Genital Pain and the Spectrum of Bladder-Related Symptoms: Findings from the Prevention of Lower Urinary Tract Symptoms Research Consortium RISE FOR HEALTH Study, USA.

A total of 2,713 women completed both baseline questionnaires and of those, 1,973 completed all questions used to classify participants according to our 3 pain categorizations (no pain, non-genital pain only, any genital pain) and those related to our bladder health scales and indices. As shown in Table 1 , 1,114 (56.5%) reported no pain in the last week . These participants had scores of less than 3 out of 7 for genital burning or pain outside of or during sexual intercourse over the past 4 weeks (i.e., no pain group). A total of 609 (30.9%) reported pain during the past week with low scores (less than 3 out of 7) for genital burning or pain (i.e., non-genital pain only group). Finally, 250 (12.7%) reported pain during the past seven days , with scores of 3 or higher for either genital burning or pain outside of or during sexual intercourse over the past 4 weeks (i.e., any genital pain group). Demographic characteristics of women across the three pain groups are also shown in Table 1 . Women with non-genital pain only were more likely to be older than those with no pain and those with any genital pain. Women with any genital pain were less educated, reported lower household income, and more commonly self-identified as Hispanic. No meaningful differences were observed by marital status, employment, household income, or geographical regions included within the RISE FOR HEALTH study population. Table 1 also includes covariates that we speculated might influence associations between genital pain and BH. Women with any genital pain were somewhat less likely to have given birth and were more likely to have sought routine medical care from multiple providers. In addition, women with genital pain were more likely to report other chronic overlapping pain conditions such as IC/BPS, IBS/Crohn’s, and other chronic pelvic pain or endometriosis. No meaningful differences were observed by cigarette smoking. Associations between pain and the Bladder Health Scales and Bladder Function Indices are shown in Figures 2A and 2B . Women who reported any genital pain had lower mean scores across all Bladder Health Scales and Bladder Function Indices after adjustment for age, education, race/ethnicity, marital status, parity, and income, compared to those with non-genital pain only, and substantially lower adjusted mean scores than those with no current pain. For each scale or index, there was a significant decreasing trend in scores from no pain to non-genital pain, to genital pain (p<0.001 for all scales and indices). The adjusted mean scores can be found in Supplemental Table 1 . We further assessed whether the differences in the Total Bladder Health Scale and Total Bladder Function Index were modified by age, a history of IC/BPS diagnosis or symptoms, the presence of IBS or Crohn’s disease and/or pelvic floor injuries, and a history of UTIs ( Figure 3 and Supplemental Table 2 ). For both Global BHS and Total BFI, adjusted mean scores for those with any genital pain were lower than those with non-genital pain only or no pain regardless of age with a significant test of trend observed. In those with no IC/BPS symptoms or diagnoses, IBS or Crohn’s disease, or pelvic floor injuries, we did not observe differences in scores between genital pain and non-genital pain or no pain. However, in those with one or more of these co-morbidities, the pattern of lower BHS and BFI scores in those with genital pain relative to those with either non-genital or no pain was present with significant test of trends across means. Finally, among women with no reported history of UTIs, those with any genital pain had lower BHS and BFI scores compared to those with non-genital or no pain (test of trend p-values 0.0014 and 0.0016, respectively), and the differences across means were substantially greater in those with a history of UTIs. Lastly, we assessed the differences among those with no pain, non-genital pain only, and any genital pain using the condition specific LURN SI instrument. As shown in Table 2 , a greater proportion of women with any genital pain reported urinary symptoms 50% or more of the time compared to women with no history of pain. These differences were present regardless of a history of UTIs. Also, women with any genital pain were more likely to express being at least very bothered with these symptoms, but clearly more so if they had a history of UTIs.

