Association of endometriosis with interstitial cystitis in chronic pelvic pain syndrome: Short narrative on prevalence, diagnostic limitations, and clinical implications

Introduction: Chronic pelvic pain (CPP) is a diagnostic and therapeutic challenge affecting women of all ages globally. The syndrome is not well understood, but the association of interstitial cystitis (IC) with endometriosis in causing CPP should not be overlooked in managing this cohort. Herein, we present a mini review of this association to evaluate the literature in determining the prevalence of endometriosis and IC concomitantly in patients with CPP, diagnostic limitations, and clinical implications. Methods: A Medline search of the key words “evil twins’ syndrome,” “interstitial cystitis,” “bladder pain syndrome,” and “endometriosis” was conducted for full-text articles published in English over the past 20 years. The search yielded 40 articles, of which 21 were selected. Cross-referencing bibliographies of each publication yielded an additional 25 references. Results: Both endometriosis and IC share a similar array of symptoms that are often exacerbated during the perimenstrual period. Multiple authors have reported the frequent coexistence of these two conditions. Over 80% of patients with CPP were found to have both conditions. The prevalence of endometriosis and IC coexistence was greater than that of each condition separately. Conclusions: It is crucial to look beyond the traditionally diagnosed endometriosis as the cause of CPP. This is true especially in patients whose previous treatment was ineffective. Simultaneous assessment for both conditions is essential to avoid the frequently delayed diagnosis and prevent unsuccessful medical and surgical therapies.


INTRODUCTION
Chronic pelvic pain (CPP) is a syndrome with diagnostic and therapeutic challenge that affects women of all ages globally. A standardized definition or diagnostic method for CPP has not been established. It is often defined as noncyclic lower abdominal or pelvic pain that lasts at least 6 months and may be intermittent or constant and may be exacerbated by menstruation or intercourse. Pain severity can range from mild to debilitating pain. It often affects the patients' quality of life. Investigation results are often vague, and the cause of the pain may not be identified. Given the paucity in epidemiological data, the true incidence of CPP is unknown. However, it is estimated to affect 1 in 7 women and 9 million women in the United States 1 . A systematic review conducted by the World Health Organization (WHO) in 2006 estimated the prevalence of CPP to range from 4% to 43.4% globally (Table 1) 2 . The diagnosis of CPP poses a clinical challenge because of an extensive list of nonspecific symptoms, an equally extensive list of possible diagnoses, and the need for invasive testing. The differential diagnoses of CPP encompass multiple specialties, including gastrointestinal, gynecologic, urologic, musculoskeletal, and psychiatric fields. Moreover, , 20% of patients with CPP seek medical treatment 3 . CPP accounts for 10%-15% of gynecological referrals, 10% -12% of hysterectomies, and 40% of gynecologic laparoscopic procedures 3,4 . During laparoscopy, pathology is not found in 35% of the cases, and when pathology is identified, it is often unclear whether it is the true cause of the CPP, which further adds to the diagnostic challenge 5 . CPP has a debilitating effect on daily activities and quality of life in 50%-60% of women 6 . It is linked to multiple conditions, including depression which is prevalent in up to 50% of women with CPP and anxiety 2,4,6 . Patients with CPP are often treated empirically for a presumed diagnosis with poor response and high recurrence rates. With their frustration of the treatment outcomes, these patients seek care from different physicians and undergo multiple unsuccessful medical and surgical therapies. Medication ingestion in women with CPP is three times higher than that of healthy women, while gynecological surgical procedures are four times higher 6 . CPP poses a massive financial healthcare burden. The estimated annual outpatient health care cost spent in the United States for the treatment of CPP is $881.5 million 2 . A cross-sectional study of inpatient care of CPP estimated that the yearly expenditure reached $25 million 7 . Moreover, 92.9% of inpatients underwent surgical intervention, and the most common were hysterectomy (47.1%) and laparoscopy (25.8%) 7 . Traditionally, endometriosis was considered the most common cause of CPP. Recently, interstitial cystitis (IC) has been emerging