia) lower abdomen, paraurethral area. Pain in these multiple sites was reported and cured by Petros with USL plication [53], by Wu et al. [9], relieved by a speculum test and in 3 BPS/IC women after the Bornstein Test which injected LA into the USLs [54].

(3) Inserting a large tampon into the apex overnight to support it shows a statistically validated relief of urge and nocturia [55]. Nocturia and other symptoms, such as urgency, abnormal emptying, and CPP associated with the posterior fornix, can be improved by surgery. Four different surgical operations suspend the vaginal apex: USL plication, infra-coccygeal sacropexy sling, posterior tissue fixation system sling, and abdominal sacrocolpopexy showed can be cured or improved in up to 86% [55]. The improved symptoms after placing a vaginal tampon or pessary ring in the posterior fornix and the impressive pain relief after uterosacral suspension done vaginally or laparoscopically suggest that the PFS and the Allen-Masters Syndrome are synonyms and caused by posterior fornix ligamentous laxity (USL) [56]. A study showed that the pessary improves many of the associated symptoms of POP and is an effective treatment option for managing POP. It is well-accepted and rapidly adequate, and its effects seem to last over time [57]. The posterior intravaginal slingplasty showed satisfactory long-term results for vault and posterior compartment prolapse, with a 75%–90% improvement in vault prolapse [58].

With reference to Fig. 2, which distils the evidence we have presented into a single diagram, our concluding hypothesis is that, at least in some women, a lax USL itself may well be the major pathogenic factor not only for anatomical uterine/apical prolapse, enterocele, but chronic pain [53] several bladder dysfunctions [35], and also, bowel dysfunctions: faecal incontinence, obstructed defecation syndrome, anterior rectal wall intussusception [59]. Viewed in this way, non-Hunner BPS/IC and PFS itself, may both be manifestations (“phenotypes”) of USL laxity.

In accordance with the UEDA criteria, and our own view, the prime research objective now is to determine the proportion of interstitial cystitis/bladder pain syndrome women fitting the proposed USL pathogenesis (PFS), as such women are potentially curable. If the number is significant, PFS pathogenesis opens a new research pathway for researching appropriate surgical/nonsurgical methodology which can relieve or cure PBPS.

In parallel with such testing, a rigorous examination of chronic pelvic pain (CPPPS) and interstitial cystitis/bladder pain syndrome (PBPS) definitions is required as a priority. Definitions are a major influence, indeed, a control, of clinical treatment, and especially, research. Existing definitions [1] are strangely in denial of USL-based CPP cure which has been in the English literature since 1996 [53], and in the German literature since 1938 [60]. Changing names of conditions to (CPPPS and PBPS) as has been done recently, does not alter the facts, and only creates further confusion. Once USL-based pathogenesis of CPP and interstitial cystitis/bladder pain syndrome have a more solid grounding, more relevant definitions and clinical guidelines can be made.