The RISE FOR HEALTH Study is a population-based cohort of community-dwelling adult women across multiple geographical regions of the United States. The study design has been described in detail elsewhere. 5 Briefly, potential study participants residing within the 50 counties including or surrounding the nine research centers (i.e., Emory University, Atlanta; University of Illinois, Chicago; Northwestern University, Chicago; University of Alabama at Birmingham; University of Michigan, Ann Arbor; University of Pennsylvania, Philadelphia; University of California—San Diego; Washington University in St. Louis; and Yale University, New Haven) were selected from a commercial marketing database containing demographic, residential and contact (i.e., email address) information for over 175 million individuals. The participant recruitment materials consisted of a mailed invitation packet followed by two mailed reminders to non-responders. The initial invitation, written in both English and Spanish, invited participants to a web portal to complete two 30-minute baseline surveys. Those who did not complete the online surveys were mailed a paper version on two separate occasions. Study invitations were mailed from May 2022 to December 2023. The University of Minnesota Institutional Review Board (IRB) served as the single IRB of record for the study, and IRBs at each of the nine participating sites ceded to the University of Minnesota single IRB. For the present analysis, all individuals who completed both baseline surveys were initially eligible. There were 10 participants who self-identified as male or intersex that were excluded. The primary exposure of interest was genital pain obtained via several self-reported items on the baseline survey, modified from the Day-to-Day Impact of Vaginal Aging questionnaire (DIVA). 7 We also included a genital pain diagram from the Brief Pain Inventory. 8 The specific questions used to classify women according to pain status and the algorithm used to classify women into 3 distinct mutually exclusive categories of no pain, non-genital pain only, and any genital pain are shown in Figure 1 . Women were first asked whether they had experienced pain other than transitory events such as minor headaches, toothaches, or sprains. If yes, they were directed to a genital diagram and asked whether they had pain or tenderness over the past week in the vulva, front of the vaginal wall, back of the vaginal wall, or perineum. Additionally, participants were asked to report, using a zero (none) to seven (most extreme) scale, genital burning or pain outside of sexual intercourse as well as genital burning and pain during sexual activity over the past 4 weeks. Because there are no validated or published definitions for genital pain for use in population based research, we developed the following definitions illustrated in the algorithm shown in Figure 1 : “No pain” was defined as reporting no pain outside of ordinary transient events and scoring less than 3 on all burning and pain scales during or not during sexual intercourse (cut-point where all those with no pain had scored); “Non-genital pain only” was defined as having pain outside of traditional transitory events but not endorsing any of the genital pain locations and scoring less than 3 on all burning and pain scales during or not during sexual intercourse; “Any genital pain” was defined as having pain outside of traditional transitory events and endorsing any of the genital pain locations, or, scoring 3 or higher on any of the burning and pain scales during or not during sexual intercourse. We chose a cut point of <3 or 3 or greater on all burning and pain scales since all those who initially endorsed no pain as described above, all scored below 3 on the 7-point scale related to pain outside or during intercourse. Baseline surveys collected information on participant demographics, including age, race/ethnicity, marital status, employment status, and household income. Additional questions relating to medical history and chronic pain conditions including IC/BPS, irritable bowel syndrome (IBS) and UTIs were included. For symptoms of IC/BPS participants reported whether they had experienced cramping, aching or stabbing sensations, discomfort or pressure, or burning in their pelvis related to peeing or holding urine. They were explicitly asked to not count or consider times when this was the result of having a UTI. For IC/BPS, IBS/Crohn’s disease, or UTIs, they were asked about these conditions separately as to whether a doctor or health care provider indicated a diagnosis. The validated BHS consists of 10 scales across the following domains: Global, Holding, Efficacy, Social-Occupation, Physical Activity, Intimacy, Travel, Emotion, Perception and Freedom. 7 Each scale is scored individually on a scale of 0 (poor) to 100 (optimal). The BHS scoring also incorporates adjustments for self-management or coping behaviors (adaptive behavior adjustments) which can decrease the overall perception of factors that can impact bladder health. BFI items score urinary frequency, sensation, continence, comfort, emptying and biosis (e.g. UTI related issues) similarly from 0 to 100, without incorporating an adaptive behavior adjustment. They can also be averaged for a total BFI score. The distribution of demographic characteristics was compared between the no pain, non-genital pain, and genital pain groups to determine which might serve as confounders. The crude and adjusted mean BHS and BFI scores were estimated for each of the three pain categories with respect to covariates that might substantially modify the associations. An a priori decision was made to stratify the analyses by those less than 40 or 40 or older since women less than 40 comprise the majority of those clinically diagnosed with genital pain consistent with vulvodynia and not impacted by the menopausal transition. In addition, to distinguish between women without known comorbidities aligned with genital pain, we a priori decided to assess participants with and without a self-reported history of IC/BPS diagnoses or symptoms, those with versus those without self-reported IBS or Crohn’s disease, and those with versus those without a self-reported history of UTIs. Finally, the pain classification categories were assessed in relation to the 10-item Symptoms Index designed by the Lower Urinary Tract Dysfunction Research Network (LURN) 9 as a means of comparing differences observed within our BHS and BFI scores. General Linear Models were used to assess adjusted means BHS and BFI scores with 95% confidence intervals.

