MAURICE K. CHUNG, MD, RPH
The more common gynecologic diagnoses of chronic pelvic pain (CPP) are pelvic adhesions, adnexal cysts, endometriosis, endosalpingiosis, ovarian remnant syndrome, pelvic congestion syndrome, residual ovarian syndrome, pelvic inflammatory disease, adenomyosis, and uterine leiomyomatas [1,2]. Often, management of women with CPP involves invasive procedures or surgical interventions. In fact, more than 40% of laparoscopies and 10% to 12% of all hysterectomies are performed as a result of CPP, which contributes to its significant economic burden [3,4]. Endometriosis is one of the more prevalent gynecologic diagnoses among women with recurrent and progressive CPP . Among 58 patients who presented to a pelvic pain center for treatment, 48 (83%) had biopsy confirmed active endometriosis . This finding is consistent with findings in the current literature [3,6-10]. Endometriosis is the presence of ectopic endometrial glandular tissue outside of the endometrial cavity. Symptoms include dyspareunia; cyclic premenstrual, menstrual, or both, low abdominal pelvic pain; irritative voiding; and flares after sexual intimacy . Ideally, the diagnosis of endometriosis involves visual confirmation of the lesion during laparoscopy and histologic confirmation of the presence of both ectopic endometrial glands and stroma .
Painful Bladder Syndrome
Interstitial cystitis (IC), or pelvic pain of bladder origin, occurs predominantly in women 30 to 59 years of age,12 with up to 85% of reported cases in those 40 to 45 years of age [13,14]. Along with endometriosis, IC is considered one of the more common disorders associated with CPP . Yet, only 500,000 patients with debilitating bladder problems have been diagnosed with IC, while the number of those with undiagnosed IC has been estimated to be more than 8 million . Still, some estimates range up to 28 million, with the overwhelming majority of these individuals incorrectly diagnosed or undiagnosed .
Symptoms include urinary urgency, frequency and/or pelvic pain in the absence of urinary tract infection. Although these symptoms represent the classic triad of IC, some patients have no pain and present with symptoms of overactive bladder. In addition, 15% of patients present with chronic pain and no urologic symptoms . Furthermore, many patients have dyspareunia and cyclic premenstrual, menstrual, or both, low abdominal pain exacerbated by sexual intimacy [16,18].
In the mid-1980s, the National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases (NIH-NIDDK) established clinical and cystoscopic diagnostic criteria for research studies of IC (Table 1) [19,20]. The consensus criteria for diagnosis of IC, including exclusions and cystoscopic evidence of ulcers and glomerulations, were widely accepted for both clinical and research purposes and thereafter became the de facto criteria for establishing a clinical diagnosis [20,21]. Glomerulations, however, are not pathognomonic of IC (Figure 1) [19,21]. A recent study reported glomerulations in about 45% of “normal” women undergoing tubal ligation . Unfortunately, the women were not specifically questioned about urinary or gynecologic symptoms, such as CPP, and were not asked to complete voiding logs or pain questionnaires. Some of these women may have had occult IC characterized by pelvic pain, irritative voiding symptoms, or both of these .
Figure 1. Left lower corner shows mucosal cracks, which are frequently found in patients with IC. All the others show glomerulations.
The NIH-NIDDK criteria were found to be too restrictive for clinical use based on results of the Interstitial Cystitis Database Study because more than 60% of patients evaluated by experienced clinicians and thought to have or to definitely have IC did not meet the NIH-NIDDK criteria .
Similar to the diagnostic criteria for IC, the pathogenesis and cause of IC remain incompletely defined. A consensus is emerging, however, regarding the central role of bladder epithelial dysfunction, bladder sensory nerve upregulation, and mast-cell activation in the genesis of IC [16,23]. The urothelial surface is lined by impermeable bladder surface mucin composed of sulfonated glycosaminoglycans and glycoproteins. Injury to this surface can cause changes in permeability that allow potassium ions to traverse the urothelium, depolarize sensory and motor nerves, and activate mast cells [18,23,24].
