1. INTRODUCTION
Pelvic pain is a heterogeneous condition, presenting in various pelvic locations with different severity, frequency, and life interference that can result in a substantially negative impact on the physical, mental, sexual, and social well-being of those affected [12, 25]. The most common subtypes are dysmenorrhea (pain with menstrual bleeding), dyspareunia (pain with vaginal penetration), and non-menstrual pelvic pain (pelvic pain unrelated to menses). Individuals can present with any combination, and often with substantial overlap among these varying pain symptoms [29]. However, most of the existing descriptive literature does not comprehensively describe the longitudinal trends in severity, frequency, and life interference of different pelvic pain types among adolescents and young adults. Many of the existing longitudinal studies only include follow-up data limited to participants who return to the same clinic, which may not validly represent the experience of all the original study participants and introduce significant selection bias.
Pelvic pain is also a prevalent symptom of endometriosis, a common gynecologic disease affecting about 10% of reproductive-aged females [50]. Approximately 60% of patients who are determined to have endometriosis at diagnostic surgery present with pelvic pain [32]. While endometriosis is frequently diagnosed in adulthood [37], emerging evidence suggests that initiation and development of endometriosis occurs earlier in the life course [50], with two-thirds of women with endometriosis diagnosed in adulthood reporting endometriosis-related symptom onset during adolescence [21, 32]. Specifically, adolescents with surgically-confirmed endometriosis most often present with severe pelvic pain that interferes with social or daily activities [13, 43]. However, these findings may be attributed to diagnostic bias in that adolescents with less impactful pain may not be referred for surgical evaluation. Additionally, among adolescents with endometriosis, superficial peritoneal lesions are the prevalent phenotype visualized at surgery. Conversely, adult women are found during imaging or diagnostic laparoscopy more often than adolescents to have endometriomas or deep fibrotic/infiltrative lesions in addition to superficial peritoneal lesions [13, 31, 37, 38]. How these macro-phenotypic differences impact pelvic pain is unknown. Furthermore, there is a sub-population of patients with endometriosis, including adolescents, who continue to suffer from chronic or recurrent pelvic pain despite surgery and post-surgical hormone therapy [2, 10, 14, 28]. The lack of fundamental pathophysiologic understanding of pelvic pain in general and its relationship to endometriosis macro-phenotypes specifically continues to impede personalized treatment planning and stall novel treatment discovery. Improving our understanding of the distribution and longitudinal changes in pelvic pain characteristics, particularly among a younger cohort, will lay the foundation to future studies to further understand who will improve over time versus who will continue to experience pain symptoms. A better understanding could in turn, inform treatment. Thus, as a first step towards furthering our understanding of pelvic pain in adolescents and adults, this study aimed to describe the prevalence and trends of pelvic pain utilizing multiple metrics and characteristics over two years of follow-up among adolescents and adults with and without endometriosis.
2. MATERIAL AND METHODS
2.1. Study population
The Women’s Health Study: From Adolescence to Adulthood (A2A) is a longitudinal observational cohort study that enrolled 1,549 participants [n=785 surgically-confirmed females with endometriosis (cases) and n=764 controls] from November 2012 to June 2018; enrolling 85% of those who were eligible to participate in the study. Details of the study have been described previously [13, 35]. In brief, participants with endometriosis were enrolled from 1) patients with a surgical diagnosis of endometriosis at Boston Children’s Hospital (BCH) or Brigham and Women’s Hospital (BWH) or 2) from patients with prior documented surgical diagnosis elsewhere but who were receiving follow-up treatment at BCH or BWH. Controls, females without a known diagnosis of endometriosis, were identified through local clinics, local advertisements, online postings, and/or word of mouth to ensure sampling from the communities served by these two hospitals and thus the underlying population that gave rise to the case participants [34]. These controls are representative of the underlying general population. All participants could have been receiving standard of care for any medical conditions including pelvic pain. Of the 764 controls, 82% were community-based and 18% were clinic-based controls. This study was approved by the BCH Institutional Review Board on behalf of both BCH and BWH. Written informed consent was obtained, with both parental consent and participant assent for individuals aged <18 years at enrollment.
All participants, regardless of endometriosis status, were asked to complete an extensive baseline questionnaire and annual follow-up questionnaires. The initial version of the baseline questionnaire assessed demographics, body mass index (BMI), physical activity, diet, smoking, alcohol consumption, reproductive factors, and other medical conditions as well as details on pain symptoms, treatment regimen, and medication use. In January 2014, an expanded version of the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) [45] clinical questionnaire was adopted for use at baseline, although there was very little change in the questionnaire with the vast majority of the questions being the same. Surveys were collected and managed with the use of REDCap electronic data capture tools [24]. Surgical details for endometriosis cases were documented using the WERF EPHect surgical form [6]. For the current analyses, of the 1,549 participants enrolled in the A2A, we restricted to the 1,291 participants who completed the baseline questionnaire (620 endometriosis cases and 671 controls). We excluded 4 controls who were diagnosed with endometriosis (incident cases) at any point from baseline through their most recent documented follow-up through July 2021, regardless of time since enrollment.
Once enrolled, all participants were followed via annual questionnaires utilizing an expanded version of the WERF EPHect clinical questionnaire, allowing repeated data collection. To maximize follow-up participation, four reminders were sent for each annual questionnaire with a paper copy of the questionnaire sent on the fourth reminder. To keep participants engaged, we distributed annual newsletters and tokens of appreciation, in addition to New Year’s cards.
2.2. Pain Measures
At baseline and during annual follow-up, participants reported details of dysmenorrhea (pain with periods), acyclic/general pelvic pain (pain occurring at times other than with menses), and dyspareunia (pain with vaginal intercourse/penetration) across more than three dozen questions and validated scales, including measures of pain severity, frequency, and life interference. The pain measures included in the A2A questionnaires were reviewed and agreed upon at the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect) global initiative involving 34 clinical/academic and three industrial collaborators from 16 countries, developing a consensus on standardization of phenotypic data collection methods in endometriosis research, including these multiple questions assessing of pelvic pain. These questions which are compliant with the WERF EPHect questionnaire are currently used across multiple sites across the globe (51 institutions in 22 countries to date)[6]. The following were evaluated for this investigation:
Severity:
Usual severity of dysmenorrhea was assessed categorically as none, mild (medication never or rarely needed), moderate (medication usually needed), and severe (medication and bed rest needed). The 11-point numeric rating scale (NRS)[8, 18] as used to assess (1) severity of pelvic pain during the last menstrual period at its worst in the past 12 months, (2) severity of acyclic pelvic pain in the past 3 months, and (3) severity of pelvic pain during and in the 24 hours after the last time the participant had vaginal intercourse/penetration in the past 12 months. For acyclic pelvic pain, the Short-form McGill Pain Questionnaire version 2 (SF-MPQ-2) was used to capture intensity of different pain qualities and symptoms on a 0–10 scale. It was used to calculate pain subscales for sensory continuous pain, sensory intermittent pain, affective pain, and neuropathic pain [16].
Frequency:
We assessed frequency of pelvic pain in the past 12 months for dysmenorrhea and vaginal intercourse/penetration (during or in the 24 hours after) as never, occasionally, often, usually, and always. Frequency of acyclic pelvic pain in the past 3 months was assessed as less than one day per month, monthly but not weekly, weekly but not daily, and daily.[48]
Pain interference:
Pain interference from dysmenorrhea was assessed by asking “During your last period, did your pelvic pain prevent you from going to work or school or carrying out your daily activities (even if taking pain-killers)?” and “During your last period, did you have to lie down for any part of the day or longer because of your pelvic pain?”. Pain interference for acyclic pelvic pain was assessed by asking “To what extent has your general pelvic/lower abdominal pain interfered with your normal social activities (work, school, or daily activities at home) in the last 3 months?”.[3] For both pain types, those who answered moderately, quite a bit, and extremely for interference with work/school/daily activities were categorized as “yes” and those who answered not at all or slightly were categorized as “no” [45].