Our findings suggest that women with any genital pain experience worse BH across all domains and functions compared to women with non-genital pain only, but even more so in comparison to women with no pain as classified in this analysis. In addition, the differences in BH scores between those with and without genital pain persisted regardless of age, and these differences were larger in women with any genital pain who endorsed IC/BPS symptoms or diagnoses, or a history of UTIs. However, these differences were largely eliminated when women reported no comorbidities including no IC/BPS, no IBS, and no other pelvic floor injuries. Yet, when one or more of these co-morbidities were present, bladder health scores and indices across the spectrum of bladder health and function was present, even if IC/BPS as a comorbidity was not present but others were. These findings suggest important associations between self-reported genital pain and BH across a variety of domains and functions. Although genital/vulvar pain and LUTS or measures of bladder health have been understudied to date, our findings are consistent with the extant literature. We found that women with self-reported genital pain had lower (worse) Bladder Health Scores and Bladder Function Indices, and a greater proportion of those with any genital pain reported LUTS 50% or more of the time based on the LURN SI-10 compared to those who reported no pain or non-genital pain only. In a case-control study of women with clinically confirmed vulvodynia and population-based controls, Sun et al. 3 found that women with vulvodynia were 19 times more likely to report severe urgency after urination, 5-times more likely to be occasionally bothered, and 4-times more likely to be usually or always bothered by bladder pain or urgency or both. 3 They also found that women with vulvodynia reported greater day and nighttime frequency of voiding, after adjustment for age, sleeping medication use, smoking history, UTI history, and diagnosis of anxiety. In their study, the questions from the Pelvic Pain, Urgency, and Frequency Questionnaire related to bladder or vulvovaginal pain (factors known to be highly correlated with vulvodynia) were excluded in the analysis and adjustment made for history of UTIs. Thus, these findings suggest that women with vulvodynia are more likely to be bothered by a wide spectrum of LUTS and not just bladder pain or UTIs. While prior work has shown an association between vulvodynia and IC/BPS, 10 , 11 our study found that women with self-reported genital pain and a history of IC/BPS, IBS, or UTIs had worse bladder health and function scores based on our novel bladder health instrument compared to those with no reported pain or non-genital pain only. In a national survey of non-pregnant women, Arnold et al. 12 found that those reporting vulvar pain consistent with vulvodynia were 6-fold more likely to report 3 or more UTIs per year than those without vulvodynia symptoms. They also found that chronic UTIs were the greatest predictor of vulvar pain in adjusted analyses. It is important to recognize, however, that in our study, participants with genital pain, but no self-reported UTIs, still had worse (lower) bladder health and function scores compared to those without pain. Although the etiology of unexplained genital pain remains unclear, it is likely multifactorial as concomitant bladder and bowel symptoms are common in women with genital pain. 13 A potential biological explanation for the association of genital pain with urinary symptoms and lower bladder health and functional scores is the well described finding of pelvic floor myofascial (PFM) pain and dysfunction in women with pelvic pain and other pelvic health conditions. 14 – 16 Genital hypersensitivity/pain, specifically of the vulvar vestibule, triggers a negative compensatory overactive/hypertonic pelvic floor muscle response. 15 Hypertonicity or increased PFM tone, on a continuum from transient increase in tone to spasm, 17 likely causes PFM strain and persistent myofascial pain or tenderness. Women with unexplained vulvar pain have documented PFM pain and improve with pelvic floor physical therapy. 18 , 19 Other studies have shown that women with PFM pain have UTI like symptoms without culture proven UTI 20 and women with PFM pain improve their LUTS with movement-based PT. 21 Additional data suggest that women with clinically-confirmed vulvodynia may also have a more compromised immune system/chronic inflammation, which may lead to a heightened myofascial response and overlapping urogenital symptoms. 22 We believe there are plausible biological explanations for these associations as discussed above, and several strengths to this study including its large population of women selected from diverse regions of the country, and the use of a novel and well validated measure of bladder health. However, it is important to consider alternative or non-causal explanations for our findings. Common symptoms of UTIs include pelvic pain, dysuria, and urinary urgency and frequency, which could lead to misclassification of genital pain and a spurious positive association between genital pain and worse BH. However, in our study, associations between genital pain and BH attenuated but persisted after restriction to individuals without a history of UTIs, arguing against this possible mechanism as a complete explanation for our findings. Genital pain and worse BH could also be related through well-known associations between chronic overlapping pain conditions, such as vulvodynia and IC/BPS, a syndrome that includes urinary symptoms, such as urinary urgency and frequency. These associations have been attributed to central sensitization pain mechanisms. Although we did not see an association between genital pain and bladder health scales or indices in those with no IC/BPS, IBS/Crohns disease, or pelvic injuries, we did see these associations when one or more of these were present, even when IC/BPS was absent. Thus, having comorbid IC/BPS with genital pain does not completely explain the associations we see with genital pain and a wide spectrum of urinary related discomfort as measured by our bladder health scales. Similarly, the persistence of the BFI scores in younger, likely pre-menopausal participants argues against the genitourinary syndrome of menopause, which includes both genital pain and LUTS, as a complete explanation for our findings. Other possible explanations that we could not explore in our study include a potential pelvic “sensation threshold hypothesis,” whereby individuals with genital pain void more frequently (i.e., before the urge to void) to reduce the overall sensory experience in their pelvic region. 