On the basis of this hypothesis, Parsons et al  developed the Potassium Sensitivity Test (PST) to indicate abnormal permeability of the epithelium, which may be used to support a diagnosis of IC. The use of PST has been validated in several studies. Over 80% of CPP patients demonstrated positive potassium sensitivity, suggesting a bladder component to their pain (IC) [18,26].
Parsons et al  also designed a Pelvic Pain and Urgency/Frequency (PUF) symptom scale that provides balanced attention to bladder-origin pelvic pain (IC) and to pelvic pain or dyspareunia. The severity of IC symptoms and the extent to which the patient is bothered by each symptom are measured on a scale of 0 (no symptoms) to 35 (most severe). PST was used to validate PUF as a diagnostic tool. In patients suspected of having IC with a PUF score of 10 to 14 (moderate symptoms), 74% showed positive potassium sensitivity . Furthermore, it was shown that a PUF score of 15 or higher is associated with an 84% chance of a positive PST, which provides strong evidence for the presence of IC .
Endometriosis is considered one of the 4 most common diagnoses in women with CPP . Based on findings from many studies, at least 80% of patients with CPP have endometriosis [5-8,10,26,27].
To establish a definitive diagnosis of endometriosis, many opinion leaders still believe that laparoscopy is necessary . However, diagnosing endometriosis during laparoscopy can be difficult and is dependent on the surgeon’s level of experience. An inexperienced surgeon may miss the diagnosis of endometriosis because its appearance can vary widely [11,28]. Diagnosis also presents other challenges. Although surgeons are urged to obtain histologic confirmation of endometriosis, it is often uncertain whether endometriotic implants or adhesions found during surgery are the source of the patient’s pain. Although pelvic adhesions are diagnosed in approximately 25% of women with CPP or without endometriosis, their relationship to CPP is still controversial . It is prudent, therefore, to consider other possible causes of CPP even in the presence of endometriosis, especially in patients whose symptoms persist despite therapy.
Although endometriosis has been recognized as a major cause of CPP, the treatment of endometriosis is often not successful. Due to a lack of adequate randomized controlled trials, evidence is insufficient to support the efficacy of medical therapy, surgical therapy, or both, for CPP and endometriosis. As a result, management of women with CPP considered secondary to endometriosis includes a vast range of therapeutic approaches that are often suboptimal and costly . To complicate management even further, endometriosis has been found in more than 60% of asymptomatic patients and progressive disease exists in close to 60% of patients overall [5,30,31].
When endometriosis is found at the time of surgery, destruction of the lesions by fulguration, excision, or both, is recommended. Although excisional surgery offers a better success rate in treating endometriosis in patients with CPP, it also requires a higher level of surgical skill . Many patients, therefore, may receive inadequate treatment for their endometriosis by less experienced surgeons, which, in turn, can lead to persistent and recurrent disease. Furthermore patients have undergone numerous laparoscopies and have had a hysterectomy and still suffer from CPP.
Interestingly, endometriosis has been found to involve the urinary tract and has been reported in at least 16% of women undergoing a laparotomy for the condition . Recently, there was a report on a small series of patients with bladder endometriosis . In addition, it has been demonstrated that 79% of patients with persistent chronic pelvic pain after a hysterectomy have IC . It is advisable, therefore, to evaluate urinary symptoms in patients with CPP and endometriosis. Strict adherence to this principle has led to the discovery that IC and endometriosis, the evil twins, can coexist in women with CPP.
ENDOMETRIOSIS AND INTERSTITIAL CYSTITIS
The Evil Twins Study
Results of recently published papers [5,26,27,35] demonstrate the presence of endometriosis and IC, the “Evil Twins,” in 38% to 80% of patients with chronic pelvic pain based on the potassium sensitivity test and laparoscopic and cystoscopic evaluation.
