A Hypothesis for Anatomical Pathways of Chronic Pelvic Pain of “Unknown Origin” Free

The current state of knowledge of pathogenesis of interstitial cystitis/bladder pain syndrome (IC/BPS) is best described by Winston Churchill’s description of Russia: “a riddle wrapped in a mystery inside an enigma: but perhaps there is a key. That key is Russian national interests.”

Whatever the IC/BPS works examined, the results are the same, “pathogenesis unknown, no cure possible.” Our hypothesis hopefully will lead to a key for better understanding of IC/BPS.

The prevalence of IC/BPS varies between 21-197/100,000 in women with the proportion for men steady at 20% that of women [1]. However, the ratio can be as high as 10.1 [2].

The American Urological Association (AUA) guidelines conclude “IC/BPS is a heterogeneous clinical syndrome. Even though patients present with similar symptoms of bladder/pelvic pain and pressure/discomfort associated with urinary frequency and strong urge to urinate, there are subgroups or phenotypes within IC/BPS.” [3] “Treatment is categorized into behavioral/non-pharmacologic, oral medicines, bladder instillations, procedures, and major surgery” [3].

The hypothesis, online supplementary VIDEO1 (for all online suppl. material, see https://doi.org/10.1159/000539647), originates from the histologically validated case report by Scheffler et al. [4] in 2021, documenting the cure of IC/BPS. Scheffler et al. applied the diagnostic and surgical criteria of the posterior fornix syndrome (PFS) [5], a component of the integral theory of female urinary incontinence. During preoperative assessment, Scheffler utilized the speculum test to mechanically support the uterosacral ligaments (USLs) [6], resulting in alleviation of both pain and urge symptoms, indicating a potential for USL repair to provide a cure. Coincidentally, a Hunner’s lesion (HL) was discovered during routine cystoscopy, further underscoring the relationship between USL dysfunction and pelvic pain. Goeschen et al. [7] subsequently corroborated Scheffler’s findings by re-examining PFS surgical data and found non-HLs among women with chronic pelvic pain.

A laparoscopically controlled study in 1996 reported cure of CPP in a significant proportion of cases following native vaginal USL plication [8]. Histological analysis revealed nerve fibers within the USL tissue, leading to the hypothesis that lax USLs fail to support visceral plexuses (VPs), resulting in aberrant pain impulses. This hypothesis was further tested in 2010, where local anesthetic injection into USLs provided immediate relief of pelvic pain in women with IC/BPS, supporting the role of VPs in pelvic pain perception [9].

Focusing on pelvic pain etiology, our hypothesis addresses the anatomical and physiological pathways leading to the formation of HL or urothelial ulceration, with similar pathophysiology for vulvodynia and other phenotypes of chronic pelvic pain (Fig. 1). Dismissing the urge component of IC/BPS [10], we emphasize the inflammatory nature of HL and Hunner’s ulcers, akin to complex regional pain syndrome (CRPS) [11‒13]. Instead of limb trauma, we implicate gravity-induced stimulation of unsupported VPs in females with characteristics of posterior fornix syndrome, leading to chronic pelvic pain. Incorporating the axon reflex concept [14, 15], we elucidate the cascade of events involving cytokine release and nociceptor stimulation, perpetuating inflammatory changes and tissue injury in affected female individuals.

Evidence supporting direct stimulation of afferent axons includes observations which attributed pain relief to gravity, as it was alleviated by lying down [8]. Furthermore, in half of the women, the use of a ring pessary relieved pain, indicating a potential origin from the posterior vaginal fornix [8]. Palpation of the cervix reproduced pain at the site felt by the patient [8]. Additionally, the speculum test and the Bornstein Test (involving injection of local anesthetic into the lower end of USLs to anesthetize the VPs), provided immediate simultaneous relief of pelvic pain [8, 16].

In the context of vulvodynia and chronic pelvic pain, immunohistochemical studies have revealed a tenfold increase in nerve fiber density in the stroma of women with vulvodynia compared to controls [17]. Nociceptor nerve fibers penetrate the basal membrane and continue vertically toward the epithelial surface, accompanied by increased numbers of immune cells such as T cells, macrophages, B cells, and mast cells in areas of heightened sensitivity [18, 19]. Heparanase discharged from mast cells plays a pivotal role in degrading connective tissue and epithelial basement membranes, facilitating the penetration of proliferating nerve fibers into the epithelium [20].

Biopsies from patients with BPS/IC with Hunner’s ulcer reveal ulceration with granulation tissue and a complete lack of the urothelium [21]. Thick nerve bundles are identified in deep granulation tissue, along with fine PGP9.5-positive nerve fibers and clusters of activated mast cells in the ulcer bed, suggesting sensory hyperinnervation [21]. Lymphocytic infiltration and urothelial defects are also observed, yielding high sensitivity and specificity for the prediction of BPS/IC with or without HLs [21].

