Chronic Pelvic Pain Syndrome in Women: Clinical Covariates and Comorbidity Patterns

Why carry out this study? Chronic pelvic pain syndrome (CPPS) is a burden for many women, has a high prevalence, and poses a significant financial strain on healthcare systems. What did the study ask?/What was the hypothesis of the study? This prospective observational study investigated the covariates of patients with CPPS compared to controls to detect potential risk factors and possible pathophysiological mechanisms of the disease. We found a high correlation of CPPS with bowel constipation, a history of endometriosis, or previous gynecological surgery, whereas the rate of risk factors previously suspected, such as depression, pelvic hypertension, or pelvic congestion, was not elevated. What has been learned from the study? According to our findings, the chronic pelvic pain syndrome has two subgroups, an endometriosis-related type and a predominantly neurovegetative type linked with other functional disorders. The absence of muscular hypertension or pelvic congestion suggests that musculoskeletal and angiological factors do not contribute to the development of CPPS.

Between July 2018 and December 2020, a total of 225 consecutive non-pregnant female patients aged 18 years and older were examined at an obstetrics/gynecology and chronic pain clinic in Karlsruhe, Germany. All bimanual gynecological examinations were conducted by the same experienced gynecologist to ensure consistency. The study cohort included two distinct groups: 41 patients presenting with chronic pelvic pain (CPPS group) and 184 asymptomatic individuals undergoing routine preventive examinations (control group). Inclusion criteria were admittance for preventive Pap smear or other preventive reasons without complaints, such as control of contraceptives, or patients admitted for lower abdominal pain lasting ≥ 6 months. The data evaluation was conducted independently of treatment and did not influence medical procedures. Patients were excluded from data evaluation for the following reasons: Pregnancy, chronic neurological diseases with loss of neuronal sensitivity (e.g. multiple sclerosis), systemic inflammatory disease, acute complaints ≤ 6 weeks, such as bleeding, acute pain disorders such as acute abdominal pain, acute vaginitis, or cystitis, for chemotherapy ≤ 3 months, malignant pelvic tumors, and ≤ 3 months following lower abdominal surgery, and the impossibility of a full gynecological examination (as in upper vaginal stenosis). Patients with menopause, genital atrophy, or vulvodynia were not excluded, altogether resulting in N  = 225 patients, 184 without and 41 with chronic lower abdominal pain. Physical examination was performed according to standard operating procedures of the clinic involving inspection of vulva, vagina, and uterine cervix, vaginal smear for bedside microbiome assessment, pH, and hormonal cell analysis, bimanual palpation of the pelvic organs, and transvaginal ultrasound. For pelvic floor assessment, functional classification based on palpation of the muscles of the pelvic floor during contraction (modified 5-digit Oxford pelvic score) [ 29 , 30 ] was performed using a five-digit scale: 0 = no innervation possible, 1 = weak innervation, 2 = muscle strength below average, 3 = normal average muscle innervation, and 4 = muscle power above normal average. Vaginal tension was assessed on a three-digit scale: 0 = no tension (vaginal laxity), 1 = normal tension, 2 = elevated, rigid vaginal tension [ 8 ]. Cervical motion tenderness was examined in all patients using the three-digit scale described in [ 28 ]. “Pelvic congestion” was defined as adnexal varicosis of the respective side of the uterus when two or more parauterine venous vessels of ≥ 5 mm diameter were found in a transvaginal ultrasound examination. All participants underwent a comprehensive clinical assessment to exclude organic pathology or severe psychiatric conditions as potential causes of chronic pelvic pain. Data on body weight, height, body mass index (BMI), and age were obtained either from patient records or measured during the initial clinical examination. Additional information—such as current medication use, comorbidities, smoking status, parity, number of cesarean sections, history of miscarriage, and exposure to psychological or physical trauma was collected through structured patient interviews as part of the standard patient care of this clinic. All patients had the possibility to not answer questions. Patients gave their informed consent about the pseudonymized data evaluation for all data, including psychological issues. A trauma history was recorded if the patient reported having experienced a severe psychological or physical event that had a lasting impact on her life. Due to the real-world observational nature of the study, standardized questionnaires for trauma or depression were not employed. “Depression” was identified in accordance with ICD-10 criteria (F32.9) and recorded if the patient reported being under psychiatric care or using psychopharmaceuticals at the time of evaluation. For this study, “gynecological surgery” was defined as any prior cervical conization, laparoscopy, hysterectomy, curettage, adnexal surgery, or similar procedures. “Lower abdominal non-gynecological surgery” included appendectomy, hernia repair, and diagnostic or therapeutic laparoscopy for non-gynecologic indications. A positive history of endometriosis was recorded only if the diagnosis had been laparoscopically confirmed. “Dysmenorrhea” was defined as a history of painful menstrual periods lasting at least 6 months at any point in the patient’s lifetime. Long-term medication use was noted if a drug such as oral contraceptives, hormone replacement therapy, intrauterine hormonal devices, analgesics, thyroxine or other medication had been taken continuously for at least 3 months. Nicotine use was classified as abuse if the patient smoked the equivalent of one or more packs of cigarettes per week. “Dental disease” was defined as the presence of one or more acutely infected teeth or evidence of apical osteitis on radiographic imaging following root canal treatment. All analyses were done using statistical software R version ≥ 4.4.0. (R-Foundation for Statistical Computing, Vienna, Austria). Demographic variables of the patients were described as frequencies and percentages for categorical variables, and as means and standard deviations or median and range for continuous variables. Differences between subgroups were evaluated using chi-squared tests or Fisher’s exact tests, as appropriate, for categorical variables, while t  tests were performed for evaluating continuous variables. Furthermore, to compensate for possible bias caused by the age variable, age-adjusted p  values were calculated post hoc by matching the age ranges of the two cohorts and excluding patients who did not match the age range. Due to the exploratory character of the study, no missing data was imputed. p  values given here have a descriptive meaning and were not adjusted for multiplicity. p  values < 0.05 were labeled as statistically significant. This study was performed in accordance with the Helsinki Declaration of 1964 and its later amendments. All patients gave their informed consent for participating in the study, pseudonymized data evaluation, and publication. The structured interviews to collect the patients’ medical history were administered as part of our standard procedures in patient’s care. The study was approved by the ethical committee of the University Hospital Heidelberg (approval number 487/2011).