In our recent “The Evil Twins” study  of 178 patients, 159 (89%) were diagnosed with interstitial cystitis by cystoscopic evidence. A positive potassium sensitivity test was achieved in 146 patients (82%). Both IC and PST were found in 140 (78.6%) patients. Biopsy confirmed endo-metriosis was found in 134 patients (75.2%). Both IC and endometriosis were found in 115 patients (65%). In the positive PST group of 146 patients, 140 (96%) were diagnosed with IC by cystoscopy. Irritable urinary symptoms occurred in 145 of 178 patients (81.5%) with chronic pelvic pain. Urinary incontinence was present in 77 (43.3%) patients. The average pelvic pain (PUF) score was 14 of 35. An average of 20% of the study patients had no urinary symptoms. Painful overactive bladder symptoms were complaints among not only patients with endometriosis but also those with negative findings following laparoscopic evaluation. In fact, the 44 patients with no endometriosis showed significant improvement in their symptoms of CPP, including their painful overactive bladder symptoms after cystoscopic hydrodistention, indicating that IC could be the cause of their CPP. It was concluded, therefore, that patients with CPP (80%) with or without urologic symptoms of urgency/frequency (20%) may in fact have IC as a component of their pelvic pain .
If cystoscopy had been performed only in patients with irritative voiding symptoms/overactive bladder, a diagnosis of IC would have been missed in approximately 20% of patients. Furthermore, cystoscopy/hydrodistention is often performed only in patients with a negative laparoscopic evaluation. Consequently, patients are required to undergo 2 separate procedures while under general anesthesia, and the diagnosis of IC is delayed in approximately 80% of patients. Cystoscopy/
hydrodistention should be considered as an integral part of the surgical evaluation of patients with CPP.
Several modalities are used to diagnose IC. Cystoscopic hydrodistention and clinical presentation remain the “gold standard.” However, this gold standard is not ideal and is considered controversial by many [21,22]. In addition, the stringent diagnostic criteria for IC developed by the NIH-NIDDK and the controversy concerning the accuracy of less stringent criteria have interfered with recognition of IC as a major cause of CPP. To make the problem worse, gynecologists in general are not accustomed to addressing irritable urinary symptoms in patients with CPP, thus making the diagnosis of IC less common.
The PUF questionnaire and the PST as advocated by Parsons and colleagues have emerged as a simple office screening tool and diagnostic procedure, respectively, for patients with symptoms of CPP and IC. These tests have been recently validated as diagnostic approaches for IC [17,36]. In this study, the diagnostic accuracy of PST increased when performed in conjunction with cystoscopic hydrodistention. Notably, it has been shown that a PUF score of 15 or higher is associated with an 84% chance of a positive PST, which provides strong evidence for the presence of IC.
It is very important to use all existing screening and diagnostic modalities to establish an early diagnosis of IC. When surgery is indicated, cystoscopic hydrodistention in conjunction with laparoscopy is recommended to establish an earlier diagnosis of endometriosis and IC/CPP of bladder origin [5,26,27,35,37], the evil twins of CPP.
Simple conservative methods exist for treating IC, including diet, pelvic floor physical therapy, and medications, such as hydroxyzine and pentosan polysulfate sodium (Elmiron, Ortho-McNeil Pharmaceutical, Inc, Raritan, NJ). Recent published articles have indicated the efficacy of oral contraceptives in treating CPP and IC [33,38]. We have presented a clinical study of using intravesical instillation of anesthetic in patients with chronic pelvic pain resulting in close to a 40% reduction in pain symptoms in 8 to 10 weeks .
Many thought leaders believe that the treatment of women with CPP has been ineffective because the underlying cause is actually urologic rather than gynecologic . Therefore, it is reasonable to conclude that ineffective management of CPP and treatment failures may be in part the result of missed diagnoses of IC.
In summary, it is desirable to have a urologist perform cystoscopy and hydrodistention, especially when these procedures are new to the gynecologist. If, however, a urologist is not available to assist in the procedure, or alternatively, if the gynecologist does not wish to perform a cystoscopy and hydrodistention, he or she should consider using the PST test. This test has validated the PUF questionnaire, and together the PUF and PST are more than adequate to confirm a diagnosis of IC.
