Bladder epithelial cells from patients with interstitial cystitis produce an inhibitor of heparin-binding epidermal growth factor-like growth factor production

PURPOSE: The etiology of interstitial cystitis is unknown. We previously identified an interstitial cystitis urine factor, antiproliferative factor, that inhibits proliferation of bladder epithelial cells in vitro and complex changes in epithelial growth factor levels, including profound decreases in heparin-binding epidermal growth factor-like growth factor (HB-EGF). Bladder and renal pelvic catheterization of patients with interstitial cystitis indicated that the antiproliferative factor is made and/or activated in the distal ureter or bladder. Therefore, we determined whether bladder epithelial cells from interstitial cystitis cases produced the antiproliferative factor and whether purified antiproliferative factor could alter production of growth factors known to be abnormal in interstitial cystitis. MATERIALS AND METHODS: Antiproliferative factor activity was determined by 3H-thymidine incorporation into primary bladder epithelial cells. The antiproliferative factor was purified by size fractionation followed by sequential chromatography involving ion exchange, hydrophobic interaction and high performance liquid chromatography. HB-EGF, epidermal growth factor, insulin-like growth factor and insulin-like growth factor binding protein 3 levels were determined by enzyme-linked immunosorbent assay. RESULTS: Bladder epithelial cells from patients with interstitial cystitis produced a single antiproliferative factor with the same purification profile as that purified from interstitial cystitis urine. Purified antiproliferative factor specifically inhibited HB-EGF production by bladder epithelial cells in vitro, and the effect of interstitial cystitis urine or purified antiproliferative factor on bladder cell proliferation was inhibited by recombinant human HB-EGF in a dose dependent manner. Similar to urine HB-EGF, serum HB-EGF was also significantly lower in interstitial cystitis cases than in controls. CONCLUSIONS: Bladder epithelial abnormalities in interstitial cystitis may be caused by a negative autocrine growth factor that inhibits cell proliferation by down-regulating HB-EGF production. Furthermore, decreased levels of urine and serum HB-EGF indicate that interstitial cystitis may be a urinary tract manifestation of a systemic disorder.     

Abnormal urinary potassium metabolism in patients with interstitial cystitis

PURPOSE: If most patients with interstitial cystitis (IC) have epithelial leakage allowing urinary K to penetrate the interstitium and provoke symptoms, urinary K should be lower in untreated patients than in healthy subjects and it should increase with successful heparinoid treatment. This study tested these hypotheses. MATERIALS AND METHODS: Na, K and creatinine (Cr) were determined in spot urine samples from new, symptomatic, untreated patients with IC meeting all National Institute of Diabetes and Digestive and Kidney Diseases clinical diagnostic criteria, returning patients with IC reporting 50% or greater symptom improvement after 4 or greater months of oral heparinoid therapy and control subjects, and in 24-hour urine samples from new untreated patients and controls. RESULTS: In spot urine specimens of 37 new patients with IC K-to-Cr ratios were significantly lower than in 18 controls (0.51 vs 0.88 mg/mg Cr, p = 0.001). A total of 50 successfully treated patients with IC had significantly higher K-to-Cr ratios than those in 37 new patients (0.66 vs 0.51 mg/mg Cr, p = 0.025). Na-to-Cr ratios in the 3 groups were not significantly different. In 24-hour urine specimens 30 new patients had lower average K (31.0 vs 46.2 mEq/l, p = 0.01) and lower K-to-Cr ratios (0.43 vs 0.52 mg K/mg Cr, p = 0.01) than in 47 controls, while Na was not significantly different. CONCLUSIONS: Our finding of lower urinary K in new, untreated patients supports the concept of abnormal epithelial permeability and K absorption in IC. Higher urinary K in successfully treated vs untreated patients may reflect decreasing urinary K absorption due to mucosal repair and a resulting decrease in epithelial permeability. K/mg Cr appears accurate for normalizing urinary K.     