In this prospective observational study, 225 patients at first examination were included in the evaluation; 184 of them visited a doctor for a preventive annual Pap smear or other preventive reasons, such as contraceptive controls, whereas 41 patients sought medical advice for chronic pelvic pain (CPP) for ≥ 6 months. The patients’ flow chart is shown in Fig.  1 . Patients’ average age was 57.6 ± 14.4 years; average body mass index (BMI) was 23.2 ± 4.0 kg/m 2 . Fig. 1 Patient selection according to the STARD criteria (Standards for Reporting of Diagnostic Accuracy) [ 25 ]. All patients were consecutively recruited and registered between July 2018 and December 2020. Yellow : all patients included in the data evaluation; green : controls, and red : patients suffering from chronic pelvic pain (CPP) Patient selection according to the STARD criteria (Standards for Reporting of Diagnostic Accuracy) [ 25 ]. All patients were consecutively recruited and registered between July 2018 and December 2020. Yellow : all patients included in the data evaluation; green : controls, and red : patients suffering from chronic pelvic pain (CPP) Patients in the control group were older ( p  = 0.001) and had a 1.1 kg/m 2 higher BMI on average ( p  = 0.046) (Table  1 ). To estimate the possible bias due to this age difference, we additionally calculated the differences in an age-adjusted model. This second set of p  values is depicted in all tables in a column named “ p  value age-adjusted”. In this calculation, the BMI difference of the two groups was correlated with age but not an independent covariate ( p adjusted  = 0.236). Table 1 Biometric factors and gynecological history of patients with chronic pelvic pain (CPP compared to patients with preventive examination as asymptomatic controls CPPS ( N  = 41) Controls ( N  = 184) All ( N  = 225) p  value, all p  value, age-adjusted Biometric factors Age (years) 49.6 ± 12.9 59.4 ± 14.1 57.6 ± 14.4   0 29/41 (70.7%) 113/180 (62.8%) 142/221 (64.3%) 0.372 0.322 Cesarean section (yes) 10/41 (24.4%) 34/177 (19.2%) 44/218 (20.2%) 0.517 0.902 Vaginal surgical delivery 4/37 (10.8%) 6/130 (4.6%) 10/167 (6.0%) 0.235 0.165 History of dysmenorrhea 19/32 (59.4%) 48/114 (42.1%) 67/146 (45.9%) 0.090 0.497 Dysmenorrhea, duration (years) 13.0 ± 8.7 13.9 ± 11.2 13.6 ± 10.4 0.745 0.860 Known endometriosis 5/15 (33.3%) 8/75 (10.7%) 13/90 (14.4%) 0.043* 0.024* History of any gynecological surgery 29/40 (72.5%) 81/177 (45.8%) 110/217 (50.7%) 0.003** 0.009** Status post hysterectomy 8/41 (19.5%) 18/184 (9.8%) 26/225 (11.6%) 0.102 0.107 Non-gynecological lower abdominal surgery 10/39 (25.6%) 47/172 (27.3%) 57/211 (27.0%) 0.999 0.651 abdomin. abdominal, age adjusted the p  values yielded after adjusting for age of the control group to the CPPS patient group, see M&M section, BMI body mass index, CPPS patients with chronic pelvic pain > 6 months, gyn gynecological, HRT hormonal replacement therapy, hx medical history, N number of individuals, tx therapy Differences to the total number of 184 and 41 are due to missing values * p  < 0.05, ** p  < 0.01 Biometric factors and gynecological history of patients with chronic pelvic pain (CPP compared to patients with preventive examination as asymptomatic controls abdomin. abdominal, age adjusted the p  values yielded after adjusting for age of the control group to the CPPS patient group, see M&M section, BMI body mass index, CPPS patients with chronic pelvic pain > 6 months, gyn gynecological, HRT hormonal replacement therapy, hx medical history, N number of individuals, tx therapy Differences to the total number of 184 and 41 are due to missing values * p  < 0.05, ** p  < 0.01 The average duration of chronic pelvic pain on admission in the CPP group was 111 months or 9.3 years (median 66 months), with a range of 6.4–364 months (0.53–30.3 years). The rate of known endometriosis was significantly higher in the CPP group (33.3% vs. 10.7%; p  = 0.043). The rate of patients who had one or several gynecological surgeries was significantly higher in CPP patients than in the control group (73% vs. 46%, p  < 0.001), see Table  1 and Fig.  2 . In contrast, the rate and duration of dysmenorrhea were not significantly different between the two groups. Fig. 2 Covariates of the chronic pelvic pain syndrome (CPPS): Examination findings with a significant difference between patients with chronic pelvic pain (CPP, red ) and control patients ( blue ): Constipation, number of gynecological surgeries, and a history of endometriosis. Vulvar pain was found in 30% of the CPPS vs. 8% in the control patients, but this difference was in part due to the age of the patients. gyn gynecological, hx history, * = significance on a p  < 0.05 level. y-axis : percentage of the individuals Covariates of the chronic pelvic pain syndrome (CPPS): Examination findings with a significant difference between patients with chronic pelvic pain (CPP, red ) and control patients ( blue ): Constipation, number of gynecological surgeries, and a history of endometriosis. Vulvar pain was found in 30% of the CPPS vs. 8% in the control patients, but this difference was in part due to the age of the patients. gyn gynecological, hx history, * = significance on a p  < 0.05 level. y-axis : percentage of the individuals For the