OVERLAP OF INTERSTITIAL CYSTITIS AND ENDOMETRIOSIS: THE UNDERLYING NEUROPATHOLOGY
Both endometriosis and IC are CPP syndromes that can be frustrating for patients and physicians alike. These CPP syndromes are associated with other pain syndromes, including irritable bowel syndrome (IBS), fibromyalgia, dyspareunia, and vulvodynia [41,42]. The association may be as a result of neuro-upregulation, and pain centralization; other neuropathic states are reviewed elsewhere [43,44] and include visceral hyperalgesia (eg, irritable bowel syndrome), viscerosomatic hyperalgesia (eg, essential vulvodynia associated with IC), viscerovisceral hyperalgesia (eg, IBS associated with IC), and abnormal visceromuscular reflexes (eg, pelvic floor tension myalgia) [45-50].
A review of the neuropathology of CPP and multisystem interactions involved in all the above-mentioned clinical pain syndromes demonstrates that the significant overlap of IC and endometriosis observed in our studies is to be expected . A multidisciplinary approach to chronic pain has been repeatedly shown to be highly efficacious [52-55]. The substantial efficacy of this approach can potentially be attributed to down-regulation of the upregulated dorsal horn with resultant relief of chronic pain. This concept of the visceral pain syndrome should encourage clinicians to abandon an organ-specific approach to the evaluation and treatment of their patients with CPP. Instead, they should pursue a more holistic and mechanistic management strategy in this patient population. Our study strongly supports the rationale for this approach.
Reprinted with permission: Maurice K. Chung, MD, RPh.
Address reprint requests to: Maurice K. Chung, MD, RPh, Midwest Regional Center for Chronic Pelvic Pain and Bladder Control, 310 S Cable Rd, Lima, OH 45805, USA. Telephone: 419 227 3085, Fax: 419 228 1000.
Maurice K. Chung, MD, RPh, is a Clinical Associate Professor at the University of Toledo School of Medicine and an Adjunct Professor of Pharmacy at Ohio Northern University. He is the Director of the Midwest Regional Center for Chronic Pelvic Pain and Bladder Control. Dr Chung is also in private practice in Lima, Ohio. He has published in JSLS, Journal of the Society of Laparoendoscopic Surgeons and other journals as well as presented his clinical studies in national and international conferences. Dr Chung sits on the boards of the International Pelvic Pain Society and the International Society of Gynecologic Endoscopy.
1. Mathias SD, Kuppermann M, Liberman RF, Lipschutz RC, Steege JF. Chronic pelvic pain: prevalence, health-related quality of life, and economic correlates. Obstet Gynecol. 1996;87:321-327.
2. Howard FM. Introduction. In: Howard FM, ed. Pelvic Pain Diagnosis and Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:3-6.
3. Howard FM. The role of laparoscopy in chronic pelvic pain: promise and pitfalls. Obstet Gynecol Surv. 1993;48:357-387.
4. Reiter RC. A profile of women with chronic pelvic pain. Clin Obstet Gynecol. 1990;33:130-136.
5. Chung MK, Chung RP, Gordon D, Jennings C. The evil twins of chronic pelvic pain syndrome: endometriosis and interstitial cystitis. JSLS. 2002;6:311-314.
6. Ling FW for the Pelvic Pain Study Group. Randomized controlled trial of depot leuprolide in patients with chronic pelvic pain and clinically suspected endometriosis. Obstet Gynecol. 1999;93:51-58.
7. Koninckx PR, Meuleman C, Demeyere S, Lesaffre E, Cornillie FJ. Suggestive evidence that pelvic endometriosis is a progressive disease, whereas deeply infiltrating endometriosis is associated with pelvic pain. Fertil Steril. 1991;55:759-765.
8. Carter JE. Combined hysteroscopic and laparoscopic findings in patients with chronic pelvic pain. J Am Assoc Gynecol Laparosc. 1994;2:43-47.
9. Ripps BA, Martin DC. Focal pelvic tenderness, pelvic pain and dysmenorrhea in endometriosis. J Reprod Med. 1991;36:470-472.
