Relationship of Sex and Diagnosis With Symptoms and Illness Impact in Urologic Chronic Pelvic Pain; A Mapp Network Analysis

ABSTRACT

Objective

To assess differences in clinical presentation and illness impact in men and women presenting with urologic chronic pelvic pain syndrome (UCPPS) and between men diagnosed with interstitial cystitis/bladder pain syndrome (IC/BPS) or chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Methods

356 men and 605 women from six sites across the United States were assessed using a comprehensive set of demographic, symptom, and illness impact measures. Multivariable regression analyses examined differences between men and women and between men previously diagnosed with CP/CPPS or IC/BPS. In a stepwise manner, analyses tested group differences, controlling for demographic variables including symptom duration and presence of bladder pain that varied with filling and voiding.

Results

Men diagnosed with IC/BPS had the most severe UCPPS symptoms, followed by women with IC/BPS, and then men with CP/CPPS only. While men and women showed similar patterns of symptoms across most of the variables, women had increased widespread non‐pelvic pain, greater pelvic floor tenderness on exam, and higher self‐reported sensory sensitivity compared to men. About 60% of men diagnosed with CP/CPPS only reported bladder symptoms of painful filling or relief with voiding.

Conclusions

A generally shared symptom pattern was found across men and women irrespective of diagnostic labels suggesting the use of key marker symptoms, such as severity of bladder symptoms and widespread pain, to better identify subgroups of UCPPS rather than diagnostic category. Women may have an increased likelihood of increased sensitivity and central sensitization than men, including those men with IC/BPS.

Trial Registration

ClinicalTrials.gov Identifier: NCT02514265 ‐ MAPP Research Network: Trans‐MAPP Study of Urologic Chronic Pelvic Pain: Symptom Patterns Study (SPS).

1. Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS) which can be diagnosed in both men and women is characterized by bladder pain or discomfort accompanied by urinary frequency and urgency. Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men is characterized primarily by pelvic area pain or discomfort [1]. While these two disorders are most often studied separately, they also share many overlapping features and are collectively referred to as urologic chronic pelvic pain syndrome (UCPPS) [1]. The Multi‐Disciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network established by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is a collaborative, multidisciplinary effort designed to identify key phenotypic and etiologic factors of these costly and difficult‐to‐treat disorders (https://www.mappnetwork.org). The MAPP Research Network carried out two large longitudinal studies of UCPPS, the Trans‐MAPP Epidemiology and Phenotyping Study (EPS) [2] and the Trans‐MAPP Symptom Patterns Study (SPS) [3]. A unique feature of the MAPP Network studies was the inclusion of the three diagnostic subgroups of UCPPS: Women with IC/BPS, men with CP/CPPS only, and men with IC/BPS (with or without CP/CPPS). This broad‐based recruitment allowed for a unique set of analyses that can address similarities and differences in clinical presentations, such as pain and urologic symptom profiles, between men and women and help separate diagnostic group differences from those related to sex as a biological variable (SBV).

Initial studies from the MAPP EP sample showed similar levels of pelvic pain severity in men and women with UCPPS, after adjustment for age, income, and symptom duration [4]. Higher levels of bladder‐focused symptoms including urgency, frequency and pain associated with bladder filling were reported in women compared to men, but the majority of men also reported these bladder‐focused symptoms. About 75% of men in this MAPP study sample reported pain during bladder filling and/or relieved by voiding although only 23% reported a prior diagnosis of IC/BPS [5]. Conclusions from these initial studies included the recognition that most men with a diagnosis of CP/CPPS have bladder focused symptoms in addition to pelvic pain and that the overlapping symptoms across men and women with UCPPS suggest at least some shared pathophysiology and, therefore, potential treatment targets [4, 6].

In addition, more frequent pain during bladder filling or voiding was associated with greater non‐pelvic pain, depression and lower quality of life in both men and women, independent of diagnosis [5]. Other non‐MAPP studies have found similar results comparing women with IC/BPS to men with IC/BPS [7, 8].