Dyspareunia specific characteristics:
Participants reported ever experiencing dyspareunia, ever avoiding and/or interrupting vaginal intercourse/penetration due to pelvic pain (no, yes), and if they had pelvic pain during or within 24 hours following the last time they had vaginal intercourse/penetration in the past 12 months (no, yes during, yes in 24 hours after, yes both).[47] Participants also reported the location of their pelvic pain the last time they had vaginal intercourse/penetration in the past 12 months as superficial (i.e. entrance of vagina) or deep (i.e. deep inside vagina or abdomen/pelvis).[39] Pain experience with vaginal intercourse/penetration in relation to menstrual cycle phase (a few days before period, during a period, a few days after period, at mid cycle) was reported as yes more painful, no not more painful, and no vaginal intercourse/penetration.
Other pain characteristics:
Pain with urination and bowel movements during periods or while having acyclic pain in the past 3 months were assessed as: never/rarely, sometimes, often, most of the time, and always. Participants were also asked if they took pain killers or hormones during their last period and the effectiveness of hormones in managing their pain. Use of pain and hormonal medications to help acyclic pelvic pain were assessed. For hormonal medications, participants were asked if the use of hormones led to improvement in acyclic pelvic pain. Participants also reported whether they have been diagnosed with other pain conditions (i.e. migraine, low back pain, bladder pain, interstitial cystitis/painful bladder syndrome, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, ulcerative colitis, Crohn’s disease, systemic lupus erythematous, rheumatoid arthritis) in the baseline questionnaire.
2.3. Statistical methods
We examined the distribution of dysmenorrhea, acyclic pelvic pain, and dyspareunia characteristics in endometriosis cases and controls at each of the three time points (i.e. Baseline, Year 1, Year 2). Differences in the baseline distribution between endometriosis cases and controls were calculated using t-tests for continuous variables and chi-square tests or Fisher’s exact tests for categorical variables. See Supplemental Table 1 for detailed sample size and restrictions per each pain type over the three timepoints. Since pelvic pain characteristics are expected to differ between endometriosis cases and controls due to the nature of the underlying disease (i.e. endometriosis cases report more severe pelvic pain in general compared to controls), the interpretation centered on change across two years. We also examined the frequencies of cross-classified categories of dysmenorrhea and acyclic pelvic pain severity among endometriosis cases who had information on severity of these two pain types. Among endometriosis cases with data on acyclic pelvic pain severity at all three time points, we examined the change in acyclic pelvic pain severity across the three time points. We also conducted a sensitivity analysis restricting to endometriosis cases and controls reporting current hormone use at each of the three time points. All descriptive statistics were conducted using SAS 9.4 (SAS Institute, Cary, NC).
3. RESULTS
3.1. Study population characteristics at baseline
At baseline, participants with surgically-confirmed endometriosis were younger compared to controls (median age: 19 vs. 24 years, respectively), although the interquartile range was similar between the two groups (Table 1). Compared to controls, endometriosis cases were more likely to be White (91% vs. 72%), while the majority of endometriosis cases and controls identified as non-Hispanic (93% and 91%, respectively). Most participants were normal weight (>60%), never smoked cigarettes (>90%), and were nulliparous (>90%). Endometriosis cases were more likely to have ever used hormones (97% vs. 76%), to report regular use of analgesics (46% vs. 16%), and to report a family history of endometriosis (49% vs. 9%) compared to controls. Additionally, endometriosis cases were more likely to report dysmenorrhea starting within 2 years of their first period (83%) compared to controls (66%). Pain conditions often collectively reported as chronic, overlapping pain conditions (i.e. fibromyalgia, irritable bowel syndrome, chronic fatigue syndrome, interstitial cystitis/painful bladder syndrome, migraine, lower back pain) were more frequently observed in endometriosis cases compared to controls. Two or more additional pain conditions were reported by 60% of endometriosis cases compared to only 22% of controls. Of these, migraine was most frequently reported by both endometriosis cases (64%) and controls (35%; Supplemental Table 2).
Table 1.
Baseline characteristics of endometriosis cases and controls in the A2A cohort
| Endometriosis cases | Controls | |
|---|---|---|
| N= 620 | N= 671 | |
| Demographic, anthropometric, medical history, and reproductive characteristics | ||
| Age at enrollment, years, median (IQR) | 19 (16,24) | 24 (22, 28) |
| Race, n (%) | ||
| Asian | 3 (<1%) | 95 (14%) |
| Black | 16 (3%) | 42 (6%) |
| White | 562 (91%) | 480 (72%) |
| Other/Unknown1 | 39 (6%) | 54 (8%) |
| Non-Hispanic ethnicity, n (%) | 566 (93%) | 607 (91%) |
| Body Mass Index2, n (%) | ||
| Underweight | 9 (1%) | 26 (4%) |
| Normal weight | 377 (61%) | 442 (66%) |
| Overweight | 157 (25%) | 136 (20%) |
| Obese | 77 (12%) | 66 (10%) |
| Never cigarette smoking, n (%) | 551 (95%) | 616 (93%) |
| Nulliparous, n (%) | 577 (94%) | 602 (91%) |
| Ever used hormonal medications, n (%) | 603 (97%) | 509 (76%) |
| Regular analgesic use (≥2 days/week)3, n (%) | 258 (46%) | 104 (16%) |
| Age at menarche, years, median (IQR) | 12 (11, 13) | 12 (11, 13) |
| Family history of endometriosis, n (%) | 302 (49%) | 58 (9%) |
| Period pain onset relative to menarche, n (%) | ||
| Had pain at first period | 270 (46%) | 189 (36%) |
| Within 2 years of first period | 219 (37%) | 157 (30%) |
| More than 2 years after first period | 97 (17%) | 172 (33%) |
| Number of other pain conditions4, n (%) | ||
| Zero other pain conditions | 91 (15%) | 272 (41%) |
| One other pain condition | 158 (25%) | 250 (37%) |
| Two or more other pain conditions | 371 (60%) | 149 (22%) |
| Endometriosis-specific characteristics | ||
| Age at endometriosis symptom onset, years, median (IQR) | 14 (12, 16) | -- |
| Years between symptom onset and surgical diagnosis, median (IQR) | 3 (1, 5) | -- |
| Symptoms prompting diagnosis, n (%) | ||
| Pain | 532 (96%) | -- |
| Pain and/or infertility or other conditions | 21 (4%) | -- |
| Number of physicians seen before surgical diagnosis, median (IQR) | 1 (1, 2) | -- |
| Surgery for endometriosis within 12 months from baseline, n (%) | ||
| No5 | 132 (21%) | -- |
| Yes, diagnostic surgery | 301 (49%) | -- |
| Yes, subsequent surgery | 187 (30%) | |
| rASRM stage at surgery closest to baseline, n (%) | ||
| Stage I/II | 472 (95%) | -- |
| Stage III/IV | 27 (5%) | -- |
| Endometriosis macro phenotype at surgery closest to baseline, n (%) | ||
| Superficial | 493 (95%) | -- |
| Endometrioma | 9 (2%) | -- |
| Deep endometriosis | 16 (3%) | -- |
| Endometrioma and Deep endometriosis | 3 (<1%) | -- |
Abbreviations: IQR = interquartile range
Participants in the Other/Unknown category included American Indian/Alaska Native (cases: 1, controls: 0), Native Hawaiian or Pacific Islander (cases: 0, controls: 1), Multiracial (cases: 22, controls: 37), other race (cases: 14, controls: 11), unknown (cases: 2, controls: 5)
For women aged ≥20 years: underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5–24.9 kg/m2), overweight (BMI 25–29.9 kg/m2), or obese (BMI ≥ 30 kg/m2) according to World Health Organization criteria; For those <20 years, the age- and gender-specific BMI Z-score was calculated, and participants were categorized as underweight (Z-score ≤ −2), normal weight (Z-score >−2 to <1), overweight (Z-score 1–2), or obese (Z-score > 2)
Regular use of analgesic medications defined as use at least once a week for a period of three months or longer and categorized as never, <2 days of use per week, or ≥2 days of use per week. Analgesic medications include aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, and narcotics.