covariates: history of endometriosis, previous gynecological surgery, previous conscious trauma, and bowel constipation the difference to controls also remained significant after adjusting for age difference (Table  1 ). Upon gynecological examination, we did not find statistically significant differences in almost all variables between CPPS and control patients, see Table  2 and Fig.  3 . We found a difference in vaginal microbiome, with more lactobacilli than in control patients ( p  = 0.015), and in the vaginal pH, which was lower in CPPS patients ( p  < 0.001). However, in the age-adjusted calculation model, none of these differences reached a significance level of p  < 0.05 (Table  2 ). Pelvic congestion, described as ultrasound adnexal varicosis, was not elevated in CPPS patients ( p  = 0.242 and 0.756, Table  2 ). Patients in the CPPS group had an even lower rate of pelvic congestion than the control patients, as shown by the lower incidence of adnexal varicosis on both parauterine sides. Paracervical tenderness on gynecological examination was significantly higher in the CPPS group (data not shown, see our previous publication on paracervical tenderness [ 29 ]). Table 2 Gynecological examination findings in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls CPPS ( N  = 41) Controls ( N  = 184) All ( N  = 225) p  value, all p  value, age-adjusted Gynecological examination Vaginal pH (average value) 4.61 ± 0.94 5.3 ± 1.3 5.2 ± 1.3  < 0.001** 0.082 Vulvar pain 8/27 (30.8%) 5/62 (8.1%) 13 (14.8%) 0.011* 0.148 Vaginal microbiome: presence of lactobacilli 24/39 (61.5%) 79/180 (43.9%) 103/219 (47.0%) 0.015* 0.106 Adnexal varicosis right side (1) 0/22 (0.0%) 10/116 (8.6%) 10/138 (7.3%) 0.242 0.142 Vaginal tension on the left side (scale 0–2) 0.667 0.195 0.264 0.318 0.125 Uterine retroversion 2/32 (6.3%) 19/143 (13.3%) 21/175 (12.0%) 0.330 0.120 Vaginal tension on the right side (scale 0–2) 0.571 0.203 0.257 0.455 0.285 Pelvic floor quality (scale 0–4) 2.65 ± 0.66 2.56 ± 0.61 2.57 ± 0.62 0.503 0.831 Uterine fibroids > 25 ml 0/41 (0.0%) 5/184 (2.7%) 5/225 (2.2%) 0.588 0.798 Adnexal varicosis left side (1) 1/21 (4.7%) 10/115 (8.7%) 11/136 (8.1%) 0.756 0.508 Ovarian cysts > 25 ml 0/41 (0.0%) 3/184 (1.6%) 3/225 (1.3%) 0.999 0.999 Gynecological findings are ordered along with their probability to correlate with CPPS according to their p  values Age adjusted the p  values yielded after adjusting for age of the control group to the CPPS patient group, see M&M section, CPPS patients with chronic pelvic pain > 6 months, N number of individuals, pH pondus hydrogenii, acidity of the vagina. (1) for definition, see Material section. (2) vaginal tension on a 3-digit scale, see Material section. Differences to the total number of 184 and 41 are due to missing values. * p  < 0.05, ** p  < 0.01 Fig. 3 Non-significant covariates of chronic pelvic pain syndrome (CPPS). A trend towards a higher rate of dysmenorrhea, vaginal surgical delivery, parity, and the number of cesarean sections was seen in CPPS patients ( red ), however, the difference to the control group ( blue ) was not significant. Gynecological findings of pelvic congestion (measured from ultrasound adnexal varicosis), and uterine retroversion were not found in the CPPS group, but even more frequently in the control group. y-axis : percentage of the individuals Gynecological examination findings in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls Vaginal microbiome: presence of lactobacilli Vaginal tension on the right side (scale 0–2) Gynecological findings are ordered along with their probability to correlate with CPPS according to their p  values Age adjusted the p  values yielded after adjusting for age of the control group to the CPPS patient group, see M&M section, CPPS patients with chronic pelvic pain > 6 months, N number of individuals, pH pondus hydrogenii, acidity of the vagina. (1) for definition, see Material section. (2) vaginal tension on a 3-digit scale, see Material section. Differences to the total number of 184 and 41 are due to missing values. * p  < 0.05, ** p  < 0.01 Non-significant covariates of chronic pelvic pain syndrome (CPPS). A trend towards a higher rate of dysmenorrhea, vaginal surgical delivery, parity, and the number of cesarean sections was seen in CPPS patients ( red ), however, the difference to the control group ( blue ) was not significant. Gynecological findings of pelvic congestion (measured from ultrasound adnexal varicosis), and uterine retroversion were not found in the CPPS group, but even more frequently in the control group. y-axis : percentage of the individuals Patients suffering from CPP complained far more frequently of bowel constipation than the controls (36 vs. 11%, p  = 0.008), see Table  3 . Bowel constipation with a threefold higher rate was a remarkable and unexpected covariate of CPPS (37% vs. 11%, p  = 0.002), which also remained constant in the age-adjusted calculation ( p  = 0.004). We found a higher incidence of vulvodynia in CPPS patients, defined as vulvar pain of ≥ 6 months (31% vs. 8%, p  = 0.011). However, in the age-adjusted calculation, this difference did not reach statistical significance. Table 3 Non-gynecological diseases in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls CPPS ( N  = 