The present study capitalizes on the large sample (n = 961) that includes UCPPS participants from the MAPP EPS and SPS cohorts to address the following specific questions with implications for both clinical practice and future clinical trial targets and design: (1) Are there sex‐based differences in clinical presentation and co‐morbidities between men and women with UCPPS beyond those attributable to demographics and degree of bladder‐based symptoms, and (2) What is the extent of bladder‐based symptoms in men diagnosed as CP/CPPS compared to those with IC/BPS, that is, is there evidence for a distinct CP/CPPS phenotype in UCPPS? To empirically address these questions, we examined the independent association of MAPP study participants' sex and prior diagnosis with key clinical outcomes in areas of symptom severity, illness impact, mood, and cognition. In addition, we examined if the associations between sex and/or diagnosis and outcomes are moderated by the presence of a bladder symptom marker (pain during filling or relief with voiding).

2. Materials and Methods

2.1. Participants

The current analysis utilizes data from the baseline assessment of UCPPS participants enrolled in either the MAPP Network EPS or SPS. A number of participants were enrolled in both protocols, but for these only their EPS data was used. Recruitment, and inclusion and exclusion criteria were generally similar for the two studies and have been published [2, 3]. In brief, participants had to have a diagnosis of IC/BPS or CP/CPPS, pain severity of at least 1 on a 0–10 numerical rating scale (NRS), over age 18 years, and had UCPPS symptoms present the majority of the time during three of the previous 6 months. The combined sample was largely White and from urban or suburban areas. Recruitment was from both clinics and community advertisement, and income levels were diverse. Treatment history varied widely and both studies were prospective longitudinal studies of usual care, so no expectation of treatment effect detection was involved.

2.2. Measures

Following informed consent and enrollment, the assessment measures for this study were completed during a brief exam and via computer‐delivered questionnaires during a single baseline visit. Prior diagnosis of CP/CPPS and IC/BPS was determined by self‐report answers to; “Have you ever been diagnosed with Painful Bladder Syndrome (PBS)/Interstitial Cystitis (IC)” and for men only “Have you ever been diagnosed with Chronic Pelvic Pain Syndrome CPPS)/Chronic Prostatitis (CP)”. The study therefore included three distinct groups of participants, men with CP/CPPS only, men with IC/BPS with or without CP/CPPS, and women with IC/BPS. The presence of bladder‐based symptoms of pain during bladder filling or relief of pain with bladder emptying (pain of bladder origin) was determined from two separate questions on the Genitourinary Pain Index (GUPI) [9].

The clinical outcome measures used have all been described in previous MAPP Network publications [3, 10] and included: the AUA symptom index [11]; a 0–10 scale of average pelvic pain severity from the GUPI; UCPPS specific QOL from the GUPI QOL scale; the Urinary Symptom Severity (USS) composite scale of urinary frequency and urgency [12]; an indication of the most bothersome symptom over the past 2 weeks (Most Bothersome Symptom) classified into either urinary frequency or pelvic pain; presence of widespread pain from a CHOIR whole‐body map categorized into 12 possible regions [13]; presence of pelvic floor muscle tenderness from a standardized exam [14]; the Sensory Sensitivity subscale of the Complex Medical Symptom Index assessing sensitivity to exteroceptive (e.g., sound, light) stimuli [15]. Physical and Mental Well‐Being assessed using the SF‐12 [16], Sleep Disturbance and Fatigue using the PROMIS short form scales [17], Anxiety and Depression using the Hospital Anxiety and Depression scales [18]; and self‐reported cognitive difficulties on the five subscales of the Multiple Ability Self‐Report Questionnaire (MASQ) [19]. Current medication usage (Medication Type) was classified hierarchically (assigned 0–3) as none, peripheral medications only, some centrally‐acting (e.g., antidepressants), or opiates.