10. Mettler L, Schollmeyer T, Lehmann-Willenbrock E, Schüppler U, Schmutzler A, Shukla D, et al. Accuracy of laparoscopic diagnosis of endometriosis. JSLS. 2003;7:15-18.
11. Howard FM, El-Minawi AM, Li R-Z. Endometriosis and endosalpingiosis. In: Howard FM, Perry CP, Carter JE, et al, eds. Pelvic Pain Diagnosis & Management. Philadelphia, PA: Lippincott Williams & Wilkins; 2000:125-149.
12. Summitt RL. Urogynecologic causes of chronic pelvic pain. Obstet Gynecol Clin North Am. 1993;20:685-698.
13. Ramahi AJ, Richardson DA. A practical approach to the painful bladder syndrome. J Reprod Med. 1990;35:805-809.
14. Parsons CL. Interstitial cystitis: what options? Contemp Ob Gyn. 1992;37:23-28.
15. Howard FM. Chronic pelvic pain. Obstet Gynecol. 2003;101:594-611.
16. Parsons CL, Stanford EJ, Kahn BS, Sand PK. Tools for diagnosis and treatment. Female Patient. 2002;May(suppl):12-17.
17. Parsons CL, Dell J, Stanford EJ, et al. Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecologic cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology. 2002;60:573-578.
18. Parsons CL, Zupkas P, Parsons JK. Intravesical potassium sensitivity in patients with interstitial cystitis and urethral syndrome. Urology. 2001;57:428-433.
19. Hanno PM, Landis JR, Matthews-Cook Y, Kusek J, Nyberg LJ and the Interstitial Cystitis Database Study Group. The diagnosis of interstitial cystitis revisited: lessons learned from the National Institutes of Health Interstitial Cystitis Database study. J Urol. 1999;161:553-557.
20. Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis. National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol. 1988;140:203-206.
21. Sant GR. Etiology, pathogenesis, and diagnosis of interstitial cystitis. Rev Urol. 2002;4(suppl 1):S9-S15.
22. Waxman JA, Sulak PJ, Kuehl TJ. Cystoscopic findings consistent with interstitial cystitis in normal women undergoing tubal ligation. J Urol. 1998;160:1663-1667.
23. Erickson DR. Interstitial cystitis: update on etiologies and therapeutic options. J Womens Health Gend Based Med. 1999;8:745-758.
24. Parsons CL, Greenberger M, Gabal L, Bidair M, Barme G. The role of urinary potassium in the pathogenesis and diagnosis of interstitial cystitis. J Urol. 1998;159:1862-1867.
25. Parsons CL. Evidence-based strategies for recognizing and managing IC. Contemp Urol. 2003;15:22-35.
26. Chung MK, Chung RP, Gordon D. Interstitial cystitis and endometriosis in patients with chronic pelvic pain: the “evil twins” syndrome. JSLS. 2005;9:25-29.
27. Paulson JD, Delgado M. Chronic Pelvic Pain: the occurrence of interstitial cystitis in a gynecological population. JSLS. 2005;9:426-430.
28. Winkel CA. Combined medical and surgical treatment of women with endometriosis. Clin Obstet Gynecol. 1999;42:645-663.
29. Gambone JC, Mittman BS, Munro MG, Scialli AR, Winkel CA and the Chronic Pelvic Pain/Endometriosis Working Group. Consensus statement for the management of chronic pelvic pain and endometriosis: proceedings of an expert-panel consensus process. Fertil Steril. 2002;78:961-972.
30. Mahmood TA, Templeton A. The impact of treatment on the natural history of endometriosis. Hum Reprod. 1990;5:965-970.
31. Moen MH. Is mild endometriosis a disease? Why do women develop endometriosis and why is it diagnosed? Hum Reprod. 1995;10:8-11.
32. Williams TJ, Pratt JH. Endometriosis in 1,000 consecutive celiotomies: incidence and management. Am J Obstet Gynecol. 1977;129:245-250.