41) Controls ( N  = 184) All ( N  = 225) p  value, all p  value, age adjusted Diseases Bowel constipation 11/30 (36.7%) 15/136 (11.0%) 26/166 (15.7%) 0.002** 0.004** Trauma history 11/41 (26.8%) 20/184 (10.8%) 31/225 (13.8%) 0.012* 0.005** Dental diseases 2/41 (4.9%) 1/184 (0.5%) 3/225 (1.3%) 0.086 0.350 Fibromyalgia 1/31 (3.2%) 0/158 (0%) 1/225 (0.5%) 0.182 0.503 Neuralgia (other locations) 1/41 (2.4%) 0/184 (0.0%) 1/225 (0.4%) 0.182 0.503 Arthrosis 6/41 (14.6%) 15/184 (8.2%) 21/225 (9.3%) 0.232 0.083 Depression 5/41 (12.2%) 15/184 (8.2%) 20/225 (8.9%) 0.376 0.350 Other gastrointestinal disorders 1/41 /2.4%) 12/184 (6.5%) 13/225 (5.8%) 0.471 0.655 Hypertension 6/41 (14.6%) 37/184 (20.1%) 43/225 (19.1%) 0.514 0.739 Diabetes 0/41 (0%) 5/184 (2.7%) 5/225 (2.2%) 0.588 0.588 Thyroid disease 7/41 (17.0%) 27/184 (14.7%) 34/225 (15.1%) 0.638 0.598 Coccygodynia 0/41 (0%) 2/184 (1.1%) 2/225 (0.9%) 0.999 0.798 Allergy 2/41 (4.9%) 12/184 (6.5%) 14/225 (6.2%) 0.999 0.903 Headache, migraine 1/41 (2.4%) 6/184 (3.3%) 7/225 (3.1%) 0.999 0.999 Diabetic neuropathy 0% 0% 0% – – Diseases are ordered along with their probability to correlate with CPPS according to their p  values, independent from the location Age adjusted the p  values yielded after adjusting the age of the control group to the CPPS patient group, see M&M section, CPP patients with chronic pelvic pain > 6 months, N number of individuals Differences to the total numbers of 184 and 41 are due to missing values * p  < 0.05, ** p  < 0.01 Non-gynecological diseases in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls Diseases are ordered along with their probability to correlate with CPPS according to their p  values, independent from the location Age adjusted the p  values yielded after adjusting the age of the control group to the CPPS patient group, see M&M section, CPP patients with chronic pelvic pain > 6 months, N number of individuals Differences to the total numbers of 184 and 41 are due to missing values * p  < 0.05, ** p  < 0.01 The rate of other diseases, such as thyroid diseases, hypertension, diabetes, musculoskeletal disorders, and different pain disorders (e.g., headache, coccygodynia, and fibromyalgia) were not different between the two groups (Table  3 ). None of the patients suffered from diabetic neuropathy. In contrast to depression ( p  = 0.376), trauma history was significantly higher in the CPPS group. The distribution of all other concomitant diseases was similar for both groups (Table  3 ). None of the medications taken by the patients was significantly different between CPPS patients and controls (Table  4 ). In detail, neither the frequent use of analgesics, nor the usage of psychopharmaceutic drugs was more frequent in CPPS patients. The rate of vaginal estriol (E3) therapy was higher in CPPS patients (22% vs. 11%). After age adjustment, this difference became significant ( p  = 0.029). Nicotine abuse (≥ 20 cigarettes per week) was evenly distributed between the two groups ( p  = 0.810) and, therefore, does not exhibit an obvious impact on CPPS. Table 4 Medication usage (analgesics and drugs taken for other reasons) in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls Medication CPPS ( N  = 41) Controls ( N  = 184) All ( N  = 225) p  value, all p  value, age-adjusted Statins 0/41 (0%) 15/184 (8.2%) 15/225 (6.7%) 0.079 0.344 Vaginal estriol (E3) therapy 8/35 (22.9%) 19/167 (11.4%) 27/202(13.4%) 0.097 0.029* Oral contraceptives 4/40 (10.0%) 10/184 (5.4%) 14/224 (6.3%) 0.284 0.438 Anticoagulants 1/30 (3.3%) 17/150 (11.3%) 18/180 (10.0%) 0.240 0.999 Anti-hypertensive drugs 3/41 (7.3%) 26/184 (14.1%) 29/225 (12.9%) 0.309 0.930 Intrauterine device 6/40 (15.0%) 18/182 (9.9%) 24/222 (10.8%) 0.397 0.865 Corticoids 0/41 (0%) 5/184 (2.7%) 5/225 (2.2%) 0.588 0.798 Antacids (pantoprazole, etc.) 0/41 (0%) 5/184 (2.7%) 5/225 (2.2%) 0.588 0.999 Analgesics 1/41 (2.4%) 9/184 (4.9%) 10/225 (4.4%) 0.694 0.999 Psychopharmaceuticals 4/41 (9.8%) 15/184 (8.2%) 19/225 (8.4%) 0.757 0.999 Nicotine abuse (> 1 pack per week) 4/40 (10.0%) 19/155 (12.3%) 23/195 (11.8%) 0.810 0.486 Hormonal replacement treatment 6/37 (16.2%) 37/178 (20.8%) 43/179 (20.0%) 0.939 0.999 Beta blockers 5/41 (12.2%) 23/184 (12.5%) 28/225 (12.4%) 0.999 0.243 Thyroxine 7/41 (17.1%) 32/184 (17.4%) 39/225 (17.3%) 0.999 0.491 Drugs are ordered along with their probability to correlate with CPPS according to their p  values, independent of their indication. Nicotine usage is listed here as a “drug” Age-adjusted the p  values yielded after adjusting the age of the control group to the CPPS patient group, see M&M section, CPP patients with chronic pelvic pain > 6 months, N number of individuals Differences to the total numbers of 184 and 41 are due to missing values * p  < 0.05 Medication usage (analgesics and drugs taken for other reasons) in two groups of patients: chronic pelvic pain (CPP) and asymptomatic controls Drugs are ordered along with their probability to correlate with CPPS according to their p  values, independent of their indication. Nicotine usage is listed here as a “drug” Age-adjusted the p  values yielded after adjusting the age of the control group to the CPPS patient group, see M&M section, CPP patients with chronic pelvic pain > 6 months, N number of individuals Differences to the total numbers of 184 and 41 are due to missing values * p  < 0.05

