Prevalence and Clinical Correlates of Endometriosis in Patients With IC/BPS

This retrospective cohort study involved a medical record review of previously collected data from consented patients (IRB00018552) who were undergoing therapeutic hydrodistension (HOD). Patients completed validated questionnaires, including the O’Leary-Sant Interstitial Cystitis Symptoms Index (ICSI), Interstitial Cystitis Problem Index (ICPI), and Pelvic Pain and Urgency/Frequency (PUF) patient symptom scale, before therapeutic HOD. Demographic data, along with patient-reported history of co-occurring diseases and NUAS (IBS, CPP, chronic fatigue, fibromyalgia, migraines, depression, allergies, vulvodynia, and pelvic floor dysfunction were recorded. Conditions were not defined for patients; our survey asked patients to report what other diagnoses they carry at the time of HOD. Data collection was from adults 18–80 years of age, excluding pregnant patients, those with history of neurologic disease, urogenital cancers, radiation cystitis, or cyclophosphamide use and was captured at time of HOD. At time of HOD, further clinical characteristics of IC/BPS such as presence of Hunner lesions (HL; ulcers seen in some patients with IC/BPS), glomerulations, and anesthetic bladder capacity (BC) – assessed by infusion of water for 5 minutes at a pressure of 100cm H 2 O, were collected. The incidence of endometriosis among female patients in the IC/BPS registry was assessed through patient self-reported medical history. Current Procedural Terminology (CPT) and International Classification of Diseases (ICD) 9&10 codes identified patients with prior cystectomy and/or hysterectomy any time before our study. CPT codes used for cystectomy were 51596, 864, 51590, and the associated date of the procedure was abstracted if available. The ICD10 code used to denote history of cystectomy to identify patients who received cystectomy at a different institution was Z90.6. CPTs used for history of hysterectomy were 58150 and included the associated procedure date, if available. The ICD10 code used to denote history of hysterectomy to identify patients who received hysterectomy at a different institution was Z90.710. Univariate analysis was used to compare demographics and clinical features between participants with and without co-occurring endometriosis, based on patient self-report of having this diagnosis. Fisher’s exact test was used for categorical value comparison, and the Mann-Whitney U test was used for continuous variables to compare the concurrent endometriosis group to those without co-occurring symptomatology. Binary logistic regression was performed to identify variables that were associated with co-occurring IC/BPS and endometriosis. P-values were considered significant if ≤ 0.05. All statistical analysis was completed with SPSS Statistics for Windows, version 27.0 (IBM Corp, Armonk, NY).

Data from 533 female IC/BPS patients, with a mean age of 53.2 ± 15.5 years, were analyzed. Most patients (88.7%) self-identified as Caucasian and 10.9% identified as other; there was no difference found in incidence of endometriosis based on race between the study groups. Of the 533 participants, 426 (79.9%) had anesthetic BCs > 500cc while 90 (16.9%) were ≤ 500cc; this cutoff has been shown to provide a clinically relevant biomarker for bladder-centric vs. non-bladder-centric groups (Sandberg et al, 2023). Average symptom questionnaire scores available for the whole cohort were NUAS 3.85 ± 3, ICSI 13.43 ± 3, ICPI 12.62 ± 3, and PUF 20.06 ± 10. Average bladder capacity was 821 ± 331 cc. Average age at diagnosis for all patients for whom data was available after HOD was 37.9 ± 14.0 years. Within this cohort, 40 (7.5%) had an ICD-coded history of cystectomy while 158 (29.6%) had ICD-coded history of hysterectomy. Among the 533 patients examined, 108 (20.3%) self-reported a history of endometriosis ( Table 1 ). Of the 108 patients who reported co-occurring endometriosis, 35 had an official endometriosis diagnosis coded in their medical record with an ICD code. Those with concurrent endometriosis were on average younger (Mann-Whitney U; p=0.029), exhibited a higher average number of NUAS (Mann-Whitney U; p<.001), had a higher anesthetic bladder capacity (Mann-Whitney U; p=0.005), and underwent cystectomy (subgroup of 40 patients) at an earlier age (Mann-Whitney U; p=0.030). There were no significant differences found between Caucasian vs other race (defined by how patients self-identify), number of Hunner lesion-positive patients, average body mass index (BMI), number of reported deliveries, age at hysterectomy, nor in ICSI, ICPI and PUF scores between the two groups ( Table 1 ). Univariate analysis revealed that patients with IC/BPS and concurrent endometriosis were less likely to undergo cystectomy (p<0.05) and less likely to report the presence of allergies (p=0.03). Conversely, they were more prone to report experiencing co-morbidities such as chronic pelvic pain (p<0.001), chronic fatigue (p<0.001), fibromyalgia (p<0.001), migraines (p<0.001), and pelvic floor dysfunction (p=0.039). No statistically significant differences were found between the two groups for report of co-occurring irritable bowel syndrome (IBS), sleep disorder, depression, and vulvodynia ( Table 1 ). Binary logistic regression identified a positive association between endometriosis and chronic pelvic pain (OR: 2.935, CI: 1.669–5.161, p<0.001), and a negative association between allergies (OR: 0.151, CI: 0.040–0.569, p= 0.005) and low bladder capacity (OR 0.351, CI: 0.241–0.990, p=0.048) for those with concurrent endometriosis.