Includes migraine, low back pain, bladder pain, interstitial cystitis/painful bladder syndrome, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, ulcerative colitis, Crohn’s disease, Lupus, Rheumatoid Arthritis. For endometriosis cases, this number indicates conditions other than endometriosis.
All cases had surgically confirmed endometriosis, but these cases had an endometriosis-related surgery more than 12 months prior to completing their baseline questionnaire.
3.2. Endometriosis-specific characteristics
Among endometriosis cases, the median age at symptom onset was 14 years, while the median time between symptom onset and diagnosis was 3 years (Table 1). The majority of endometriosis cases had superficial endometriosis (95%) visualized and destroyed or removed at the surgery closest to baseline. Only 3% had deep lesions, all of which were excised at surgery. The most common indication for surgery was pain symptoms (96%). All endometriosis cases had surgical diagnosis and 79% of endometriosis cases had an endometriosis-related surgery (diagnostic or subsequent surgery) within one year before or after completing the baseline questionnaire. At all endometriosis-related surgeries that the participants received, endometriotic lesions were visualized and destroyed or removed. The first endometriosis-related surgery which led to a definitive surgical confirmation of endometriosis was called a “diagnostic surgery” in this manuscript. All surgeries following the first endometriosis-related surgery were called “subsequent surgery”.
3.3. Longitudinal follow-up
Among the 620 endometriosis cases and 671 controls who completed the baseline questionnaire, 443 (71%) endometriosis cases and 531 (79%) controls completed the Year 1 questionnaire while 405 (65%) endometriosis cases and 524 (78%) controls completed the Year 2 questionnaire, resulting in 358 (58%) endometriosis cases and 482 (72%) controls completing all three questionnaires. There was little difference, among both cases and controls, when comparing baseline demographics, clinical characteristics, and pelvic pain severity between those who did and did not complete the Year 1 or Year 2 questionnaires (Supplemental Tables 3 and 4). Additionally, during follow-up, 17 endometriosis cases had a subsequent surgery for endometriosis at Year 1 and 29 cases had a subsequent surgery at Year 2. Among endometriosis cases, 88% were using hormonal medications at baseline, 92% in Year 1 and 87% in Year 2 whereas about 56% of controls were using hormonal medications across the two years of follow-up (Supplemental Table 5). Of those who were using hormonal medications, combined birth control pills were the most common type in both endometriosis cases and controls. Aygestin was the second most frequently used hormones among endometriosis cases (16%−25% across all timepoints) and a hormonal intrauterine device was the second most frequently used hormone among controls (23% at baseline, 32% in Year 1, and 36% in Year 2).
3.4. Dysmenorrhea
The percentage of endometriosis cases who reported having periods in the past 3 months decreased from 361 (58%) at baseline to 126 (28%) in Year 1 and 128 (32%) in Year 2 whereas the percentage of controls with periods stayed relatively similar with 551 (82%) at baseline, 414 (78%) at Year 1, and 408 (78%) at Year 2 (Supplemental Table 1). We observed statistically significant differences between endometriosis cases and controls for dysmenorrhea severity, frequency, and life interferences at baseline (all p-values <0.0001). Among those who were cycling, usual dysmenorrhea severity did not change substantially for endometriosis cases (64% at baseline, 60% at Year 1 and 62% at Year 2 reported severe pain) nor controls (8% reported severe pain at each time point) (Table 2). The percentage of endometriosis cases reporting “always” experiencing dysmenorrhea decreased from 80% at baseline to 64% at Year 2; while colinearly the percentage reporting experiencing dysmenorrhea “never” or “occasionally” increased from 3% at baseline to 12% at Year 2. Dysmenorrhea frequency did not change over time for control participants. The prevalence of life interference from dysmenorrhea did not change substantially over time for either group. Of participants who took hormonal medications during their last period, 34–41% of endometriosis cases at each time point reported that their dysmenorrhea did not improve from taking hormones, compared to 5–6% of controls. The percentage of endometriosis cases reporting that their period pain improved or stopped following a bowel movement increased from 48% at baseline to 61% at Year 2, while the percentage of endometriosis cases who reported pain with urination during their periods decreased from 40% at baseline to 31% at Year 2. Pain with urination and bowel movements did not change for controls. We observed similar frequencies when restricting to those who were on hormones at each timepoint (Supplemental Table 6).
Table 2.
Distribution of dysmenorrhea characteristics across the first 2 years of follow-up among A2A participants who self-reported having periods in the last 3 months1
| Endometriosis cases | Controls | |||||
|---|---|---|---|---|---|---|
| Baseline | Year 1 | Year 2 | Baseline | Year 1 | Year 2 | |
| N= 361 | N= 126 | N= 128 | N= 551 | N= 414 | N= 408 | |
| Usual severity of pelvic pain with periods | ||||||
| None/Mild | 23 (7%) | 13 (10%) | 18 (14%) | 360 (66%) | 258 (62%) | 244 (60%) |
| Moderate | 106 (29%) | 38 (30%) | 30 (24%) | 145 (26%) | 123 (30%) | 129 (32%) |
| Severe | 231 (64%) | 75 (60%) | 77 (62%) | 46 (8%) | 31 (8%) | 33 (8%) |
| Severity of pelvic pain during the past 12 months at its worst 2 | ||||||
| Median (Min-Max) | 9 (1–10) | 8 (1–10) | 8 (1–10) | 5 (1–10) | 5 (0–10) | 5 (0–10) |
| None /Mild | 8 (3%) | 7 (6%) | 10 (8%) | 127 (29%) | 103 (30%) | 99 (28%) |
| Moderate | 43 (12%) | 22 (18%) | 21 (18%) | 189 (44%) | 135 (39%) | 150 (43%) |
| Severe | 300 (85%) | 91 (76%) | 89 (74%) | 118 (27%) | 108 (31%) | 103 (29%) |
| Usual frequency of pelvic pain with periods 3 | ||||||
| Never/Occasionally | 7 (3%) | 21 (17%) | 12 (12%) | 234 (49%) | 187 (46%) | 147 (49%) |
| Often | 18 (7%) | 6 (5%) | 11 (11%) | 86 (18%) | 75 (19%) | 47 (16%) |
| Usually | 26 (10%) | 14 (11%) | 14 (14%) | 69 (14%) | 69 (17%) | 55 (18%) |
| Always | 198 (80%) | 81 (66%) | 66 (64%) | 89 (19%) | 72 (18%) | 53 (18%) |
| Life interference during last period 3,4 | ||||||
| Pelvic pain prevented going to work, school, or carrying out daily activities | 133 (55%) | 67 (56%) | 56 (47%) | 29 (9%) | 25 (9%) | 22 (7%) |
| Had to lie down during the day because of pelvic pain | 211 (87%) | 96 (81%) | 97 (82%) | 119 (37%) | 109 (38%) | 103 (34%) |
| Took pain killers for pelvic pain during last period 3,4 | ||||||
| No | 27 (11%) | 20 (17%) | 20 (17%) | 111 (34%) | 109 (38%) | 111 (37%) |
| Yes, took over the counter pain killers | 142 (60%) | 66 (55%) | 63 (53%) | 205 (63%) | 171 (60%) | 182 (60%) |
| Yes, took prescription pain killers | 22 (9%) | 21 (18%) | 25 (21%) | 7 (2%) | 3 (1%) | 8 (3%) |
| Yes, took over the counter and prescription pain killers | 47 (20%) | 12 (10%) | 11 (9%) | 3 (1%) | 2 (1%) | 0 (0%) |
| Took hormones during last period 3,4 | ||||||
| No | 87 | 47 | 51 | 266 | 235 | 257 |
| Yes, but pain did not get better | 98 (64%) | 46 (65%) | 41 (60%) | 15 (25%) | 15 (31%) | 17 (40%) |
| Yes, pain got at least somewhat better | 54 (36%) | 25 (35%) | 27 (40%) | 45 (75%) | 33 (69%) | 25 (60%) |
| Pain with urination and bowel movements in the past 3 months 3,4 | ||||||
| Had pain with urination during periods | 129 (40%) | 37 (31%) | 37 (31%) | 35 (10%) | 28 (10%) | 38 (13%) |
| Period pain got better or stopped after bowel movement | 105 (48%) | 77 (65%) | 72 (61%) | 203 (65%) | 181 (63%) | 194 (64%) |
| Period pain got worse after bowel movement | 84 (39%) | 38 (32%) | 39 (33%) | 49 (16%) | 26 (9%) | 39 (13%) |
Total number of respondents at each timepoints were analyzed.