Psychophysical evidence of hypersensitivity in subjects with interstitial cystitis

PURPOSE: We quantified differences in somatic and visceral sensation in healthy subjects and subjects with interstitial cystitis (IC). MATERIALS AND METHODS: A total of 13 subjects with IC and 13 healthy subjects answered psychological questionnaires and underwent psychophysical testing of thermal and pressure thresholds for sensation as well as the ischemic forearm test of pain tolerance. A subset of subjects also underwent bladder sensory testing with the determination of 3 consecutive cystometrograms. Ratings of intensity and unpleasantness were determined. RESULTS: Subjects with IC were significantly more sensitive to deep tissue measures of sensation related to pressure, ischemia and bladder than healthy subjects. Cutaneous thermal pain measures were similar in the 2 groups. Psychological measures indicated higher reactivity in subjects with IC. CONCLUSIONS: Similar to other visceral pain disorders, such as irritable bowel syndrome, hypersensitivity to somatic stimuli was noted in subjects with IC. This suggests altered central mechanisms in the processing of sensory events from the bladder.     

Long-term results of amitriptyline treatment for interstitial cystitis

Purpose:

We performed a prospective, open label study to examine the safety and efficacy of the long-term administration of the tricyclic antidepressant amitriptyline in patients with interstitial cystitis (IC).

Materials and Methods:

A total of 94 patients were stratified into 2 groups, namely a National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) group of those who fulfilled NIDDK criteria for IC and a nonNIDDK group of those who presented with characteristic IC symptoms but met at least 1 NIDDK exclusion criterion. Amitriptyline was received strictly at bedtime following an established self-titration protocol without a limitation of the maximum daily dose. Patients reporting improvement in a global response assessment questionnaire were considered treatment responders. Further efficacy measures were changes in pain and urgency, functional bladder capacity and frequency. Changes in the O′Leary-Sant IC index and rating of overall satisfaction with the therapeutic outcome were also reported.

Results:

Mean study followup ± SD was 19.0 ± 12.5 months. The response rate was 64% (60 patients). The overall mean dose was 55 mg (range 12.5 to 150). Side effects occurred in 79 patients (84%), including dry mouth in 79% and weight gain in 59%. Patient overall satisfaction with the therapeutic result was excellent or good in 43 (46%). The dropout rate was 31% (29 patients) after a mean treatment period of 6 weeks at a mean dose of 70 mg. Nonresponse to treatment was the primary reason for dropout in all cases, while side effects contributed to dropout in 25 (86%). Improvement in the various IC symptoms was statistically significant compared with baseline.

Conclusions:

Long-term administration of amitriptyline is a feasible, safe and effective treatment for IC, provided that the drug is used judiciously to minimize adverse effects. The therapeutic response to amitriptyline was uniformly observed in patients fulfilling NIDDK criteria and in those with the pure clinical diagnosis of IC.     

Menstrual cycle affects bladder pain sensation in subjects with interstitial cystitis

PURPOSE: Using psychophysical methods we compared the effect of the menstrual cycle on bladder sensation in subjects with the diagnosis of interstitial cystitis (IC) and in controls. MATERIALS AND METHODS: Female participants with normal menstrual cycles, including 7 with IC and 8 healthy controls, were recruited into this study. They completed daily diaries related to bladder pain and other body pain, and tracked daily micturition frequency. In a subset formal psychophysical testing of thermal and ischemic pain was performed at 2 times of the menstrual cycle, corresponding to the luteal and follicular phases. Cystometrograms were performed at the same time. RESULTS: Subjects with IC had higher pain scores and frequency than controls throughout the entire menstrual cycle. Pain scores were highest in the perimenstrual period in subjects with IC and controls. Micturition frequency was highest in the perimenstrual period in subjects with IC. Cystometric evaluation of a first need to void and the evocation of bladder pain demonstrated that lower intravesical volume and pressure were necessary to evoke bladder pain during the follicular period than during the luteal period in subjects with IC, although there was no effect on the first need to void. CONCLUSIONS: These findings are consistent with clinical lore that suggests a perimenstrual flare in pain in subjects with IC. To our knowledge it also demonstrates for the first time a menstrual cycle effect on bladder sensory function in subjects with IC. This suggests a potential role of gonadal hormones on bladder sensory processing and, therefore, a potential role for hormonal modulation as a therapeutic modality in this patient population.     