23 We recognize that we were unable to identify women with specific vulvar pain conditions such as vulvodynia, vaginismus, or even other dermatological conditions such as lichen planus or sclerosus. Thus, we cannot be sure which conditions were included in our “genital pain” definition. In addition, women self-reported medical conditions they indicated was “diagnosed by a doctor”. Thus, we cannot rule out a certain amount of misclassification of these diagnoses. We also cannot be sure of the temporal relation between genital pain and BH related issues. However, the magnitude of the differences observed with respect to indicators of BH in those with genital pain, even in comparison to those with non-genital pain, regardless of temporality, suggests that these women clearly differ in their need for urological care. We also had difficulty achieving high response rates, and our participants represent a more highly educated sample, which may not be generalizable across the US. In considering the clinical implications of our findings, in addition to these strong associations using our Bladder Health Scales and Functional Indices, we found that women with genital pain had worse urinary symptoms in every domain measured by the LURN SI compared to those with no self-reported pain and those with non-vulvovaginal self-reported pain. We believe that women presenting for evaluation of vulvovaginal or genital pain, if screened for LUTS, may have significant bladder symptoms such as urinary urgency, leakage with urgency, slow urinary stream, and dribbling of urine. While clinical time constraints for providers and patients with vulvar/genital pain may limit discussion and physical examination to the vulva, our work adds to the growing literature that women with vulvar pain may likely suffer from significant urinary symptoms as well. In addition, in the United States current changes to billing requirements that do not require utilization of a full review of systems further reduce the chance that clinicians may identify the presence of LUTS in these women. Based on the growing literature in this area, and the non-invasive nature of screening for LUTS, we recommend that women presenting with vulvar or genital pain be screened for LUTS. Clinicians can accomplish this by asking about LUTS during the history portion of the visit. Conditions that may be uncovered include recurrent UTIs, genitourinary syndrome of menopause or urological conditions such as overactive bladder or incontinence. If conditions beyond the scope of primary care providers are found, these women may benefit from referral to a subspecialist for further evaluation and management. Further research is needed on the pathophysiology of co-existing genital pain and urologic symptoms. Longitudinal studies should explore the temporal relationship of urologic symptom onset in women with genital pain to better understand factors leading to the development of co-existing genital pain and urologic symptoms. A better understanding of the causal relationships will aid in the development of targeted strategies for both treatment and prevention. Although treatment algorithms exist for genital pain and urologic symptoms, additional investigation is needed into the efficacy of these treatments when both conditions are present. Studies should also explore the effect of treatment for one condition on the presence and severity of the other; for example, whether treating genital pain leads to an improvement in urologic symptoms. Also, assessing how pelvic floor muscle and anatomic conditions can contribute to both genital pain and LUTS would be informative. In conclusion, given the lack of documented research in this area, gynecologists, dermatologists, general practitioners, and other women’s health providers in the position of treating women with vulvar/genital pain, may not consider assessing urological issues. Our findings suggest that genital pain is not just comorbidly observed in those with IC/BPS, but across a wide spectrum of urological disorders. Heightened awareness of this correlation should prompt all clinicians that see women with genital pain to further assess and appropriately manage LUTS in these women.

Vulvovaginal or genital pain, when clinically defined as vulvodynia, has been shown to occur in up to 8% of women by age 40. 1 This debilitating pain is associated with bladder related morbidity such as Interstitial Cystitis or Bladder Pain Syndrome (IC/BPS), and urinary tract infections (UTIs). 2 Evidence suggests that women with genital pain are more likely to experience voiding and urgency symptoms, compared to those with no vulvar pain, independent of comorbid IC/BPS or a history of UTIs. 3 Thus, the spectrum of lower urinary tract symptoms (LUTS) may be more commonly observed in women with unexplained vulvar or genital pain, compared to women without. Although the mechanisms underlying these associations have not been fully elucidated, it is possible that the proximity and neuroanatomic relation of the genitalia, bladder and visceral organs to the pelvic floor enables bidirectional signaling, resulting in concomitant symptomatology. 4 The Prevention of Lower Urinary Tract Symptoms (PLUS) research consortium was established to study bladder health (BH) and prevention of LUTS including identification of risk and protective factors associated with the spectrum of BH. 5 Thus, in 2022 the PLUS consortium initiated the RISE FOR HEALTH study, a regionally representative population-based cohort study of U.S. women. 6 The aim of this analysis was to examine the association between genital pain and all aspects of bladder health and function in the RISE FOR HEALTH study, using a novel validated instrument that assesses the spectrum of bladder health and function from poor to optimal. 7 An additional goal was to investigate this association in subsets of women with and without known genital pain comorbidities such as IC/BPS and in those with recurrent UTIs.