The prevalence of concurrent endometriosis and IC/BPS observed in our study (~20%), defined through patient reports of carrying that diagnosis aligns with the 20–30% reported in earlier studies. 13 , 15 , 16 However, there was no significant difference in the incidence of co-occurring endometriosis between patients socially self- classified as Caucasian vs those who were not , aligning with other studies that report similar incidence rates across racial and ethnic groups. 17 Nevertheless, it is important to recognize that the reported prevalence of this cooccurrence varies depending on how IC/BPS is defined/diagnosed. For example, in a prospective study by Cheng et al, 18% of patients with visually proven endometriosis also had a diagnosis of IC (defined as CPP with at least one urinary symptom and glomerulations seen upon cystoscopy). However, within the same study, if the European Society for the Study of Interstitial Cystitis (ESSIC) definition of BPS (defined as pressure or discomfort perceived to emanate from the bladder with at least one other urinary symptom) was used, the percentage of patients with co-occurring endometriosis increased to 60% 18 - similar to other studies that have reported a 60–69% cooccurrence of endometriosis and CPP. 12 , 19 , 20 The difficulty in understanding the true prevalence and contribution of co-occurring endometriosis (and other symptoms and syndromes) in the overall IC/BPS clinical picture arises largely from the heterogeneous way in which IC/BPS is currently defined, and highlights the potential value in establishing a more standardized definition. Differences in reported symptomatology between patients with and without endometriosis further highlight the complex interplay between these two conditions. A prospective study by Wu et al. designed to assess the risk of developing IC/BPS in patients with endometriosis, found over a 3-year observation period a four-fold higher incidence of IC/BPS in patients with endometriosis compared to those without. Subjects with concurrent endometriosis and IC/BPS were more likely to experience a myriad of co-morbidities, including IBS, fibromyalgia, chronic fatigue syndrome, depression, panic disorder and migraine, compared to those without endometriosis. 21 Results are consistent with what was found in our cohort of patients with IC/BPS where patients with co-occurring endometriosis (per patient report of) diagnosis had higher overall average number of NUAS and were more likely to report co-morbidities such as CPP, chronic fatigue, fibromyalgia, migraines, and chronic pelvic floor dysfunction. Previous research has established a correlation between anesthetic bladder capacity and symptomatology in IC/BPS patients. In the present study, a significant difference emerged in the percentage of patients exhibiting low bladder capacity; 20% in the non-endometriosis group compared to 9% in those with endometriosis ( Table 1 ). In addition, clinical correlates from our logistic regression analysis ( Table 2 ) revealed a negative association between low bladder capacity and concurrent endometriosis diagnosis, indicating endometriosis is associated with the non-bladder centric phenotype of IC/BPS. This finding aligns with the work of Walker et al, which observed that patients with non-low bladder capacity typically report a higher number of non-urological symptoms. 14 Subsequent investigations have underscored the nuanced relationship between symptom variation and anesthetic bladder capacity, suggesting underlying genomic differences between low and non-low bladder capacity groups. Colaco et al elucidated transcriptomic variance in bladder biopsy tissues, noting an upregulation in pathways associated with inflammatory cell signaling among samples from patients with a low anesthetic bladder capacity. These molecular distinctions potentially signify fundamental differences in the disease process between individuals with low versus non-low bladder capacity. 22 The observed differences in bladder capacity and concurrent symptom burden in our study lend support to the hypothesis that endometriosis and other chronic pain conditions are more likely to co-occur in the non-bladder-centric phenotype of IC/BPS. Functional pain syndromes have been associated with an augmented likelihood of undergoing surgical interventions. Warren et al. demonstrated that the presence of functional somatic syndromes independently increased the risk of hysterectomy in early IC/BPS cases. 23 This finding aligns with other studies indicating a correlation between functional syndromes, like IBS, and heightened susceptibility to various surgical procedures. 