Pilot study of sequential oral antibiotics for the treatment of interstitial cystitis

PURPOSE: Interstitial cystitis is a chronic disease of unknown etiology characterized by bladder pain, urgency and frequency. Although a single microbe has not been implicated as a cause of interstitial cystitis, several groups noted various organisms in the urine of some women with interstitial cystitis and some patients reported that antibiotics decrease symptoms. Consequently we performed a prospective, randomized, double-blinded, placebo controlled pilot study of sequential oral antibiotics. MATERIALS AND METHODS: We randomized 50 patients with interstitial cystitis to receive 18 weeks of placebo or antibiotics, including rifampin plus a sequence of doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin and ciprofloxacin for 3 weeks each. RESULTS: Intent to treat analysis demonstrated that 12 of 25 patients (48%) in the antibiotic and 6 of 25 (24%) in the placebo group reported overall improvement (p = 0.14), while 10 and 5, respectively, noticed improvement in pain and urgency (p = 0.22). In the antibiotic group 20 participants (80%) had adverse effects compared with 10 (40%) in the placebo group (p = 0.009). CONCLUSIONS: Our findings suggest that these antibiotics alone or in combination may sometimes be associated with decreased symptoms in some patients but they do not represent a major advance in therapy for interstitial cystitis.     

Interstitial cystitis: bladder training with intravesical oxybutynin

PURPOSE: We assess the efficacy of intravesical administration of oxybutynin chloride in patients with interstitial cystitis. MATERIALS AND METHODS: The study included 36 women with a mean age of 45 years with a diagnosis of interstitial cystitis. Patients were treated with gradual intravesical instillation of saline oxybutynin solution (oxybutynin group) or gradual filling of simple saline (control group). Evaluation parameters consisted of symptom problem index, voids per day, volume per void, functional bladder capacity, volume at first sensation, cystometric bladder capacity and cystometric volume at first sensation. RESULTS: Statistically significant improvement of all evaluated parameters was found in both groups. When comparing the outcomes statistically significant improvement of parameters favored the oxybutynin group. CONCLUSIONS: Bladder training alone produces a satisfactory result by gradually expanding the bladder, and an additional statistically significant improvement is evident with intravesical oxybutynin.     

The association of elevated urinary total to sulfated glycosaminoglycan ratio and high molecular mass hyaluronic acid with interstitial cystitis

PURPOSE: A decrease in the glycosaminoglycan (GAG) layer on the urothelium is believed to be one of the possible causes of interstitial cystitis. Consequently, GAG-like substances and hyaluronic acid (HA) have been prescribed for treating this condition. To delineate the possible role of GAG and HA in the interstitial cystitis disease process, we compared the urinary levels of total GAGs (sulfated + non-sulfated), sulfated GAGs and HA in interstitial cystitis patients and normal controls. We also examined different HA species present in the urine of interstitial cystitis patients. MATERIALS AND METHODS: The total GAG and sulfated GAG levels in urine specimens of normal individuals (n = 20) and interstitial cystitis patients (n = 25) were determined by utilizing the carbazole reaction assay and the Farndale method, respectively, and were expressed as microg./mg. creatinine. Urinary HA levels were measured by applying the HA test and were expressed as ng./mg. creatinine. Gel filtration column chromatography was used to examine the profile of urinary GAGs and HA species. RESULTS: Total urinary GAGs were 2.5 to 4-fold elevated in interstitial cystitis patients with moderate to severe symptoms (Group 2; 76.2 +/- 24.8) when compared with those in normal individuals (19.9 +/- 2.5) and patients with mild symptoms (Group 1; 30.4 +/- 5.1) (p <0.001). Three urinary GAG peaks were detected in both normal and interstitial patients. However, each GAG peak from interstitial cystitis patient urine was 3 to 5-fold higher than that from normal patient urine. The sulfated GAG levels, however, remained unchanged among normal individuals (1.4 +/- 0.22), Group 1 (2.2 +/- 0.96) and Group 2 (1.6 +/- 0.38) patients (p >0.05). Consequently, the ratio of total GAGs to sulfated GAGs was elevated 3 to 3.5-fold in Group 2 patients (49.9 +/- 13.9) in comparison to that in normal individuals (16.7 +/- 2.5) and group 1 patients (14.4 +/- 4.6) (p <0.001). Urinary HA levels were marginally elevated in Group 2 patients (821. 4 +/- 247.9) when compared with those in the normal group (337.3 +/- 106.1) and Group 1 patients (540.9 +/- 166.5). In addition, a distinct high molecular mass HA species was present only in Group 2 patients. CONCLUSIONS: The increased ratio of total GAGs to sulfated GAGs and marginally elevated HA levels in urine indicate that the GAG layer is altered in interstitial cystitis patients. However, these results are in contrast to the accepted concept that a reduction in urothelial GAGs causes interstitial cystitis. The high molecular mass HA species detected in patients with severe symptoms may play a role in the pathophysiology of this disease.     