This prospective analysis identified several clinical covariates significantly associated with CPPS, including prior gynecological surgery (72% vs. 45%, p  = 0.003), confirmed history of endometriosis (33% vs. 11%, p  = 0.043), and bowel constipation (37% vs. 11%, p  = 0.002). These findings suggest distinct pathophysiological mechanisms defining different CPPS phenotypes. Several commonly proposed etiological factors showed no association with CPPS in our cohort, thus challenging prevailing assumptions about disease mechanisms. Our data provides compelling evidence against pelvic floor muscle hypertension as a primary mechanism in CPPS, contradicting extensive literature and supporting myofascial theories [ 19 – 22 ]. The myofascial pelvic pain syndrome concept, as described by Kotarinos [ 21 ] and Spitznagle and Robinson [ 22 ], proposes that pelvic floor muscle dysfunction is central to CPPS pathophysiology. However, our pelvic floor assessment using the validated Oxford scale [ 30 ] showed no differences between CPPS and control patients ( p  = 0.503), and vaginal tension measurements were similarly unremarkable. This finding is significant because it challenges a substantial body of literature that has influenced current treatment approaches. While Proulx et al. [ 31 ] found increased lumbopelvic muscle stiffness in CPPS patients, they questioned whether muscular abnormalities represent causative factors or secondary consequences of chronic pain, supporting our findings that pelvic floor dysfunction may not be a primary cause. Furthermore, our data does not support the theory of a pelvic congestion syndrome [ 4 , 14 – 18 ]. This theory, first proposed by Beard et al. [ 16 ] and subsequently supported by studies from Borghi and Dell’Atti [ 17 ] and others, attributes chronic pelvic pain to pelvic venous congestion and varicosities. However, our data showed adnexal varicosis was actually lower in CPPS patients than in controls (0–7% vs. 10–12%). This finding challenges the rationale for interventional procedures targeting pelvic veins and suggests that pelvic congestion may represent incidental, age-dependent venous insufficiency rather than a pain-generating mechanism. The vaginal microbiome and vaginal pH were more dominated by the presence of lactobacilli than in the control group. However, in the age-adjusted model calculation, both factors were no more significant and therefore, could not be attributed to CPPS. We conclude that vaginal microbiome and pH are more likely correlated to age rather than covariates of the disease. All other gynecological findings were similar in the CPPS group compared to controls. Uterine retroversion does not seem to play a role in CPPS, as it was assumed before [ 32 ]. Furthermore, the rate of ovarian cysts and fibroids > 25 ml volume was not statistically different between CPPS and control patients. Thus, CPPS does not seem to be induced by or correlated with these morphological findings. Contrary to influential studies of several working groups [ 24 , 25 , 27 , 33 ] who reported high rates of depression and psychological trauma in CPPS, we only found a weak but not significant difference in depression rates between the groups (12.2% vs. 8.2%, p  = 0.376). This questions the widespread assumption that psychological factors are the primary drivers of CPPS. However, due to methodological constraints, the results should be treated with caution. In our investigation, the rate of diabetes or hyper- or hypothyroidism was similar in both groups. CPPS seems to be independent from these diseases. The rate of other neuropathic diseases was not increased, and there was no patient with diabetic neuropathy, both of which argue against a systemic neuropathic factor in the pathogenesis of CPPS. There is a weak but not significant correlation with a lower dental health status in CPPS patients (5% vs. 0.5%). This putative correlation needs further investigation. Dental diseases are correlated with gynecological disorders such as endometriosis [ 34 ] and may also be associated with CPPS. Among all other co-existing diseases known in the patients, none of them showed any correlation with CPPS. Furthermore, even smoking did not seem to play a role in the pathogenesis of CPPS. There was no correlation of CPPS with estradiol medication, oral contraceptives, or the use levonorgestrel intrauterine devices. Only the rate of vaginal usage of estriol (E3) was higher in the CPPS group, independent of age, which may be rather due to a therapeutic application in the context of the therapy than a covariate of the disease. This assumption is supported by the fact that in the age-adjusted calculation, the difference in vaginal E3 application reached a significance level of p  < 0.05. Taking all these into account, we conclude that CPPS is not influenced by hormonal factors. Do analgetic drugs influence the CPPS? The use of analgesics or corticoids in the CPPS group was approximately identical to that in the control group. We had expected a higher rate due to the persistent complaints of the patients. Our findings argue against a potential concealing effect of analgesics on chronic pelvic pain. Other Drugs . We found no correlation with the intake