Resticted to participants who reported having periods at least once in the last 3 months (261 cases and 120 controls excluded at baseline, 316 cases and 117 controls excluded at Year 1, 277 cases and 116 controls excluded at Year 2). Due to the phrasing in the questionnaire, participants who self-reported having periods could have been on cyclic hormone therapy or having bleeding despite being on continuous hormones
Severity categories created using the 0–10 numeric rating scale (none=0; mild=1–3; moderate=4–6; severe=7–10)
For baseline responses, restricted to 252 endometriosis cases and 485 controls who answered the WERF EPHect compliant version of the baseline questionnaire from January 2014 onwards
Restricted to those who reported having experienced period pain in the last 3 months
3.5. Acyclic pelvic pain
We observed statistically significant differences between endometriosis cases and controls for acyclic pelvic pain severity, frequency, and life interferences at baseline (all p-values <0.0001). The presence of acyclic pelvic pain did not change over time, remaining between 63–65% for cases and 14–19% for controls (Supplemental Table 1). However, severity, frequency, and life interference from acyclic pelvic pain trended towards improvement over time among endometriosis cases while remaining stable among controls (Table 3). The median NRS scores for severity declined from 8 (Min-Max: 1–10) at baseline to 6 (Min-Max: 1–10) at Year 2 among cases, with 69% of cases reporting severe acyclic pelvic pain at baseline compared to 46% at Year 2. In comparison, 27–35% of controls reported severe acyclic pelvic pain across the two years. Among endometriosis cases, 28% reported daily acyclic pelvic pain at baseline, which decreased to 14% at Year 2. Conversely, very few controls experienced daily acyclic pelvic pain (<5%). Two-thirds (68%) of endometriosis cases reported life interference from acyclic pelvic pain at baseline, decreasing to 38% at Year 2. The percentage of control participants reporting life interference from acyclic pelvic pain did not change (23–28%). The distribution of endometriosis cases and controls with pain with urination or bowel movements in the past 3 months did not change substantially over the two years. The total score of the SF-MPQ-2 specific to acyclic pelvic pain was similar across two years. Interestingly, compared to controls, endometriosis cases had higher values for all the subscales (difference in median > 1 point) except the neuropathic pain subscale, which is not specific to pelvic pain and could capture sensory characteristics from other forms of pain and indicate nociplastic or mixed pain (Supplemental table 7). Similar results were observed when restricting to those on hormones at each timepoint (Supplemental Table 8).
Table 3.
Distribution of acyclic pelvic pain characteristics across 2 years of follow-up among A2A participants who reported experiencing acyclic pelvic pain in the last 3 months1
| Endometriosis cases | Controls | |||||
|---|---|---|---|---|---|---|
| Baseline | Year 1 | Year 2 | Baseline | Year 1 | Year 2 | |
| N= 387 | N= 276 | N= 258 | N= 92 | N= 98 | N= 95 | |
| Severity of acyclic pelvic pain 2 | ||||||
| Median (Min-Max) | 8 (1–10) | 7 (2–10) | 6 (1–10) | 5 (1–10) | 5 (1–10) | 4 (1–10) |
| Mild | 35 (10%) | 28 (10%) | 33 (13%) | 28 (33%) | 30 (31%) | 29 (31%) |
| Moderate | 80 (21%) | 105 (38%) | 103 (41%) | 27 (32%) | 37 (38%) | 39 (42%) |
| Severe | 259 (69%) | 141 (52%) | 118 (46%) | 30 (35%) | 30 (31%) | 25 (27%) |
| Frequency of acyclic pelvic pain | ||||||
| Less than one day per month | 36 (10%) | 23 (8%) | 22 (9%) | 16 (18%) | 25 (26%) | 24 (26%) |
| Monthly but not weekly | 91 (24%) | 91 (33%) | 120 (47%) | 47 (52%) | 47 (48%) | 55 (59%) |
| Weekly but not daily | 146 (39%) | 109 (40%) | 78 (30%) | 24 (26%) | 24 (24%) | 15 (16%) |
| Daily | 104 (28%) | 49 (18%) | 36 (14%) | 4 (4%) | 2 (2%) | 0 (0%) |
| Life interference in past 3 months | ||||||
| Acyclic pelvic pain interfered with work or school | 253 (68%) | 123 (46%) | 96 (38%) | 25 (28%) | 23 (23%) | 24 (25%) |
| Pain medications taken in past 3 months to help with acyclic pelvic pain 3 | ||||||
| None | 53 (23%) | 51 (20%) | 62 (27%) | 36 (46%) | 53 (55%) | 48 (52%) |
| Yes, over the counter medications only | 106 (46%) | 117 (47%) | 110 (47%) | 36 (46%) | 39 (40%) | 42 (46%) |
| Yes, prescription (with or without over the counter medications) |
69 (30%) | 82 (33%) | 61 (26%) | 7 (9%) | 5 (5%) | 2 (2%) |
| Hormonal medications used in past 3 months to help acyclic pelvic pain 3 | ||||||
| None | 106 | 53 | 63 | 65 | 53 | 49 |
| Yes, but pain did not get better | 70 (57%) | 56 (48%) | 49 (57%) | 8 (57%) | 1 (33%) | 5 (71%) |
| Yes, pain got at least somewhat better | 52 (43%) | 60 (52%) | 37 (43%) | 6 (43%) | 2 (67%) | 2 (29%) |
| Narcotic prescription pain medication use 3 | ||||||
| Used for 3 months or longer | 16 (7%) | 22 (8%) | 23 (9%) | 3 (4%) | 3 (3%) | 2 (2%) |
| Pain with urination in past 3 months while having acyclic pelvic pain 3 | ||||||
| Never/rarely | 129 (62%) | 181 (66%) | 171 (67%) | 57 (80%) | 85 (87%) | 75 (79%) |
| Sometimes | 48 (23%) | 63 (23%) | 50 (20%) | 11 (15%) | 9 (9%) | 15 (16%) |
| Often/Most of the time/Always | 30 (14%) | 31 (11%) | 34 (13%) | 3 (4%) | 4 (4%) | 5 (5%) |
| Acyclic pelvic pain got better or stopped after bowel movement in past 3 months 3 | ||||||
| Never/rarely | 96 (47%) | 91 (33%) | 83 (32%) | 27 (36%) | 26 (27%) | 36 (38%) |
| Sometimes | 69 (34%) | 122 (44%) | 121 (47%) | 29 (39%) | 37 (38%) | 32 (34%) |
| Often/Most of the time/Always | 38 (19%) | 63 (23%) | 52 (20%) | 18 (24%) | 34 (35%) | 27 (28%) |
| Acyclic pelvic pain got worse after bowel movement in past 3 months 3 | ||||||
| Never/rarely | 127 (63%) | 176 (64%) | 156 (61%) | 58 (81%) | 79 (81%) | 83 (87%) |
| Sometimes | 50 (25%) | 68 (25%) | 71 (28%) | 12 (17%) | 17 (18%) | 9 (9%) |
| Often/Most of the time/Always | 25 (12%) | 31 (11%) | 28 (11%) | 2 (3%) | 1 (1%) | 3 (3%) |
| Short-form McGill Pain Questionnaire version 2 (Median (IQR)) 3,4,5 | ||||||
| Total Score | 3 (2, 4.7) | 3.3 (2.4, 4.9) | 3.2 (2.2, 4.5) | 1 (0.5, 1.7) | 2.2 (1.6, 3) | 2.1 (1.5, 2.8) |
| Sensory Continuous pain subscale | 4.7 (2.5, 6.8) | 4.7 (3, 6.2) | 4.3 (2.7, 6.3) | 1.7 (1, 2.7) | 2.8 (2, 4.2) | 3 (2, 4) |
| Sensory Intermittent pain subscale | 4.3 (2.3, 6.2) | 3.8 (2.7, 5.7) | 3.8 (2.2, 5.8) | 1.2 (0.3, 2.7) | 2.2 (1.2, 3.7) | 2.3 (1.2, 3.5) |
| Neuropathic pain subscale | 0.7 (0, 2) | 1.3 (1, 2.2) | 1.3 (1, 2.3) | 0 (0, 0.5) | 1 (1, 1.3) | 1 (1, 1.2) |
| Affective pain subscale | 3.5 (1.8, 6) | 3.3 (1.8, 5.3) | 2.8 (1.3, 5.2) | 0.5 (0, 1.3) | 2 (1, 3) | 1.5 (1, 2.8) |
Total number of respondents at each timepoints were analyzed.