Absence of bacterial and viral DNA in bladder biopsies from patients with interstitial cystitis/chronic pelvic pain syndrome

PURPOSE: We examined bladder biopsies from women with interstitial cystitis/chronic pelvic pain syndrome (IC/CPPS) for the presence of bacterial and viral DNA sequences using polymerase chain reaction. MATERIALS AND METHODS: Bladder biopsies were taken during cystoscopy from patients under investigation for IC/CPPS, or controls undergoing colposuspension for stress incontinence. Biopsies were snap frozen to -70C. After DNA extraction, polymerase chain reaction (PCR) using specific primers for the hypoxanthine-guanine phosphoribosyl transferase gene confirmed the presence of human DNA. PCR for bacterial and viral gene sequences was performed using specific primers. Positive reactions were repeated to confirm the signal. RESULTS: A total of 92 patients with IC/CPPS (12 who met the National Institute of Diabetes and Digestive and Kidney Diseases criteria and 80 who did not) and 91 controls were recruited. PCR for hypoxanthine-guanine phosphoribosyl transferase gene was positive in all samples. PCR for the 16S ribosomal RNA gene, as well as for adenovirus, cytomegalovirus, herpes simplex virus types I and II, human papillomavirus (all subtypes) and Chlamydia trachomatis were negative in all samples. CONCLUSIONS: IC/CPPS is not associated with persistence of viral and bacterial DNA in the bladder. A chronic infective etiology for the condition is excluded by these findings.     

A randomized controlled trial of intravesical bacillus calmette-guerin for treatment refractory interstitial cystitis

PURPOSE: We compared intravesical bacillus Calmette-Guerin (BCG) to placebo instillations in patients with treatment refractory interstitial cystitis (IC). MATERIALS AND METHODS: Subjects who met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC, and reported at least moderate pain and frequency for a minimum of 6 months before study entry, were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34. Secondary outcomes included a 24-hour voiding diary, pain, urgency, validated IC symptom indexes and adverse events. The target sample size was 260 participants, designed to detect a difference in response rates between placebo and BCG of 30% and 50%, respectively. RESULTS: A total of 265 participants were randomized and 17 (6%) patients withdrew from study. The response rates for the primary outcome were 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes, some more so with BCG, but these differences were of borderline statistical significance. Although a large number of adverse events were reported in the BCG arm, there was no statistically significant difference between the treatment arms in overall adverse event rates. CONCLUSIONS: Although the BCG safety profile was acceptable, the response rate for the primary outcome was low. Effective medical treatment for patients with moderate to severe interstitial cystitis remains elusive.     

Bladder necrosis following hydrodistention in patients with interstitial cystitis

PURPOSE: Bladder hydrodistention is used to diagnose and treat patients with interstitial cystitis. This procedure has been shown to have minimal morbidity and provide symptomatic relief in a subset of patients with interstitial cystitis. We report our experience with almost total bladder necrosis after hydrodistention at 2 institutions. To our knowledge this rare complication has not been previously reported in the literature. We also reviewed the literature regarding complications of hydrodistention and discuss their possible etiology. MATERIALS AND METHODS: We report 3 cases of bladder necrosis after therapeutic hydrodistention for interstitial cystitis at 2 institutions. All records were reviewed, and the clinical presentation, findings and treatments are discussed. A literature review was performed to evaluate the effectiveness and complications of hydrodistention for interstitial cystitis. RESULTS: There were 2 female and 1 male patient between ages 29 and 46. All patients had a previous diagnosis of interstitial cystitis and had been previously treated with hydrodistention. All patients presented with severe abdominal pain and had necrosis of the entire bladder wall with sparing of the trigone. Two patients were treated with supratrigonal cystectomy. A review of the literature revealed little data on the effectiveness of hydrodistention for interstitial cystitis. CONCLUSIONS: Vesical necrosis is a rare but devastating complication of hydrodistention. It can occur in young patients in the absence of a contracted bladder and it usually presents as severe postoperative abdominal pain. At exploration bladder necrosis with sparing of the trigone was observed. All patients required enterocystoplasty.     