of any of the other medications and conclude that none of them are covariates of the disease. The rate of vulvar pain of ≥ 6 months (vulvodynia) in CPPS patients was about 3.5 times higher than in the control group. Vulvodynia was initially thought to be correlated with CPPS in the past [ 26 ]. Our data support this view (30.8% vs. 8.1%). However, after the age-adjusted calculation, this correlation was no longer significant for CPPS. Although vulvodynia seems to have a different risk profile, as demonstrated by its covariates [ 35 ], some common characteristics with CPPS may exist. Our confirmation of significantly higher endometriosis rates in CPPS patients supports inflammatory theories of pain generation and aligns with extensive literature linking endometriosis to chronic pelvic pain [ 36 , 37 ]. The threefold higher rate in our CPPS cohort is consistent with Zondervan et al.’s [ 37 ] population studies showing 10% prevalence in reproductive-age women. Interestingly, the lack of difference in dysmenorrhea duration between groups suggests that residual inflammatory processes, rather than active endometriotic symptoms, may drive persistent pain. This may explain why some patients continue to experience pain despite apparently successful endometriosis treatment. Our trauma history findings (27% vs. 11%, p  = 0.013) partially support psychological theories [ 24 , 25 , 27 , 33 ], suggesting that trauma may contribute to CPPS development in a subset of patients. This finding was independent of age and is in line with former research assuming a post-traumatic covariate in CPPS [ 24 , 25 , 27 , 33 ]. However, in this analysis of real-world data, our data relied on self-reported information gathered as a part of a standard anamnesis without conducting a validated trauma questionnaire. Although the information was collected in the same way in both groups, the rate of unknown trauma may have been different. The findings indicate that post-traumatic factors may be relevant for some patients but are not universal CPPS characteristics. The significantly higher rate of prior gynecological surgery in CPPS patients providing strong support for neuropathic pain theories [ 38 ]. Kronenberg et al. [ 38 ] demonstrated that nerve injury following pelvic surgery can lead to chronic pain through peripheral and central sensitization. Our finding that 72% of CPPS patients had a history of gynecological surgery, compared to 45% of controls, suggests that iatrogenic nerve irritation may be an underrecognized CPPS mechanism. The specificity for gynecological versus general abdominal surgery (no significant difference in appendectomy rates) supports the view of an anatomically specific neural pathway involvement. This finding has important implications for surgical decision-making in CPPS patients and suggests that additional pelvic procedures should be approached with caution. The remarkable association with bowel constipation (37% vs. 11%, p  = 0.002) provides strong support for autonomic dysfunction theories and reasserts the relevance of the historical concept of “parametropathia spastica” [ 10 – 13 , 39 , 40 ]. This finding aligns with modern understanding of visceral hypersensitivity in chronic pain conditions [ 28 , 39 , 41 ]. The magnitude of this association was unexpected and suggests that autonomic nervous system dysfunction may be a unifying mechanism in non-endometriosis CPPS. This connects CPPS to broader concepts of functional disorders and visceral pain syndromes [ 39 ], indicating that gastrointestinal symptoms deserve greater attention in CPPS evaluation. Based on our covariate analysis, we propose two distinct CPPS subtypes with different therapeutic implications: This subtype, representing approximately one-third of our CPPS patients, is characterized by a confirmed endometriosis history. The absence of active dysmenorrhea in many patients suggests that residual inflammatory processes drive pain persistence, requiring targeted anti-inflammatory or neuromodulatory approaches beyond standard hormonal and surgical treatments. This subtype is characterized by constipation, gyn-surgical history, and absence of endometriosis, suggesting primary autonomic dysfunction with visceral hypersensitivity [ 39 , 40 ]. These patients may benefit from treatments targeting autonomic function [ 28 , 38 , 42 ] rather than treating structural abnormalities. Our findings challenge current diagnostic and treatment paradigms for CPPS. The lack of association with pelvic floor dysfunction and vascular congestion questions the utility of extensive assessments in routine CPPS evaluation. Instead, comprehensive surgical history and gastrointestinal symptom assessment may be diagnostically more relevant. The surgical trauma association raises important questions about repeat interventions in CPPS patients. Future research should examine whether surgical approaches perpetuate symptoms through continued neural injury. Additionally, the proposed phenotypic classification requires validation in larger cohorts with standardized assessment tools. We observed a limited number of patients in a single clinic. However, this prospective, descriptive data reveals first insights into possible pathophysiological mechanisms of CPPS. The consistency provided by a