33. Westney OL, Amundsen CL, McGuire EJ. Bladder endometriosis: conservative management. J Urol. 2000;163:1814-1817.
34. Chung MK. Interstitial cystitis in persistent post hysterectomy chronic pelvic pain. JSLS. 2004;8:329-333.
35. Clemons JL, Arya LA, Myers DL. Diagnosing interstitial cystitis in women with chronic pelvic pain. Obstet Gynecol. 2002;100:337-341.
36. Parsons CL, Bullen M, Kahn BS, Stanford EJ, Willems JJ. Gynecologic presentation of interstitial cystitis as detected by intravesical potassium sensitivity. Obstet Gynecol. 2001;98:127-132.
37. Seitzinger MR. Correlation of endometriosis with interstitial cystitis. J Am Assoc Gynecol Laparosc. 2000;7(suppl):S57.
38. Lentz GM, Bavendam T, Stenchever MA, Miller JL, Smalldridge J. Hormonal manipulation in women with chronic, cyclic irritable bladder symptoms and pelvic pain. Am J Obstet Gynecol. 2002;186:1268-1273.
39. Chung MK, Medina RJ, Shriver JS. Anesthetic and Elmiron Rescue Therapy in treatment of chronic pelvic pain. Paper presented at: 14th International Congress and Endo Expo 2005, SLS Annual Meeting; September 14–17, 2005; San Diego, CA.
40. Mattox JH, Parsons CL, Sand PK. Chronic pelvic pain of bladder origin. Female Patient. 2002;May(suppl):3.
41. Jones CA, Nyberg L. Epidemiology of interstitial cystitis. Urology. 1997;49(suppl 5A):2-9.
42. Alagiri M, Chottiner S, Ratner V, Slade D, Hanno PM. Interstitial cystitis: unexplained associations with other chronic disease and pain syndromes. Urology. 1997;49:52-57.
43. Giamberardino MA. Recent and forgotten aspects of visceral pain. Eur J Pain. 1999;3:77-92.
44. Ness TJ, Gebhart GF. Visceral pain: a review of experimental studies. Pain. 1990;41:167-234.
45. Mayer EA, Gebhart GF. Functional bowel disorders and the visceral hyperalgesia hypothesis. In: Mayer EA, Raybould HE, eds. Basic and Clinical Aspects of Chronic Abdominal Pain. Amsterdam, the Netherlands: Elsevier Science Publishers BV; 1993:3-28.
46. Cervero F. Sensory innervation of the viscera: peripheral basis of visceral pain. Physiol Rev. 1994;74:95-138.
47. Wesselmann U. Interstitial cystitis: a chronic visceral pain syndrome. Urology. 2001;57(suppl 6A):32-39.
48. Markenson JA. Mechanisms of chronic pain. Am J Med. 1996;101(suppl 1A):6S-18S.
49. Giamberardino MA, De Laurentis S, Affaitati G, Lerza R, Lapenna D, Vecchiet L. Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women. Neurosci Lett. 2001;304:61-64.
50. Giamberardino MA, Berkley KJ, Affaitati G, et al. Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats. Pain. 2002;95:247-257.
51. Brookoff D. Chronic pain: 1. A new disease? Hosp Pract. 2000;35:45-59.
52. Peters AAW, van Dorst E, Jellis B, van Zuuren E, Hermans J, Trimbos JB. A randomized clinical trial to compare two different approaches in women with chronic pelvic pain. Obstet Gynecol. 1991;77:740-744.
53. Flor H, Fydrich T, Turk DC. Efficacy of multidisciplinary pain treatment centers: a meta-analytic review. Pain. 1992;49:221-230.
54. Maruta T, Swanson DW, McHardy MJ. Three year follow-up of patients with chronic pain who were treated in a multidisciplinary pain management center. Pain. 1990;41:47-53.
55. Milburn A, Reiter RC, Rhomberg AT. Multidisciplinary approach to chronic pelvic pain. Obstet Gynecol Clin North Am. 1993;20:643-661.
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