Recruitment, distribution and phenotypes of mast cells in interstitial cystitis

PURPOSE: Interstitial cystitis (IC) is a chronic disabling condition of unknown etiology. One of its major characteristics is an increase in mast cells (MC) showing signs of activation. It has been suggested that the proteinase content defines two MC types: MC(TC), containing chymase and tryptase, and MC(T), which contains tryptase but lacks chymase. Here, we investigated the MC distribution and the MC proteinase expression in IC together with the tissue expression of the major MC growth factors, stem cell factor (SCF) and interleukin-6 (IL-6). MATERIALS AND METHODS: MC were enumerated in bladder specimens from patients with classic IC, nonulcer IC and controls. MC were visualized in terms of metachromasia, reflecting glycosaminoglycan content, and immunohistochemically, visualizing tryptase, chymase and IL-6 as well as the surface markers CD117 and SCF. RESULTS: Classic IC displayed a 6 to 10-fold increase of MC identified by proteinase content while in nonulcer IC there were twice as many MC as in controls. In contrast to nonulcer IC and controls, classic IC displayed an abundance of epithelial MC. Fewer CD117+ than proteinase+ MC were detected in IC but not in controls. Classic IC coexpressed SCF and IL-6 in the epithelium and displayed numerous SCF and IL-6+ cells in the mucosa and detrusor muscle, many of which were MC. CONCLUSIONS: Redistribution of MC into the epithelium and a high bladder wall MC density distinguish classic IC from nonulcer IC. Our findings suggest an SCF/IL-6-driven MC response in IC. They also indicate a downregulation of the SCF receptor in IC.     

Urinary nerve growth factor level is increased in patients with interstitial cystitis/bladder pain syndrome and decreased in responders to treatment

OBJECTIVE

To measure urinary nerve growth factor (NGF) levels in patients with interstitial cystitis/bladder pain syndrome (IC/BPS), and to evaluate the role of urinary NGF in predicting the response to treatment, as the clinical diagnosis of IC/BPS is based on subjective symptoms and recent investigations suggest that urinary NGF is increased in patients with IC/BPS.

PATIENTS, SUBJECTS AND METHODS

Urine samples from 122 patients with IC/BPS and 28 normal controls were measured for NGF levels using an enzyme‐linked immunosorbent assay. The diagnosis of IC/BPS was based on bladder pain symptoms and the results of cystoscopic hydrodistension. Patients’ perception of pain was assessed by a visual analogue scale (VAS) and a ‘global’ response assessment after treatment. Urinary NGF levels were further normalized to the concentration of urinary creatinine (NGF/Cr) and compared between control and IC/BPS subgroups at diagnosis and after treatment.

RESULTS

Urinary NGF/Cr levels were very low when the bladder was not distended and significantly elevated with a full bladder in patients with IC/BPS. However, urinary NGF/Cr levels were not correlated with VAS scores or cystometric bladder capacity at diagnosis, or maximum bladder capacity during hydrodistension. Patients who responded to treatment and had an improvement in VAS pain score of ≥2 had significantly lower NGF/Cr levels than nonresponders who had a VAS improvement of <2.

CONCLUSIONS

Patients with IC/BPS had greater urinary NGF/Cr levels than controls. A decrease of urinary NGF level was associated with greater pain reduction and a successful response, suggesting that urinary NGF levels can be a useful biomarker for detecting the severity of the bladder condition in patients with IC/BPS.     