24 , 25 In our cohort, 31% of patients had undergone hysterectomy, consistent with prior research reporting rates ranging from 30%−53.5% in IC/BPS patients. 15 , 26 – 28 While our study did not find a significant difference in the incidence of hysterectomy between those with and without co-occurring endometriosis, this may be attributed to the overall elevated risk of hysterectomy observed for all IC/BPS patients 28 . Notably, when compared to other groups, individuals experiencing comorbid endometriosis-associated bladder pain syndrome (EABP) reported heightened levels of dyspareunia, and greater interference with work and daily activities due to pain. 29 Although the present study found no significant difference in IC/BPS symptom-specific validated questionnaire scores between the two groups, IC/BPS patients with co-occurring endometriosis experience a lower quality of life based on the greater number of NUAS and co-morbidities experienced. An endometriosis diagnosis in patients with IC/BPS has far-reaching implications for diagnosis, disease course, and treatment strategies. Currently, there is a paucity of comprehensive, long-term prospective studies scrutinizing the trajectory and course of IC/BPS. Existing research does not focus specifically on IC/BPS as currently defined by AUA guidelines, and generally focuses on symptom changes over the span of ~9 years, lacking substantial data on changes in BC, clinical outcomes, presence of HL and more specific disease charactertics. 30 – 32 One of the few studies that have addressed the clinical course of IC/BPS suggests about 10% of patients transition to an “end-stage” disease group. 33 This small number aligns with the subgroup of patients (7.5%) in our cohort with severe symptoms refractory to all other treatments. This subgroup represents a fraction of the broader IC/BPS population, and comprehensive longitudinal studies will be required to characterize disease progression, refine diagnostic criteria, and optimize treatment strategies for these patients. Of note, extirpative removal of the bladder has been shown to have a 23% risk of no improvement in symptoms 34 ; this outcome could in indicate a potential misdiagnosis or a disease process extending beyond the bladder resulting in ongoing symptoms. Further studies that are prospective in nature with detailed inclusions and exclusion criteria for surgical removal of the bladder in IC/BPS are required to investigate this concept and true cause of pain in this patient population. While this study provides some valuable insights, it is not without limitations. Although the retrospective design and reliance on patient-reported medical history data can introduce inherent recall bias, we attempted to mitigate this by employing validated IC/BPS questionnaires and standardized intake forms to record past medical history and co-occurring symptomatology. While patient reporting may not always be 100% reliable, it still provides an advantage to this study by allowing us to capture patients with endometriosis who may have been missed if we were to rely solely on coding data, especially considering the delay often associated with diagnosing endometriosis. Furthermore, studies have shown a low correlation between the number of biopsy proven lesions and symptom correlation. This has resulted in a greater reliance on a clinical diagnosis anchored by cyclic pain and symptoms reported by patients. 9 The lack of correlation between lesions and the amount of pain experienced by patients is a shared characteristic of endometriosis and IC/BPS where patients without Hunner lesions can present with severe pain and further emphasizes the need for more studies of these chronic pain conditions. A second limitation involves variations in coding practices across providers that might have influenced the accuracy of reported surgical procedures. To address potential coding biases, we cross-referenced CPT codes for specific procedures like “cystectomy” with ICD codes indicating a history of procedures, such as “history of cystectomy,” enabling us to include patients who underwent surgeries outside our healthcare system. Despite these limitations, our findings augment the expanding literature on the clinical implications of concurrent endometriosis on clinical correlates in IC/BPS patients. We emphasize the need for further research to refine management strategies for this complex patient cohort. In conclusion, this study provides valuable insights into the prevalence of endometriosis in patients with IC/BPS, emphasizing the need for further studies to elucidate clinical implications on patient outcomes and disease trajectory. The association between