2.3. Statistical Analyses

The main variables of interest were sex (MAPP Network data only includes biological sex) and UCPPS diagnosis. Because women cannot have CP/CPPS, we combined sex and diagnosis to create a categorical variable with three groups: men with IC/BPS (with or without CP/CPPS), men with CP/CPPS only, and women with IC/BPS. Using men with IC/BPS as the reference level, we can then compare men with CP/CPPS only to the reference to examine the effect of IC diagnosis in males and can compare women with IC/BPS to the reference to assess the sex difference in subjects with IC. For brevity and clarity, the categorical variable described above, denoting sex and diagnosis categories, will be referred to as SxDx throughout the remainder of this paper.

Statistical analysis included descriptive statistics with corresponding statistical tests and multivariable regression analysis. Summary statistics of frequencies and percentages were generated for categorical variables, and mean, standard deviation, median, minimum, and maximum were calculated for continuous variables. Differences in variables between SxDx groups were assessed using either Chi‐squared or Fisher's exact tests for categorical variables, as appropriate, and one way ANOVA for continuous variables. Linear, binary logistic, and ordinal logistic regression models were used to assess continuous, binary, and ordinal outcome variables of interest, respectively. For each outcome variable, the following three‐step model approach was used: Model 1‐ SxDx only; Model 2 ‐ add demographic variables and symptom duration to model 1; and Model 3 ‐ add the combined pain with bladder filling or pain relief with bladder voiding variable (coded 0: Neither, 1: Either or Both) to model 2. p values of < 0.05 were considered statistically significant. All analysis was performed in R, version 4.3.1.

3. Results

3.1. Diagnostic Group Descriptives

Table 1 shows the breakdown of participants from the two MAPP Network studies and demographic and bladder symptom data for the three groups based on prior diagnosis. Means for all the variables examined are tabled in Supplementary Appendix 1. A total 59% of men diagnosed only with CP/CPPS reported painful filling or relief with voiding, while men and women with IC/BPS reported 87% and 83%, respectively. Similarly, 67% of men diagnosed only with CP/CPPS had AUA index scores in the moderate to severe range compared to 89% and 84% for men and women with IC/BPS, respectively.

Table 1.

Clinical descriptive variables.