Possible mechanisms inducing glomerulations in interstitial cystitis: relationship between endoscopic findings and expression of angiogenic growth factors

PURPOSE: Glomerulation has been one of the requisite criteria for the diagnosis of interstitial cystitis (IC) but the mechanisms for glomerulation remain unclear. Therefore, we investigated the relationship between the cystoscopic findings of vascular events and the expression of angiogenic growth factors in IC bladders to identify the possible mechanisms inducing glomerulations in IC. MATERIALS AND METHODS: In 45 patients suspected of having IC continuous, fixed point cystoscopic observation was performed during hydrodistention using spinal anesthesia. Bladder biopsies were performed in these cases and in an additional 5 asymptomatic cases. Thereafter, the expression of platelet derived endothelial cell growth factor/thymidine phosphorylase (PDECGF/TP) was measured by enzyme-linked immunosorbent assay. Immunohistochemical staining for PDECGF/TP and vascular endothelial growth factor was also performed. RESULTS: Of 45 symptomatic patients 38 had glomerulations during cystoscopic examination. In these patients during hydrodistention the blood flow in bladder wall vessels was interrupted by whitish fibrous bundles. Thereafter petechial bleeding began from capillaries distal to obstructed vessels during bladder emptying. PDECGF/TP expression in patients with glomerulation was significantly higher than in symptomatic patients without glomerulation or asymptomatic patients (p < 0.001). In patients with glomerulations a high positive rate for PDECGF/TP (97.4%) and vascular endothelial growth factor (68.4%) staining was observed, while no positive staining was found in asymptomatic patients. CONCLUSIONS: Glomerulations during hydrodistention are highly associated with the over expression of angiogenic growth factors in the bladder. Thus, it seems likely that neovascularization promoted by angiogenic growth factors has an important role in the pathogenesis of IC, inducing glomerulations during hydrodistension.     

Heparin-binding epidermal growth factor-like growth factor functionally antagonizes interstitial cystitis antiproliferative factor via mitogen-activated protein kinase pathway activation

OBJECTIVE

To delineate the mechanism underlying the potential functional relationship between interstitial cystitis antiproliferative factor (APF) and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), as APF has previously been shown to decrease the proliferation rate of normal bladder epithelial cells and the amount of HB‐EGF produced by these cells.

MATERIALS AND METHODS

APF‐responsive T24 transitional carcinoma bladder cells were treated with high‐pressure liquid chromatography‐purified native APF with or without HB‐EGF to determine the involvement of signalling pathways and proliferation by Western blot analysis, p38 mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (Erk)/MAPK assays, and 3‐(4,5‐dimethylthiazolyl‐2)‐2,5‐diphenyltetrazolium bromide (MTT) assay.

RESULTS

Cyclic stretch induced the secretion of HB‐EGF from T24 cells overexpressing the HB‐EGF precursor, resulting in enhanced proliferation. T24 cells treated with APF had increased p38MAPK activity and suppressed cell growth, events that were both reversed by treatment with a p38MAPK‐selective inhibitor. Activation of Erk/MAPK by HB‐EGF was inhibited by APF, and APF did not stimulate p38MAPK in the presence of soluble HB‐EGF or when cells overexpressed constitutively secreted HB‐EGF. Lastly, APF inhibitory effects on cell growth were attenuated by HB‐EGF.

CONCLUSIONS

These results indicate that HB‐EGF and APF are functionally antagonistic and signal through parallel MAPK signalling pathways in bladder cells.     