Heparanase-mediated degradation of connective tissue and epithelial basement membranes facilitates the penetration of nerve fibers into the epithelium [20] in vulvodynia. It also explains the “bare areas” (ulcers) in the urothelium [21], which is much thinner than vulval tissue, and therefore more likely to break down into an ulcer than vulval tissue. Elevated heparanase levels in richly innervated tissues correlate with other pelvic inflammatory states [22]. Our hypothesis may extend to formation of glomerulations: heparanase could also degrade the connective tissue in the bladder veins causing them to bulge balloon-like if bladder wall distension by cystometry leads to venous blockage, venous bulging (glomerulations) and subsequent bursting of blood vessels. Though not infrequently encountered in IC/BPS, the potential role of glomerulations as an objective diagnostic marker is controversial, and not supported by a systematic review [23]. Such group findings in systematic reviews, do not, however, necessarily invalidate the possibility of glomerulations as an early warning sign of IC/BPS in an individual patient. If so, our hypothesis provides an anatomical pathway. Our hypothesis also predicts evidence of inflammation upon biopsy of other end organ pain sites, such as the paraurethral area.

The European Urology Guidelines which addressed chronic pelvic pain in both females and males, concluded that understanding the aetiopathogenesis of the condition remains inadequate, and current treatment strategies were frequently ineffective [24]. Our data as regards the end organ inflammatory response are mainly from female experiments, and for USL etiology of CPP also. However, successful cure of post-prostatectomy incontinence by a TFS minisling using surgical protocol based on the female [25], and subsequent discovery of a male USL analog [26] suggested that there may indeed be parallel anatomy between female and males. This caused us to extend the hypothesis to nonbacterial chronic prostatitis in the male (Table 1).

If our hypothesis for pathogenesis holds, the question then becomes what will act as a “circuit breaker” in this situation. There are two choices:

Theoretically, a Gabapentin-like drug which inhibits the voltage gated calcium channels in nerves – reducing both pain impulses and cytokine secretion may help. Though Gabapentin itself is said to be not effective for chronic pelvic pain [27], other pharmacotherapy which inhibits the voltage gated calcium channels in nerves may be effective.

Testing the hypothesis surgically presents ethical challenges regarding the proposal of USL surgery as a diagnostic method for a condition with a multifactorial origin [24], despite the predictive value of local anesthetic and speculum tests [6, 8, 16]. Moreover, the reports of both HL and non-HL cases were based on surgery for posterior fornix syndrome, rather than IC/BPS [4, 7]. Thus, a less invasive approach is warranted. One such method under development is the “Control Plus” device, which employs two small inflatable balloons in the posterior fornix of the vagina to mechanically support lax USLs. Pre- and post-use cystoscopy, with or without biopsy, would be employed to assess inflammatory cells.

The discovery of a male USL analog via laparoscopy, confirmed by biopsy, near the VPs, offers insight into the possible applicability of our IC/BPS hypothesis to males with noninfective “chronic prostatitis,” mirroring symptoms of women with Posterior Fornix Syndrome (Table 1) [26]. Plication laparoscopy of the male USL analog ligament is predicted to alleviate or improve symptoms of “chronic prostatitis.” Such an initiative faces the ethical problem of experimental surgery without adequate proof of pathogenesis. Preoperative mechanical support of USL, as in the female, is not possible in the male.

The hypothesis explores whether weakened USL support of VPs serves to activate VPs as a primary source of pelvic pain impulses, leading to development of an inflammatory condition seen in both vulvodynia and IC/BPS. The hypothesis raises the question, “are IC/BPS, vulvodynia, and other pelvic pain sites (Fig. 1), different phenotypes of a chronic pelvic pain syndrome based on weak USLs? If so, the hypothesis opens several new research directions and would predict inflammatory findings in tender end organ pain sites, such as the paraurethral area of the vagina.

Patient consent statement, permission to reproduce material from other sources, and clinical trial registration are not applicable.

Other than application for a patent for the Control Plus device, Peter Petros has no financial interest or royalties, or any form of support or financial involvement (e.g., employment, consultancies, honoraria, stock ownership and options, expert testimony, grants which took place in the previous 3 years). Peter Petros has received no sales or royalties. There are no sponsors to the study design, execution and analysis, and manuscript conception, planning, writing and decision to publish. There are no nonfinancial relationships (personal, political, or professional) that may potentially influence the writing of the manuscript. John Papadimitriou and Jacob Bornstein have no conflicts of interest in the above or otherwise.

The authors have received no externa funding.

P.P., J.P., and J.B. contributed to conceptualization and writing. Figures and table were contributed by P.P.