	Males (IC+/−CP) (N = 93)	Males (CP Only) (N = 263)	Females (IC) (N = 605)	Overall (N = 961)	p value three groups	p value sex	p value diagnosis
Data source					< 0.001	0.133	0.192
MAPP I Epidemiology & Phenotyping Study (EPS)	44 (47.3%)	147 (55.9%)	233 (38.5%)	424 (44.1%)
MAPP II Symptom Patterns Study (SPS)	49 (52.7%)	116 (44.1%)	372 (61.5%)	537 (55.9%)
Age					< 0.001	0.006	0.795
Mean (SD)	46.9 (16.2)	46.4 (15.1)	41.9 (15.3)	43.6 (15.5)
Median [Min, Max]	44.3 [18.8, 80.0]	45.1 [19.2, 81.6]	39.1 [18.4, 79.9]	41.6 [18.4, 81.6]
Race					0.342	0.154	0.311
1: White	80 (86.0%)	232 (88.2%)	524 (86.6%)	836 (87.0%)
2: Black	8 (8.6%)	13 (4.9%)	29 (4.8%)	50 (5.2%)
3: Others	4 (4.3%)	17 (6.5%)	51 (8.4%)	72 (7.5%)
Missing	1 (1.1%)	1 (0.4%)	1 (0.2%)	3 (0.3%)
Education level attained					0.174	0.634	0.623
1: < College Degree	31 (33.3%)	74 (28.1%)	219 (36.2%)	324 (33.7%)
2: College Degree	36 (38.7%)	113 (43.0%)	244 (40.3%)	393 (40.9%)
3: Grad/Prof Degree	26 (28.0%)	76 (28.9%)	142 (23.5%)	244 (25.4%)
Education Level (1–3)					0.053	0.401	0.514
Mean (SD)	1.95 (0.785)	2.01 (0.757)	1.87 (0.763)	1.92 (0.765)
Median [Min, Max]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]
Family Income					< 0.001	0.017	0.191
1: < = $50K	24 (25.8%)	62 (23.6%)	232 (38.3%)	318 (33.1%)
2: > $50–$100K	38 (40.9%)	86 (32.7%)	173 (28.6%)	297 (30.9%)
3: > $100K	25 (26.9%)	96 (36.5%)	126 (20.8%)	247 (25.7%)
Missing	6 (6.5%)	19 (7.2%)	74 (12.2%)	99 (10.3%)
Family Income (1–3)					< 0.001	0.018	0.183
Mean (SD)	2.01 (0.755)	2.14 (0.794)	1.80 (0.797)	1.92 (0.806)
Median [Min, Max]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]	2.00 [1.00, 3.00]
Missing	6 (6.5%)	19 (7.2%)	74 (12.2%)	99 (10.3%)
UCPPS symptom duration					< 0.001	< 0.001	0.316
Mean (SD)	7.70 (7.94)	8.80 (11.5)	11.3 (11.6)	10.3 (11.4)
Median [Min, Max]	5.00 [0.800, 47.2]	3.00 [0, 54.1]	7.00 [0, 59.0]	6.00 [0, 59.0]
Missing	3 (3.2%)	1 (0.4%)	10 (1.7%)	14 (1.5%)
Pain w/filling or relief w/voiding					< 0.001	0.446	< 0.001
0: Neither pain w/fill nor pain relieved w/void	12 (12.9%)	102 (38.8%)	98 (16.2%)	212 (22.1%)
1: Either pain w/fill and/or pain relieved w/Void	79 (84.9%)	144 (54.8%)	478 (79.0%)	701 (72.9%)
Missing	2 (2.2%)	17 (6.5%)	29 (4.8%)	48 (5.0%)
AUA total score (0–35)					< 0.001	0.017	< 0.001
Mean (SD)	18.3 (8.03)	11.6 (7.42)	16.1 (8.29)	15.1 (8.34)
Median [Min, Max]	18.0 [1.00, 34.0]	10.0 [0, 30.0]	16.0 [0, 35.0]	15.0 [0, 35.0]
Missing	2 (2.2%)	16 (6.1%)	26 (4.3%)	44 (4.6%)
AUA total score (ordinal scale)					< 0.001	0.026	< 0.001
Mild (0–7)	11 (11.8%)	82 (31.2%)	98 (16.2%)	191 (19.9%)
Moderate (8–19)	36 (38.7%)	126 (47.9%)	285 (47.1%)	447 (46.5%)
Severe (19–35)	44 (47.3%)	39 (14.8%)	196 (32.4%)	279 (29.0%)
Missing	2 (2.2%)	16 (6.1%)	26 (4.3%)	44 (4.6%)

3.2. Sequential Regression Models

The complete 3 step model statistics and graphs for all 19 of the outcome variables are contained in Supplementary Appendix 2. Here we focus on effects of the fully controlled model which includes control for demographics, chronicity, and presence of bladder symptoms of pain with filling or relief with voiding. As an example, Figure 1 and Table 2 show the analysis for UCPPS‐specific QOL. The full model (Model 3) has significant effects for both sex (β = −0.97, CI = −1.62, −0.32, p = 0.003) and diagnosis in men (β = −0.71, CI = −1.41, −0.01, p = 0.045) with less QOL interference in women, and in men with CP/CPPS compared to men with IC/BPS. Also, the presence of pain of bladder origin was a strong predictor of QOL interference (β = 1.79, CI = 1.33, 2.25, p < 0.001).

Figure 1.

Forest plots of regression models for UCPPS quality of life scale.

Table 2.

Three model regression analysis of UCPPS Quality of Life.