Restricted to participants who reported acyclic pain in the past 3 months (excluded baseline: 216 cases and 571 controls, Year 1: 159 cases and 428 controls, Year 2: 136 cases and 422 controls) Note: 146 endometriosis cases and 12 controls who completed the initial version of the baseline questionnaire reported on acyclic pelvic pain in the past year.
Severity categories created using the 0–10 numeric rating scale (none=0; mild=1–3; moderate=4–6; severe=7–10)
For baseline responses, restricted to 241 endometriosis cases and 80 controls who answered the WERF EPHect compliant version of the baseline questionnaire from January 2014 onwards
Further restricted to participants without missing information (excluded: 20 endometriosis cases and 7 controls at baseline, 9 endometriosis cases and 1 control at Year 1, 10 endometriosis cases and 1 control at Year 2)
Participants rated each type of pain on 0–10 scale in the SF-MPQ-2. Please see Supplemental Table 5 for components of each subscale with median and IQR for all subscale components.
We examined change in acyclic pelvic pain severity over time among the endometriosis cases with acyclic pelvic pain at baseline who completed all three questionnaires. Multiple trends in pain severity across the three time points were observed, with some reporting severe pain at all three timepoints and some reporting change in pain severity from severe to mild from baseline to Year 1 and/or Year 2, and others reporting pain severity going up or up and down, although this was a small fraction of cases (Figure 1). Of the 213 endometriosis cases, 148 (69%) reported severe acyclic pelvic pain at baseline, 81 (38%) at Year 1, and 74 (35%) at Year 2. Almost one-fifth (38 [18%]) of endometriosis cases reported severe acyclic pelvic pain at all three time points. Conversely, only 6 (3%) endometriosis cases reported mild pain at all three time points. Of the 148 cases who reported severe acyclic pelvic pain at baseline, 25 (17%) reported mild pain at both Years 1 and 2. When we compared baseline characteristics between those endometriosis cases who reported severe pain at all three timepoints and those who reported having severe pain at baseline but none/mild pain in Years 1 and 2, few characteristics differed objectively or statistically significantly between these two extremes of longitudinal acyclic pelvic pain experience. However, we observed with borderline statistical significance [17] that a higher proportion of those who at baseline reported experiencing two or more pain conditions would report severe acyclic pain at all three timepoints compared to those who at baseline reported zero other pain conditions (82% vs 56%, p-value testing any difference among all three categories of number of pain conditions=0.07). When restricting to those who were on hormones at all three timepoints, we observed similar change in frequencies (Supplemental Figure 1).
Figure 1. Change in severity of acyclic pain across 2 years of follow-up among endometriosis cases who reported ever having acyclic pain at baseline in the A2A.
This figure is restricted to the 213 participants who answered all three questionnaires and reported acyclic pelvic pain at baseline. Severity of acyclic pain was categorized based on 0–10 numeric rating scale (NRS). At baseline, severity of acyclic pain was categorized based on Mild (1–3), Moderate (4–6), Severe (7–10). At Years 1 and 2, severity of acyclic pelvic pain was categorized on the NRS as: None/Mild (0–3), Moderate (4–6), Severe (7–10). The distribution across these pain categories is indicated proportionally by the height of the text boxes that indicate pain severity at each timepoint (i.e. Mild, Moderate, Severe). The lines or ribbons track the pain trajectory of different participant groups over time. The pink lines indicate endometriosis cases who had severe acyclic pain at baseline, the yellow lines indicate endometriosis cases who had moderate acyclic pain at baseline, and the blue lines indicate endometriosis cases who had mild acyclic pain at baseline. At baseline, 148 (69%) reported severe acyclic pelvic pain, 46 (22%) reported moderate acyclic pelvic pain, and 19 (9%) reported mild acyclic pelvic pain.
3.6. Dysmenorrhea and acyclic pelvic pain
We examined the concordance between dysmenorrhea and acyclic pelvic pain severity at baseline, Year 1, and Year 2 for participants with endometriosis (Supplemental Table 9). At each of the three time points, approximately 20% of endometriosis cases without periods (i.e. classified as not cycling) reported severe acyclic pelvic pain (19% baseline, 22% Year 1, 19% Year 2). Conversely, 19% of endometriosis cases at baseline reported both severe dysmenorrhea and acyclic pelvic pain, which decreased to 8% at Years 1 and 2. The percentage of endometriosis cases who did not have periods and had no/mild acyclic pelvic pain increased from 16% at baseline to 29% at Year 1 and 30% at Year 2. Finally, the percentage with severe dysmenorrhea and no/ mild acyclic pelvic pain decreased from 15% at baseline to 7% at Year 1 and 6% at Year 2.
3.7. Dyspareunia
Among participants who reported having vaginal sexual intercourse or penetration in the past 12 months (endometriosis cases: 251 baseline, 213 Year 1, 227 Year 2; controls: 475 baseline, 402 Year 1, 405 Year 2), the percentage reporting dyspareunia slightly declined over time for endometriosis cases (79% baseline, 70% Year 1, 74% Year 2) and was similar over time among controls (32% baseline, 32% Year 1, 30% Year 2; Supplemental Table 1). We observed statistically significant differences between endometriosis cases and controls for severity and frequency of dyspareunia at baseline (all p-values ≤0.001). The frequency of those who reported ever avoiding vaginal intercourse or penetration due to pelvic pain was similar across the two years among endometriosis cases (75% baseline, 72% Year 1, and 65% Year 2) and decreased in Year 2 among controls (47% at baseline, 45% at Year 1, and 34% at Year 2) (Table 4). Among endometriosis cases, dyspareunia frequency declined over time, with 50% reporting they usually or always experienced dyspareunia at baseline and 40% at Year 2. Dyspareunia frequency was similar across the two years among controls, with 14% reporting usually or always experiencing dyspareunia at baseline and 12% at Year 2. The percentage of endometriosis cases and controls who had moderate or severe dyspareunia either during or in the 24 hours after intercourse or penetration remained fairly stable. In terms of timing of dyspareunia, endometriosis patients most commonly reported experiencing pelvic pain both during and 24 hours after vaginal intercourse or penetration but controls most commonly reported experiencing pain during vaginal intercourse or penetration. Participants most commonly experienced deep dyspareunia, with 97% of endometriosis cases and 71–86% of controls reporting deep dyspareunia with or without superficial pain. We observed similar results when restricting to those on hormones at each of the three timepoint (Supplemental Table 10).