endometriosis and chronic pelvic pain underscores the need for comprehensive evaluation and management of pelvic pain disorders. Clinicians are encouraged to consider screening for endometriosis in patients with IC/BPS, particularly those presenting with refractory symptoms or atypical clinical features. Future research is warranted to elucidate the underlying mechanisms driving the co-occurrence of these conditions and to explore optimal treatment approaches for affected patients. Further studies will focus on identifying what role central sensitization and other neurologic mechanisms in patients with IC/BPS and whether disease characteristic differ between patients with low vs non-low bladder capacity.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain condition estimated to affect approximately 83,000 men and 1.2 million women across the United States. 1 The American Urological Association (AUA) guidelines utilize the Society for Urodynamics and Female Urology (SUFU) definition of IC/BPS, highlighting an unpleasant sensation thought to emanate from the bladder in the absence of infection or other identifiable causes, with associated lower urinary tract symptoms (LUTS) for at least six weeks. 1 , 2 While the etiology remains incompletely understood, research indicates an association between IC/BPS and several non-urological associated symptoms (NUAS) and conditions, some of the most common being endometriosis, irritable bowel syndrome (IBS), and fibromyalgia. 3 – 5 A common feature in patients with a diagnosis of IC/BPS is chronic pelvic pain (CPP), however this symptom is also reported in several of the IC/BPS-associated conditions, including IBS and endometriosis. Furthermore, one or more conditions, rather than a single cause of pain, are present in at least half of the instances of patients with CPP. 6 , 7 While IC/BPS and endometriosis are common causes of CPP, both conditions remain difficult to diagnose. Endometriosis has a diagnostic delay of 10–11 years from symptom-onset to surgical confirmation, primarily manifesting during a woman’s reproductive years, and affects approximately 10% of women. 8 , 9 A condition generally defined by histology, endometriosis is the implantation of glandular endothelial tissue outside of the endometrium. It is characterized by cyclic pain, at time of menses, infertility and a variety of symptoms. An official diagnosis of this condition requires surgical evaluation with visualization of ectopic endometrial tissue implantation. However, patients with endometrial lesions can have other causes of chronic pain while not having obvious lesions does not negate a diagnosis of the condition 9 . Notably, 80% of patients with CPP have a non-gynecologic source of pain, emphasizing the need for interdisciplinary team collaboration in the treatment of these patients to decipher and treat the root cause of their pain. 6 , 10 , 11 While prior studies have noted the coexistence of IC/BPS and endometriosis, dubbed the “evil twins” syndrome, and identified their shared characteristics, 12 there remains a scarcity of literature enumerating potential differences in disease clinical correlates among IC/BPS patients with concurrent endometriosis. A prior investigation surveyed the prevalence of co-diagnosis of endometriosis and IC/BPS within a sizable registry comprising 431 IC/BPS patients, and revealed a notable association between both conditions, highlighting an elevated prevalence of non-low bladder capacity (>400 cc), and a heightened likelihood of co-occurring systemic pain diagnoses such as IBS, fibromyalgia, and CPP. 13 Additionally, an earlier study observed differences in co-occurring symptomatology based on patient’s measured bladder capacity under anesthesia, noting that IC/BPS patients with low bladder capacity were less likely to experience other common systemic pain syndromes. 14 Building upon this previous work, our study aims to extend these findings by examining the prevalence of endometriosis in an expanded IC/BPS patient registry. We seek to elucidate relevant disease correlates and assess clinical sequela, including but not limited to the history of hysterectomy and/or cystectomy (surgical removal of the bladder) and age at the time of these procedures. While not a direct causal relationship, clinical correlates including eventual bladder and uterus removal may correlate with symptoms refractory to more conservative treatment and therefore indicate relevant disease sequela. Such investigations are paramount in providing comprehensive insights into the interplay between IC/BPS and endometriosis, thereby informing tailored management strategies for affected patients.