Outcome: UCPPS‐specific QoL Score
Predictors	Model 1			Model 2			Model 3
	Estimates	CI	p	Estimates	CI	p	Estimates	CI	p
(Intercept)	8.42	7.83 to 9.01	< 0.001	10.69	9.65–11.73	< 0.001	8.93	7.82 to 10.03	< 0.001
Males (IC+/−CP)	Reference			Reference			Reference
Males (CP Only)	−1.33	−2.02 to −0.64	< 0.001	−1.21	−1.92 to −0.49	0.001	−0.71	−1.41 to −0.01	0.045
Females (IC)	−0.86	−1.50 to −0.22	0.008	−1.08	−1.75 to −0.41	0.002	−0.97	−1.62 to −0.32	0.003
Age				−0.02	−0.04 to −0.01	0.004	−0.02	−0.03 to −0.01	0.005
Black				1.02	0.18 to 1.86	0.018	1.14	0.33 to 1.95	0.006
Education level (1–3)				−0.34	−0.61 to −0.07	0.013	−0.35	−0.61 to −0.09	0.008
Family income (1–3)				−0.40	−0.66 to −0.14	0.003	−0.32	−0.58 to −0.07	0.014
UCPPS symptom duration				0.00	−0.01 to 0.02	0.641	0.01	−0.01 to 0.02	0.568
Pain w/filling or relief w/voiding							1.79	1.33 to 2.25	< 0.001
Observations	920			807			800
R2	0.016			0.067			0.131
AIC	4563.782			3972.581			3881.978

In Model 3, men with CP/CPPS only compared to men with IC/CPPS also showed lower pelvic pain severity (β = −0.74, CI = −1.27, 0.21, p = 0.007), higher SF‐12 physical well‐being (β = −2.63, CI = 0.23, 5.02, p < 0.031), had less urinary frequency and urgency symptom (USS) (β = −3.03, CI = −4.45, −1.62, p < 0.001), and had lower values on our medication hierarchy (OR = 0.47, CI = 0.30, 0.75, p = 0.001). No other variables showed a significant diagnosis effect for men. In summary, men diagnosed with CP/CPPS only had less severe urinary symptoms and better overall physical well‐being on a few measures, but on most measures were similar to men diagnosed with IC/CPPS.

After controlling for demographics, diagnosis, and presence of bladder‐based symptoms, women had lower levels of pelvic pain severity (β = −0.77, CI = −1.26, −0.27, p = 0.002) and better UCPPS specific QOL (β = −0.97, CI = −1.62, −0.32, p = 0.003) than men. In contrast, women had more widespread pain (β = 0.65, CI = 0.22, 1.08, p = 0.003), increased incidence of pelvic floor muscle tenderness (OR = 3.22, CI = 1.90, 5.47, p < 0.001), increased sensory sensitivity (β = 0.42, CI = 0.11, 0.72, p = 0.008) and greater difficulties with visual perception (β = 1.47, CI = 0.54, 2.40, p = 0.002). To illustrate these effects, Figure 2 shows the sex contribution for all three models from these analyses. All other variables tested showed no effects of sex (see Supplementary Appendix 2). In summary, although women had less severe UCPPS specific symptoms compared to men (primarily due to the higher UCPPS symptoms in the men with IC/BPS) they showed a pattern of increased sensory sensitivity and pain comorbidity. Notably, the bladder symptom variable of pain with filling and relief with voiding was significantly related to worse clinical outcomes across all the variables examined except for widespread pain, sensory sensitivity, and medication type.

Figure 2.

Forest plots of significant sex and diagnosis relationships with outcomes.

4. Discussion

This study represents the largest direct comparison of men and women with UCPPS, including men diagnosed with CP/CPPS and IC/BPS. Past studies have shown mixed results regarding the importance of sex as a biological variable in UCPPS. This is likely due to sample variability across the studies, especially in the male participants, and lack of consideration of degree of bladder‐based symptoms. Our results reveal men diagnosed with IC/BPS displayed the most severe UCPPS symptoms followed by the women diagnosed with IC/BPS, and men diagnosed with CP/CPPS only, respectively.