Table 4.
Distribution of dyspareunia characteristics across 2 years of follow-up among A2A participants who reported having had vaginal sexual intercourse or penetration and experiencing dyspareunia in the past 12 months1
| Endometriosis cases | Controls | |||||
|---|---|---|---|---|---|---|
| Baseline | Year 1 | Year 2 | Baseline | Year 1 | Year 2 | |
| N= 198 | N= 149 | N= 168 | N= 153 | N= 129 | N= 121 | |
| Ever Life Interference due to pelvic pain | ||||||
| Avoided intercourse or penetration | 147 (75%) | 91 (72%) | 101 (65%) | 71 (47%) | 56 (45%) | 40 (34%) |
| Interrupted intercourse or penetration | 145 (74%) | 90 (71%) | 98 (63%) | 77 (51%) | 69 (56%) | 66 (55%) |
| In past 12 months | ||||||
| Frequency of pelvic pain during or in the 24 hours after vaginal intercourse or penetration | ||||||
| Occasionally | 49 (25%) | 36 (28%) | 55 (35%) | 103 (67%) | 91 (73%) | 76 (64%) |
| Often | 50 (25%) | 34 (27%) | 37 (24%) | 28 (18%) | 20 (16%) | 28 (24%) |
| Usually | 46 (23%) | 34 (27%) | 27 (17%) | 14 (9%) | 10 (8%) | 8 (7%) |
| Always | 53 (27%) | 24 (19%) | 36 (23%) | 8 (5%) | 3 (2%) | 6 (5%) |
| Last time participant had vaginal intercourse or penetration in the past 12 months | ||||||
| Occurrence and timing of pelvic pain 2 | ||||||
| None | 11 (10%) | 32 (23%) | 26 (16%) | 79 (57%) | 62 (49%) | 63 (53%) |
| Yes, during | 31 (29%) | 30 (22%) | 41 (25%) | 33 (24%) | 31 (24%) | 28 (24%) |
| Yes, in 24 hours after | 16 (15%) | 24 (17%) | 26 (16%) | 14 (10%) | 19 (15%) | 16 (13%) |
| Yes, both | 48 (45%) | 54 (39%) | 68 (42%) | 12 (9%) | 15 (12%) | 12 (10%) |
| Severity of pelvic pain during vaginal intercourse or penetration | ||||||
| Median (Min-Max) | 6 (0–10) | 5 (0–10) | 5 (0–10) | 4 (0–10) | 4 (0–10) | 4 (0–8) |
| None /Mild (0–3) | 52 (26%) | 27 (26%) | 29 (21%) | 62 (41%) | 30 (46%) | 24 (43%) |
| Moderate (4–6) | 87 (44%) | 42 (40%) | 73 (54%) | 72 (48%) | 27 (42%) | 25 (45%) |
| Severe (7–10) | 57 (29%) | 36 (34%) | 32 (24%) | 17 (11%) | 8 (12%) | 7 (13%) |
| Severity of pelvic pain in 24 hours after vaginal intercourse or penetration | ||||||
| Median (Min-Max) | 4 (0–10) | 5 (0–10) | 4 (0–10) | 3 (0–9) | 3 (0–8) | 2 (0–8) |
| None /Mild (0–3) | 89 (46%) | 32 (29%) | 49 (37%) | 95 (64%) | 46 (71%) | 40 (72%) |
| Moderate (4–6) | 65 (33%) | 41 (38%) | 56 (42%) | 36 (24%) | 14 (22%) | 12 (21%) |
| Severe (7–10) | 42 (21%) | 35 (33%) | 29 (22%) | 16 (11%) | 5 (8%) | 4 (7%) |
| Location of pelvic pain 2 | ||||||
| Superficial Only | 3 (3%) | 3 (3%) | 4 (3%) | 8 (14%) | 15 (23%) | 16 (29%) |
| Deep Only | 70 (74%) | 77 (71%) | 97 (72%) | 32 (55%) | 36 (55%) | 30 (55%) |
| Superficial and Deep | 22 (23%) | 28 (26%) | 34 (25%) | 18 (31%) | 14 (22%) | 9 (16%) |
Total number of respondents at each timepoints were analyzed.
Restricted to participants aged ≥18 (at the baseline questionnaire from Nov 2012 to April 2018) or ≥16 (at the baseline questionnaire from April 2018 onwards) who reported having dyspareunia in the past 12 months among those who ever had sexual vaginal intercourse or penetration.
For baseline responses, restricted to 106 endometriosis cases and 138 controls who answered the WERF EPHect compliant version of the baseline questionnaire from January 2014 onwards
Severity categories created using 0–10 numeric rating scale (none=0; mild=1–3; moderate=4–6; severe=7–10)
Participants who had menstruation noted changes in their dyspareunia based upon timing of the menstrual cycle (Supplemental Table 11). Endometriosis cases were more likely to report having dyspareunia a few days before their period (46%), a few days after their period (32%), and at mid-cycle (38%) compared to controls (35%, 15%, and 15%, respectively). Conversely, a similar proportion of cases and controls reported dyspareunia during a period at baseline (13%). When comparing across years, the frequencies reporting pain at different phases of the menstrual cycle over two years were fairly consistent for cases and controls.
4. DISCUSSION
We examined trends in pelvic pain characteristics over two years in the A2A longitudinal cohort including adolescents and adults with and without endometriosis. Endometriosis cases more often reported severe, frequent, and life interfering pelvic pain compared to controls. Among endometriosis cases, we observed different trends of severity, frequency, and life interference for the three pelvic pain types. Conversely, trends among controls remained fairly stable. Adding to the existing literature, A2A is a young cohort with high response retention that examines multiple aspects of “pelvic pain” (acyclic pain, dysmenorrhea, dyspareunia); thus, providing unique longitudinal data of endometriosis cases who are more proximal to symptom onset and earlier in their treatment journey.
Prior clinic-based cross-sectional studies with sample sizes <50 suggested that endometriosis diagnosed in adolescents may be a more severe sub-type[7, 9, 42]. Approximately 20–30% of endometriosis patients report recurrent or persistent pelvic pain after endometriosis-related surgery[1, 2, 10]. However, previous studies often define persistent pain as any pelvic pain rather than assessing pain types separately. Our longitudinal data show that persistence of dysmenorrhea is common among menstruating patients, including those on cyclic hormone therapy. The prevalence of severe, frequent, and life-interfering pelvic pain due to dysmenorrhea was stable across two years among endometriosis cases, with ~60% reporting severe dysmenorrhea at each time point. More than 70% of endometriosis patients in our study were taking hormonal medications, and similar results were observed when restricting to those taking hormonal medications at each time point. Interestingly, about 30–40% of endometriosis cases reported hormonal medications did not improve their dysmenorrhea or acyclic pelvic pain, potentially due to early development of central sensitization or progesterone resistance. These results suggest that at least some of our adolescent and young adult cases continue to experience significant dysmenorrhea. Thoughtful interpretation is needed when considering the percentages of dysmenorrhea characteristics. As dysmenorrhea can only be experienced by those who are menstruating, these descriptive statistics were restricted to those participants who reported having periods in the last 3 months. Therefore those who were on continuous hormones or on cyclic hormones but did not report having a period in the last 3 months were excluded from this table. The percentage of menstruating participants who reported that their dysmenorrhea pain did not get better with hormones is high for both endometriosis cases (60–64%) and controls (25–40%). However, when quantified among the whole study population – whether they had a period in the last 3 months or not - the frequencies range from 10–16% for endometriosis cases and 2–3% for controls, which are proportions comparable to the existing dysmenorrhea literature [20]. A clinically translatable interpretation can be that hormones work for some – perhaps even most – but not all patients (10–16% for endometriosis cases and 2–3% for controls), and selection of treatment formulation and dosing must consider successful suppression of menstruation (without which the lack of remediation jumps considerably (endometriosis cases (60–64%) and controls (25–40%)).