single experienced gynecologist strengthens methodological clarity, but at the same time introduces a lack of objectivity. Furthermore, the number of patients with CPPS was significantly lower than the number of control patients. This was caused by the fact that CPPS patients receive intensive therapy with several appointments in the respective period, whereas preventive patients usually come only once a year. These limitations will be overcome by future multicenter studies based on the findings of this pilot study. This study is observational in nature, and the findings should be interpreted as exploratory and hypothesis-generating rather than confirmatory. CPPS patients were significantly younger and had a lower BMI than the patients in the control group. We therefore re-calculated all covariates in an age-adjusted approach. The main covariates of CPPS—endometriosis, bowel constipation, and the number of previous gynecological surgeries—remained as significant covariates with this calculation as well, whereas BMI, vaginal pH, and the vaginal microbiome were revealed to be age-dependent and are therefore not found to be significant covariates of CPPS. Furthermore, some other factors could not be attributed to CPPS. There were differences regarding some other potential factors between the two groups in both the whole cohort as well as in the age-adopted model, but these differences were not on a significant level. Thus, even if there were an age difference between the two groups, it seemed to have no influence on the main results of this investigation. Pelvic floor assessment was done by a routine screening with palpation of the muscle contraction according to the five-digit modified Oxford scale [ 29 , 30 ]. This may have induced a certain bias in pelvic floor assessment. However, the examination is well established and has a high inter-rater reproducibility [ 43 ], so the bias most likely remained low. Furthermore, the examination was performed by a single, well-experienced gynecologist. We found no difference in the results of CPPS and control patients ( p  = 0.503), with that we can assume that pelvic floor hypo- or hypertension is no relevant covariate of CPPS. Also, the examination of the vaginal wall tension was done by palpation, not by measurement. Due to this, we cannot exclude bias caused by the palpation technique. Nevertheless, the results in both scales were far from a significant range, which supports the view that there is no relevant influence of the pelvic floor quality on CPPS. The database concerning some potential cofactors, such as trauma and fibromyalgia, was weak in our investigation. Due to the observational nature of the study, we were not able to use structured questionnaires in daily routines. Therefore, an underestimation or selection bias cannot be excluded but seems unlikely as the rate of missing data was similar in both groups for all covariates examined. Some researchers have assumed that psychological factors play an important role in CPPS [ 1 , 3 , 24 – 27 , 33 ]. In a clinic with all-day patient care, a psychological inventory questionnaire was not given out to the patients. Using structured questionnaires for study reasons only would have violated the character of an observational study. However, as the patient’s self-reports on prevalence and diagnosis of depression or traumatic experiences were taken similarly by all patients in both groups, a comparison was possible but is limited by a possible under-assessment of these factors. Conclusions from our data concerning depression and trauma experience as possible cofactors of CPPS should be drawn with caution. Further studies on this important factor should be planned to distinguish between depression as a cause or as a sequela of CPPS. Due to the design of the study, a possible under-assessment of psychological factors, such as depression and trauma history, may have occurred. Information on the presence or absence of proven endometriosis conducted using laparoscopy was available in only approximately 45% of the patients. However, the positive correlation with a known history of endometriosis suggests endometriosis to be a strong cofactor of CPPS. In contrast, one of the most important covariates of endometriosis, dysmenorrhea, was not different in either group. Given that endometriosis is a significant potential cause of CPPS, and it affects 10% of women within reproductive ages [ 37 ], its detection in a preventive care setting, such as during a Pap smear examination, is crucial. Due to the design of our study, we cannot rule out undiagnosed cases of endometriosis. The even distribution of dysmenorrhea in both groups suggests that active endometriosis is not a main denominator of CPPS. This question should be examined in further studies focusing on patients with CPPS and a proven endometriosis. The study is based on a prospective observational design. Therefore, there were no dropouts, which could have caused a data selection bias. We examined a relatively large population of 225 individuals, including a control group of 184 individuals. Our data serve as a foundation for further research and randomized studies on risk factors, covariates, and possible therapeutic approaches to the CPPS, which can be performed based on this study.