as a major player in the CPP complex. Numerous authors have reported the coexistence of these two conditions and the predicament faced in attributing which of the two caused CPP when both conditions are present. In 2002, Chung et al. retrospectively reviewed 60 patients with CPP and found a high likelihood of the two conditions co-occurring, coining the term the "evil twins" of CPP 3 . Although this term never gained standardization, the co-occurrence of these two conditions garnered much attention. Thus, this review aimed to determine the prevalence of endometriosis and IC found concomitantly in patients with CPP and to compare the prevalence of endometriosis and IC individually. Bladder-origin pelvic pain has become widely recognized since the introduction IC and painful bladder syndrome (PBS) in 1887 and 1957, respectively 8,9 . Over time, as the definition of IC evolved, so has its reported prevalence 10 . According to the European Society for the Study of Interstitial Cystitis definition, PBS was diagnosed in cases where CPP and at least one urinary symptom were experienced. IC was defined as CPP with at least one urinary symptom and the presence of glomerulations in at least two quadrants 10 . In the United States, approximately 1 in 4.5 women may have IC 5 . In addition, 85% of patients with CPP have IC, and a positive potassium sensitivity test (PST) was found in 82% of cases with CPP 5 . IC presents with a heterogeneous array of symptoms including urinary urgency, frequency, and nocturia. It is also associated with sexual dysfunction with deep dyspareunia, bladder pain during and after intercourse, and the urge to urinate during intercourse. Pain or lack of sensation in the genital area as well as reduced libido, sexual arousal, and orgasm frequency have also been reported 11 . Furthermore, 75% of patients with IC report exacerbation of symptoms following sexual intercourse 12 . Different studies have reported that the rate of sexual dysfunction in patients with IC range from 13% to 87% 11,13 . Early, mild disease presents with intermittent symptoms, which may progress to persistent debilitating disease. Early recognition is challenging as IC shares presenting symptoms with multiple other conditions, making it difficult to distinguish IC from conditions such as endometriosis, urinary tract infections, vulvodynia, and overactive bladder (OAB) 14 . The diagnosis of IC is generally delayed if the patient has had experienced symptoms for several years and undergone multiple pelvic surgeries 12,13 . IC is usually symptomatic for 4-7 years before the diagnosis is made 12,14 . Most patients are diagnosed in their early 40s, 30% are diagnosed in their 30s, and 27% are diagnosed within the ages of 19 -34 13 . Endometriosis is believed to be one of the most common causes of CPP accounting for 71%-87% of the cases 3,8,14,15 . Endometriosis affects 5% -15% of women of reproductive age 3,5,12 . The diagnosis of endometriosis has increased in the past 15-20 years. Pain is experienced by 50%-70% of women with endometriosis 16 . In addition to pain, endometriosis causes dysmenorrhea, vulvodynia, dyspareunia, dyschezia, menorrhagia, and infertility. Dyspareunia is reported by 86% of patients, 69% avoid intercourse, and 19% are no longer sexually active 17 . The diagnosis can only be confirmed by laparoscopy and histology, which are expensive and invasive and require general anesthesia. As a result, the diagnosis is often delayed up to 12 years 16 . Despite laparoscopy being the accepted gold standard for the diagnosis of endometriosis, many national and international guidelines have recommended initiation of empiric therapy and monitoring for response. Therefore, many women will be diagnosed clinically without histologic confirmation 18 . Only 28% -35% of patients with CPP have biopsy-confirmed endometriosis 5 . Visual identification of lesions is not sufficient in confirming the diagnosis 19 . Treatment in many patients presumed to suffer from endometriosis produces temporary, insufficient pain relief in a progressive disease with high recurrence rates reaching 50% 3 . These patients were more likely to undergo multiple surgical procedures, use two or more medications to treat endometriosis, undergo appendectomies and cholecystectomies, and develop mood disorders 20 . Endometriosis is associated with multiple comorbid pain conditions, including irritable bowel syndrome, fibromyalgia, chronic headache, depression, and anxiety. In a previous study 34, thirty sex percent of patients with endometriosis reported that their quality of life and academic performance were affected 20 .