Conversely, we observed a decreasing trend in severity, frequency, and life interference of acyclic pelvic pain over time, although almost half (46%) of endometriosis cases with acyclic pelvic pain at Year 2 reported severe pain; similar results were observed when restricting to those taking hormone medications at each time point. Among endometriosis cases with acyclic pelvic pain at baseline and questionnaire data at all three time points, 18% reported severe acyclic pelvic pain across the two years of follow-up. These cases may represent participants with endometriosis who have centralized pain sensitivity[11], meaning that at least some of these participants may not respond to peripherally directed treatments (e.g. any treatment directed at the endometriosis lesions, such as endometriotic lesion removal). Interestingly, we observed an improving trend over time for acyclic pelvic pain but not for dysmenorrhea, potentially due to our endometriosis patients being oversampled for dysmenorrhea that is treatment-resistant. The younger patients in our cohort needed to present with severe pelvic pain resistant to hormonal treatment to justify surgical intervention.
When we examined cross-classified groups by dysmenorrhea and acyclic pelvic pain severity, there was little concordance between severe dysmenorrhea and severe acyclic pelvic pain. The percentage of those reporting severe acyclic pelvic pain but not cycling (e.g. not experiencing dysmenorrhea) was stable across two years (~20%), suggesting that continuous hormones may relieve endometriosis-related pain for some patients; however, some endometriosis patients will continue to experience severe acyclic pelvic pain despite hormonal treatment.
Previous research noted an association between endometriosis and co-morbid pain conditions[27, 40, 41]. Among A2A endometriosis cases, 60% reported having ≥2 other pain conditions in addition to their endometriosis. Endometriosis cases were more likely to report chronic, overlapping pain conditions compared to controls, suggesting that endometriosis cases may be more likely to be impacted by widespread pain or increased sensitization to pain[5, 22, 29, 33, 46]. Future research is needed into the mechanisms underlying co-morbid pain conditions and the influence of central pain sensitization.
An endometriosis diagnosis is commonly prompted by pelvic pain, infertility, or both. In adult-focused literature, approximately two-thirds of endometriosis patients reported that pelvic pain symptoms prompted their diagnosis[32]. Conversely within the A2A cohort, 96% presented with pain, as our cohort primarily consists of adolescents and young adults who have not yet tried to conceive. This difference may explain the very low percentage of A2A endometriosis cases (3%) who reported none or mild acyclic pelvic pain at all three time points. Furthermore, those with mild, less impactful pain symptoms may not be referred for surgical evaluation.
Dyspareunia was difficult to assess in our cohort, as exclusion of participants aged<18 years and participants who never had sexual vaginal intercourse reduced the sample to ~30%. We observed that 29% of endometriosis cases reported severe dyspareunia during penetration and 21% in the 24 hours after penetration at baseline, which were lower than the >50% of endometriosis patients reporting dyspareunia in the ENDO Study[36]. Limited evidence exists on whether the occurrence of dyspareunia differs with menstrual cycle phase. One prior study noted that endometriosis patients reported the most severe dyspareunia just before their period, with the least pain experienced after their period[36]. We observed similar trends, with most dyspareunia occurring a few days before menses began. The decline in the frequency and severity of dyspareunia among endometriosis cases from baseline to Year 2 may be because ~75% of endometriosis cases received surgical treatment close to baseline. Previous observational cohort studies have reported an improvement in dyspareunia after surgical treatment among endometriosis patients[19, 44].
Importantly, our study also explored pelvic pain prevalence and its characteristics among controls sampled from the general population in the Boston Area that gave rise to the endometriosis cases. Reported dysmenorrhea prevalence among adolescents has varied from 30–90%[23, 26]. We observed that ~80% of our controls reported at least mild dysmenorrhea, with 8% reporting severe dysmenorrhea and ~30% reporting severe pain when their dysmenorrhea was at its worst. A study among university students aged 18–45 observed that 1/3 had dysmenorrhea that interfered with attending lectures, and 1/2 had dysmenorrhea that interfered with their concentration[4, 15]. These proportions are similar to that observed in A2A controls (35% reported they had to lie down due to dysmenorrhea), although only 9% reported their dysmenorrhea interfered with going to work, school, or carrying out daily activities. Our results provide data on longitudinal pelvic pain trends among adolescents and young adult women without known endometriosis.
Among participants who completed the baseline questionnaire, our cohort had a high retention with 70% of endometriosis cases and 80% of controls completing Year 1 or Year 2 questionnaires. Controls were more likely to complete follow-up questionnaires. Our controls were slightly older than our endometriosis cases at baseline; thus, they may be at a more stable point in their lives for returning questionnaires. Importantly, our cohort retention and maintenance methods were independent of participants’ choice of future medical care and had little evidence of biased loss to follow-up, with major pelvic pain characteristics being similar across those who completed and did not complete follow-up questionnaires.
This study has multiple strengths. This is a large study primarily consisting of adolescents and young adults with and without endometriosis. This study included detailed information on pain characteristics utilizing validated scales widely used in the pain research field and conforming to tools and protocols recommended by the WERF EPHect international consortium. The majority of endometriosis cases in our study are in an earlier phase of the endometriosis disease trajectory as they are more proximal to their endometriosis symptom onset. We were able to assess trends in multiple pelvic pain characteristics across two years of follow-up regardless of where our endometriosis cases were receiving their treatment; differing from the majority of previous studies that require participants to return to the same clinic to be included in follow-up data.
However, our study has several limitations. The A2A cohort includes clinic- and community-based controls sampled to represent the underlying population that gave rise to the endometriosis cases. Selection bias thus is minimized, allowing a valid approximation of the true prevalence of pain presentation in this age group without bias toward the null evident in solely clinic-based populations due to comparison with other pain-associated pathologies for which surgical evaluation was indicated[30]. However, our control group may include undiagnosed endometriosis cases, which could bias our results for controls towards more severe pelvic pain and minimizes differences observed between cases to controls. We expect the impact of this to be minimal as we annually follow-up with controls to ascertain endometriosis diagnoses, and in any general community-based population, the estimated prevalence of undiagnosed symptomatic endometriosis is ~2%[49]. Additionally, while rigorously defined and reflective of the racial distribution of adolescents and adults seeking endometriosis-related treatment at the two participating hospitals given the high enrollment rate (85%), it is important to consider that the A2A cohort consists of a primarily White population, particularly for our endometriosis cases, and a population overall with high access to tertiary care. Thus, further studies including diverse populations are needed. The objective of this study was to provide needed descriptive population-level data on frequencies and prevalence of different types of pelvic pain cross-sectionally as well as trends observed longitudinally in the adolescent and young adult population. Therefore, our manuscript focused on presenting descriptive data based on absolute numbers and proportions, which should be considered when interpreting the presented results. This is a descriptive study that included documentation of visually observed endometriosis phenotype and rASRM staging via the WERF EPHect surgical form for all those participants who had surgery after enrollment. However, given the absence of technology to prospectively monitor potential return and characteristics of superficial peritoneal endometriotic lesions, we cannot infer differential impact of treatment versus post-surgical peritoneal disease on change in pelvic pain over these years of follow-up.