This exploratory study identified several covariates significantly associated with CPPS, including prior gynecological surgery, confirmed history of endometriosis, and bowel constipation. These associations suggest that CPPS may encompass distinct phenotypic subtypes with different underlying mechanisms. In some patients, residual endometriotic processes may be associated with pain persistence, while in others, patterns consistent with autonomic dysfunction may be observed. Our findings generate hypotheses for two potential CPPS subgroups: an endometriosis-associated phenotype and a neurovegetative phenotype characterized by gastrointestinal dysfunction and surgical history. While these observations require validation in larger controlled studies, they can already provide a novel conceptual framework for understanding CPPS heterogeneity. We recommend a comprehensive endometriosis evaluation in patients presenting with CPPS. Additionally, in the case where endometriosis is absent, assessment of gastrointestinal symptoms and autonomic function may be clinically relevant. The proposed phenotypic classification warrants further investigation in prospective multicenter studies to confirm these preliminary observations and guide the development of different targeted therapeutic approaches.

The chronic pelvic pain syndrome (CPPS) in women is defined as lower abdominal pain without an obvious origin for more than 6 months [ 1 – 4 ]. With a prevalence ranging from 5 to 25% across different populations [ 5 ], CPPS represents a significant clinical burden that imposes substantial healthcare costs and profoundly impacts quality of life [ 6 , 7 ]. The condition affects women across all age groups, often leading to repeated medical consultations, extensive diagnostic workups, and therapeutic interventions with variable success rates [ 8 , 9 ]. The concept of neurovegetative dysregulation, historically termed “parametropathia spastica”, proposes that elevated sympathetic tone and autonomic dysfunction underlie the condition [ 10 – 13 ]. Additionally, vascular theories have gained attention, with some researchers proposing pelvic congestion syndrome as a primary mechanism, attributing symptoms to venous insufficiency and parauterine varicosities [ 4 , 14 – 18 ]. Pelvic floor hypertension was also suspected to cause CPPS [ 19 – 22 ]. However, empirical support for these proposed mechanisms has been inconsistent across studies, with weak associations reported for most putative risk factors, leaving the etiology of CPPS largely unresolved. The heterogeneous nature of CPPS presentation suggests the condition may encompass multiple distinct pathophysiological subtypes rather than representing a single disease entity [ 23 ]. Previous investigations have yielded conflicting results regarding potential risk factors and associated comorbidities, including psychological factors [ 1 , 3 , 24 – 27 ], anatomical variations, hormonal influences, and inflammatory processes. This inconsistency highlights the critical need for systematic covariate analysis to identify clinically meaningful subgroups and establish evidence-based diagnostic and therapeutic approaches. Furthermore, the substantial overlap between CPPS and other chronic pain conditions, including endometriosis, irritable bowel syndrome [ 28 ], and vulvodynia, suggests shared pathophysiological mechanisms that remain incompletely characterized. Understanding these relationships is essential for developing targeted therapeutic strategies and avoiding ineffective treatments that may perpetuate patient suffering and healthcare resource utilization. In this study, we defined chronic pelvic pain (CPP) as a symptom and chronic pelvic pain syndrome (CPPS) as a clinical diagnosis characterized by persistent pelvic pain without an identifiable organic cause. We hypothesized that systematic identification of clinical, demographic, and medical history covariates would elucidate distinct pathophysiological mechanisms underlying this debilitating condition. Our primary aim was to identify potential risk factors and pathophysiological associations through a comprehensive comparison of clinical covariates between women with CPPS and asymptomatic controls, with the goal of both enhancing diagnostic strategies and therapeutic interventions.