METHODS
A Medline search of "interstitial cystitis" OR "bladder pain syndrome" OR "evil twins' syndrome" AND "endometriosis" was conducted. The search was limited to English full-text articles that were published over the past 20 years, with female patients aged 13 -44 years. The inclusion criteria were limited to this age group, as the majority of cases of endometriosis and IC initially present and are investigated during this age. Although the diagnosis of both conditions is often delayed with years of symptoms before diagnosis, the majority of patients are diagnosed in their early 40s, 30% are diagnosed in their 30s, and 27% are diagnosed within the ages of 19 -34 years 13 . Case reports, clinical trials, metaanalyses, observational studies, and reviews were included. The search yielded 40 results. Crossreferencing bibliographies of each publication yielded an additional 25 references. As this was a review of published literature, institutional ethical board approval was not required.

RESULTS
The association of IC with endometriosis has been well reported by multiple authors, and their findings are summarized in Table 2

Similar symptomatology
IC and endometriosis share the same pathogenesis, with mast cell infiltration and degranulation occurring in both conditions 5 . In addition, viscerovisceral hyperalgesia allows painful stimuli from the bladder to be transmitted to the spinal cord and perceived as pain anywhere in the pelvis. Thus, it is difficult to identify the organ that generates pain and whether the pain is caused by multiple or a single origin 5 . Endometriosis and IC also share symptomatology. Both conditions cause dyspareunia and vulvodynia and are associated with menstrual exacerbation of symptoms (Table 3). Premenstrual flares of IC were found in 75% of the patients 5 . Powell-Boone et al. recruited seven women with IC and eight and asked them to document and track their daily bladder and other body pains in a diary. In the IC group, pain scores and urinary frequency were the highest in the perimenstrual period. Cystometry performed during the follicular premenstrual period showed that bladder pain was evoked with lower intravesical infused volume and pressure when compared with the results obtained during the luteal period 27 . Dyspareunia and sexual dysfunction are also reported in both conditions. Dyspareunia is found in 40%-57% of cases of IC and 43%-62% of endometriosis 11,28 . Moreover, 60%-80% of patients with endometriosis undergoing surgery experience dyspareunia, while 50%-90% of patients on medical treatment suffer from dyspareunia 28 13 . The association of IC with vulvodynia is not well understood. The reported prevalence of vulvo-dynia ranged from 7% to 28% 14,29,30 . The prevalence of vulvodynia in patients with IC has ranged from 51.4% to 85.1% 14,30 . Among patients with persistent vulvodynia, 22% had IC 14 . In a study by Kahn et al. where 122 patients with vulvodynia underwent PUF and PST, 84% of women with vulvodynia had a positive PST and 80% of these patients reported urinary urgency and frequency 29 . The study suggested that vulvodynia was a symptom of a more complex disease, i.e., IC, originating in the bladder. A common etiology for the two conditions has been suggested as both the vulva and bladder originate from the urogenital sinus and share neurologic innervation by the common sacral nerve 14 . IC profoundly affects sexual function with 23.4% of patients reporting abstinence from sexual activity in the previous year compared with 9% of controls, and 50% of the women avoided intercourse 30 .

Limitations and clinical implications
The true prevalence of both IC and biopsy-confirmed endometriosis is unknown because of several limitations. Laparoscopy is considered the gold standard for the diagnosis of endometriosis. Visualization of endometriotic lesions during laparoscopy has not been found to be reliable in confirming the diagnosis. Only 49% of lesions appearing positive for endometriosis were confirmed to be histologically positive 19 . IC is diagnosed with hydrodistension at cystoscopy and visualization of grade 2-3 glomerulations, or Hunner's lesions, or both. These diagnostic methods are invasive and expensive, require anesthesia and training, and involve a recovery period and the patient missing work. Moreover, they both involve potential risks, including infection, bladder rupture, vascular, and organ injury.
As IC and endometriosis have the same symptoms, the patient is likely to attribute menstrual worsening of symptoms to gynecological causes of pain and therefore seeks gynecological care 31 . Pain is usually the symptom that patients find most troublesome. They may disregard any other symptom including urinary symptoms as insignificant 31,32 . Patients may also fail to disclose any dyspareunia because of discomfort associated with its discussion. Gynecologic practice does not typically focus on urinary symptoms, and the diagnosis of IC is made by a gynecologist in only 8% of cases 33 . Approximately 75% of patients followed up with gynecological services for CPP have urinary symptoms, which often go unrecognized 12

CONCLUSION
The rates of concurrent endometriosis and IC reported by different studies vary widely. However, all studies agree that the prevalence of the two concurrent conditions is high. The relationship between the two conditions is poorly understood, as the pathogenesis behind each condition is not known. Multiple theories, including that both conditions are caused by mast cell degranulation or neurogenic upregulation with viscerovisceral hyperalgesia, have been proposed but not yet proven. The coexistence of IC and endometriosis is frequently overlooked. The results of multiple studies have supported that this association is more likely to exist in patients with CPP than making the diagnosis of endometriosis or IC alone. However, it is difficult, if not impossible, to ascertain which of the two conditions is the major source of pain. Simultaneous assessment with cystoscopy and laparoscopy and treatment for both conditions are crucial, especially in patients who continue to experience symptoms despite previous treatment. The presence of endometriosis does not exclude IC as a cause of CPP. CPP may be caused by either or both of these conditions, raising the need to look beyond the conventional diagnosis of endometriosis in treating patients with CPP. This review emphasizes the importance of an interdisciplinary approach involving both urologists and gynecologists to avoid delayed or missed diagnosis as well as prevent unnecessary surgical interventions. Early referral of patients with CPP by clinicians for multidisciplinary care is paramount. In addition, clinician focus should consider the bladder as a possible generator of pain early in the workup. Future research of the outcome and patient response is required when standardized diagnostic protocols are employed to investigate for both endometriosis and IC concurrently. This will produce a validated diagnostic approach to help the clinician in identifying patients with these potential diagnoses, ascertain a relevant history of symptoms, investigate other potential differential diagnoses, and rapidly test for IC and endometriosis. Less stringent criteria for diagnosis that are applicable in clinical practice are required. Homogenizing definitions and diagnostic criteria will eliminate differences between clinical practice and research.