Diurnal cortisol variations and symptoms in patients with interstitial cystitis

PURPOSE: Little attention has focused on systemic factors that may allow a state of chronic bladder inflammation to be established and maintained in interstitial cystitis cases. Abnormalities of the hypothalamic-pituitary-adrenal feedback system result in poorer regulation of the inflammatory response and are present in many chronic inflammatory and pain conditions, of which some have high co-morbidity with interstitial cystitis. MATERIALS AND METHODS: A total of 48 patients with interstitial cystitis and 35 healthy, age matched controls collected 24-hour urine samples and 3 days of salivary samples at 7 to 8 a.m., 4 to 5 p.m. and 8 to 9 p.m. for cortisol analysis. In addition, they completed a concurrent symptom questionnaire. Prospective symptom diaries also were completed in the month before sampling. RESULTS: Mean urinary or salivary cortisol did not differ in patients and controls. However, patients with interstitial cystitis and higher morning cortisol had significantly less pain and urgency, while those with higher urinary free cortisol reported less overall symptomatology (p <0.05). Relationships with morning cortisol were also observed when controlling for co-morbid conditions known to be affected by the hypothalamic-pituitary-adrenal axis, such as fibromyalgia, chronic fatigue and rheumatoid arthritis. Patients with morning cortisol less than 12.5 nmol./l. were 12.8 times more likely to report high urinary urgency than those with values above this cutoff. CONCLUSIONS: These findings imply that regulation of the hypothalamic-pituitary-adrenal axis may be associated with interstitial cystitis symptomatology and there may be different diurnal hypothalamic-pituitary-adrenal patterns in patients with interstitial cystitis who do and do not have co-morbid conditions. These findings may have treatment implications for patients with interstitial cystitis who have early morning cortisol deficiencies.     

膀胱水扩张加肝素灌注治疗女性间质性膀胱炎10例报告

目的观察膀胱水扩张加肝素灌注治疗间质性膀胱炎（IC）的疗效。方法该组10例IC患者均为女性。平均年龄36岁。平均病程30个月。所有患者在麻醉下行膀胱镜检加水扩张,次日均使用肝素钠10^5u加入无菌生理盐水20mL膀胱灌注,完成治疗后以O’Leary-Sant间质性膀胱炎症状评分（ICSI）、每日排尿次数及最大膀胱容量作为疗效评判标准,观察治疗前后患者各项指标情况。结果10例患者按照疗程治疗后随访4-12个月,平均7.5个月,症状缓解4例,症状显著缓解或消失6例;O’Leary-Sant ICSI治疗前为（12.5±4.9）分,平均治疗7个月后降为（6.5±2.3）分（P〈0.01）;治疗前患者平均排尿次数为（14.9±2.6）次／d,完成治疗后患者排尿次数减少至（7.8±2.8）次／d（P〈0.01）;膀胱最大容量治疗前为（73±10）mL,治疗后为（260±56）mL（P〈0.01）。治疗期间发生轻微肉眼血尿2例。结论膀胱水扩张联合肝素膀胱灌注治疗可有效缓解间质性膀胱炎患者症状,提高生活质量,是一种有效的治疗方法。     

A comparison of multiple urine markers for interstitial cystitis

PURPOSE: We measured several urine markers in 24-hour specimens from patients with interstitial cystitis and healthy controls. For each marker we determined whether the urine level was significantly different in interstitial cystitis and control cases, and whether the marker level correlated with the symptom score. MATERIALS AND METHODS: Study participants included 36 female patients with interstitial cystitis and 36 age matched female volunteers. Multiple urine aliquots were obtained to measure the various markers. RESULTS: Certain markers were significantly increased in interstitial cystitis, including anti-proliferative factor, epidermal growth factor, insulin-like growth factor (IGF) binding protein-3 and interleukin (IL)-6. Markers significantly decreased in interstitial cystitis were heparin-binding epidermal growth factor-like growth factor, cyclic guanosine monophosphate and methylhistamine. Other markers were not significantly different in the interstitial cystitis and control groups, including total glycosaminoglycans, epitectin, hyaluronic acid, IL-8, IL-1 and nitrates plus nitrites. IGF-1 was undetectable in 24-hour urine samples but spot voided samples from the same interstitial cystitis population had IGF-1 levels similar to previously reported levels. The only significant association of marker with symptom score was a positive correlation of IL-6 with nocturia. For all markers the conclusions were the same whether the marker was normalized to creatinine or to 24 hours. CONCLUSIONS: This study confirmed several previously reported urine alterations in interstitial cystitis, including increased anti-proliferative factor, epidermal growth factor, IGF binding protein-3 and IL-6, and decreased heparin-binding epidermal growth factor-like growth factor and cyclic guanosine monophosphate. Of all markers studied anti-proliferative factor had the least overlap in the interstitial cystitis and control groups, and so it is the most likely candidate to become a diagnostic test.