In our analyses controlling for demographic variables, male diagnostic category, and presence of pain of bladder origin there was an interesting pattern of sex differences including lower pelvic pain severity and better UCPPS QOL in women compared with men, primarily due to the increased severity in the men with IC/BPS. In contrast, women had increased widespread non‐pelvic pain, greater pelvic floor tenderness on exam, and higher self‐reported sensory sensitivity and visual perception difficulty.

Previous research has shown increased widespread symptoms in women compared to men both in chronic pain and general population samples. This may be in part due to altered pain processing as evidenced by increased central summation of experimental pain in women and differences in brain circuits engaged in pain modulation seen in neuroimaging [20, 21, 22, 23]. A more general difference in attention to bodily processes has also been reported between healthy men and women [24]. Likely multiple variables contribute to these sex differences in interceptive and sensory processing including genetic, hormonal, and gender related experiences [22]. Thus, while there are many similarities across men and women with UCPPS, including the shared importance of phenotype variables such as presence of widespread pain and degree of bladder symptoms, it is likely that women with IC/BPS will have an increased likelihood of increased sensitivity and central sensitization than men, including those men with IC/BPS.

As expected from prior studies, there was a significant prevalence of bladder‐based symptoms across all the groups, including those men previously diagnosed only with CP/CPPS. About 60% of men diagnosed with CP/CPPS only reported painful filling or relief with voiding and 67% had AUA scores in the moderate to severe range. These results demonstrate a substantial portion of men, perhaps the majority, identified in routine practice as having CP/CPPS, have similar bladder symptom profiles to those with IC/CPPS including women with IC/CPPS. The under‐recognition of bladder symptoms in men with CP/CPPS is reflected in the lack of bladder symptoms on the widely used Chronic Prostatitis Symptom Index (CPSI) [25] and many practitioners, especially those who primarily see men, may not inquire about bladder filling and voiding symptoms. The regression analyses also support the hypothesis that there is significant overlap between men diagnosed with CP/CPPS and IC/BPS, and perhaps these two entities are best seen not as two different diseases, but instead as a continuum of men with pelvic pain that vary in amounts of bladder‐based symptoms. Support for this hypothesis is also found in the strong association of presence of pain of bladder origin with most of clinical variables across all groups.

The findings of the present study have important implications for both clinical care and trial design for men and women suffering from UCPPS. The generally shared symptom patterns across men and women and diagnostic labels strongly support continued research on common underlying mechanisms for the broad range of patients under the umbrella of UCPPS. The results also clearly support the use of key marker symptoms to better identify subgroups of UCPPS, rather than diagnostic category. The presence of pain of bladder origin and the degree of widespread non‐pelvic symptoms are two easily identifiable markers of potentially important phenotypes within UCPPS across sexes and diagnoses. For future trials, the data also supports the inclusion of men and women and for men, both IC/BPS and CP/CPPS. Instead of a focus on diagnostic label, it will be important to target inclusion and exclusion criteria or stratification on key symptoms, such as presence of bladder pain and/or widespread symptoms to control for the heterogeneity of the UCPPS population.

This analysis does have some limitations. While diverse in many ways, including geographic, age, sex, and chronicity of UCPPS, participants were primarily recruited from major university affiliated clinics and urban communities. Education and income were included as covariates in the analyses, but further study of sex differences incorporating diversity and equity measures and a more diverse population would be very helpful to better understand how social and environment factors might impact the clinical presentation of UCPPS. Diagnoses for the men in the sample was based on self‐report and this may have impacted the results, although the levels pain and bladder symptoms are consistent with other reports of CP/CPPS and IC/BPS in men [4].

Ethics Statement

UCLA IRB#15‐000531 and all participants signed approved consent forms.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting information.

Supporting information.

Data Availability Statement

The data that support the findings of this study are openly available in the NIDDK Repository (https://repository.niddk.nih.gov/home).