In conclusion, our study summarizes numerous pelvic pain characteristics of endometriosis cases and controls across two years of follow-up. Different trends were observed by different pelvic pain types over time and by endometriosis status, supporting the importance of considering multi-dimensional features of pelvic pain in clinical practice when assessing and treating pelvic pain among adolescents and young adults with and without endometriosis. Results from this study will provide foundationally important information that will build toward future studies to further our understanding of the underlying pathophysiology of different types and trends in pelvic pain in both women with and without endometriosis, which will lead to new research avenues for personalized treatment.
Supplementary Material
Acknowledgements:
The authors would like to thank all the participants of the Women’s Health Study: From Adolescence to Adulthood for their valuable contributions and all staff of the Boston Center for Endometriosis. Financial support for establishment of and data collection within the A2A cohort was provided by the J. Willard and Alice S. Marriott Foundation. A.L.S., K.L.T., S.A.M were supported by NICHD R01 HD094842 and NICHD R21 HD096358. A.L.S. was supported by the Marriott Daughter’s Foundation.
Footnotes
Conflict of interest: Authors have no conflict of interest to declare.
REFERNCES
- [1].Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004;82(4):878–884. [DOI] [PubMed] [Google Scholar]
- [2].Abbott JA, Hawe J, Clayton RD, Garry R. The effects and effectiveness of laparoscopic excision of endometriosis: a prospective study with 2–5 year follow-up. Hum Reprod 2003;18(9):1922–1927. [DOI] [PubMed] [Google Scholar]
- [3].Amtmann D, Cook KF, Jensen MP, Chen WH, Choi S, Revicki D, Cella D, Rothrock N, Keefe F, Callahan L, Lai JS. Development of a PROMIS item bank to measure pain interference. Pain 2010;150(1):173–182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [4].Armour M, Ferfolja T, Curry C, Hyman MS, Parry K, Chalmers KJ, Smith CA, MacMillan F, Holmes K. The Prevalence and Educational Impact of Pelvic and Menstrual Pain in Australia: A National Online Survey of 4202 Young Women Aged 13–25 Years. J Pediatr Adolesc Gynecol 2020;33(5):511–518. [DOI] [PubMed] [Google Scholar]
- [5].As-Sanie S, Kim J, Schmidt-Wilcke T, Sundgren PC, Clauw DJ, Napadow V, Harris RE. Functional Connectivity is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain. J Pain 2016;17(1):1–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [6].Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA, Zondervan KT, Adamson GD. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. Fertil Steril 2014;102(5):1213–1222. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [7].Benagiano G, Guo SW, Puttemans P, Gordts S, Brosens I. Progress in the diagnosis and management of adolescent endometriosis: an opinion. Reprod Biomed Online 2018;36(1):102–114. [DOI] [PubMed] [Google Scholar]
- [8].Birnie KA, Hundert AS, Lalloo C, Nguyen C, Stinson JN. Recommendations for selection of self-report pain intensity measures in children and adolescents: a systematic review and quality assessment of measurement properties. Pain 2019;160(1):5–18. [DOI] [PubMed] [Google Scholar]
- [9].Brosens I, Gordts S, Benagiano G. Endometriosis in adolescents is a hidden, progressive and severe disease that deserves attention, not just compassion. Hum Reprod 2013;28(8):2026–2031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [10].Coccia ME, Rizzello F, Palagiano A, Scarselli G. Long-term follow-up after laparoscopic treatment for endometriosis: multivariate analysis of predictive factors for recurrence of endometriotic lesions and pain. Eur J Obstet Gynecol Reprod Biol 2011;157(1):78–83. [DOI] [PubMed] [Google Scholar]
- [11].Coxon L, Horne AW, Vincent K. Pathophysiology of endometriosis-associated pain: A review of pelvic and central nervous system mechanisms. Best Pract Res Clin Obstet Gynaecol 2018;51:53–67. [DOI] [PubMed] [Google Scholar]
- [12].Denny E, Mann CH. Endometriosis-associated dyspareunia: the impact on women’s lives. Journal of Family Planning and Reproductive Health Care 2007;33(3):189–193. [DOI] [PubMed] [Google Scholar]
- [13].DiVasta AD, Vitonis AF, Laufer MR, Missmer SA. Spectrum of symptoms in women diagnosed with endometriosis during adolescence vs adulthood. Am J Obstet Gynecol 2018;218(3):324.e321–324.e311. [DOI] [PubMed] [Google Scholar]
- [14].Doyle JO, Missmer SA, Laufer MR. The effect of combined surgical-medical intervention on the progression of endometriosis in an adolescent and young adult population. J Pediatr Adolesc Gynecol 2009;22(4):257–263. [DOI] [PubMed] [Google Scholar]
- [15].Durand H, Monahan K, McGuire BE. Prevalence and impact of dysmenorrhea among University students in Ireland. Pain Med 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [16].Dworkin RH, Turk DC, Revicki DA, Harding G, Coyne KS, Peirce-Sandner S, Bhagwat D, Everton D, Burke LB, Cowan P, Farrar JT, Hertz S, Max MB, Rappaport BA, Melzack R. Development and initial validation of an expanded and revised version of the Short-form McGill Pain Questionnaire (SF-MPQ-2). Pain 2009;144(1–2):35–42. [DOI] [PubMed] [Google Scholar]
- [17].Farland LV, Correia KF, Wise LA, Williams PL, Ginsburg ES, Missmer SA. P-values and reproductive health: what can clinical researchers learn from the American Statistical Association? Hum Reprod 2016;31(11):2406–2410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [18].Ferreira-Valente MA, Pais-Ribeiro JL, Jensen MP. Validity of four pain intensity rating scales. Pain 2011;152(10):2399–2404. [DOI] [PubMed] [Google Scholar]
- [19].Ferrero S, Abbamonte LH, Giordano M, Ragni N, Remorgida V. Deep dyspareunia and sex life after laparoscopic excision of endometriosis. Hum Reprod 2007;22(4):1142–1148. [DOI] [PubMed] [Google Scholar]
- [20].Ferries-Rowe E, Corey E, Archer JS. Primary Dysmenorrhea: Diagnosis and Therapy. Obstet Gynecol 2020;136(5):1047–1058. [DOI] [PubMed] [Google Scholar]
- [21].Greene R, Stratton P, Cleary SD, Ballweg ML, Sinaii N. Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis. Fertil Steril 2009;91(1):32–39. [DOI] [PubMed] [Google Scholar]
- [22].Grundström H, Gerdle B, Alehagen S, Berterö C, Arendt-Nielsen L, Kjølhede P. Reduced pain thresholds and signs of sensitization in women with persistent pelvic pain and suspected endometriosis. Acta Obstet Gynecol Scand 2019;98(3):327–336. [DOI] [PubMed] [Google Scholar]
- [23].Gunn HM, Tsai MC, McRae A, Steinbeck KS. Menstrual Patterns in the First Gynecological Year: A Systematic Review. J Pediatr Adolesc Gynecol 2018;31(6):557–565.e556. [DOI] [PubMed] [Google Scholar]
- [24].Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009;42(2):377–381. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [25].Kennedy S, Bergqvist A, Chapron C, D’Hooghe T, Dunselman G, Greb R, Hummelshoj L, Prentice A, Saridogan E. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod 2005;20(10):2698–2704. [DOI] [PubMed] [Google Scholar]
- [26].Knox B, Ong YC, Bakar MA, Grover SR. A longitudinal study of adolescent dysmenorrhoea into adulthood. Eur J Pediatr 2019;178(9):1325–1332. [DOI] [PubMed] [Google Scholar]
- [27].Larrosa Pardo F, Bondesson E, Schelin MEC, Jöud A. A diagnosis of rheumatoid arthritis, endometriosis or IBD is associated with later onset of fibromyalgia and chronic widespread pain. Eur J Pain 2019;23(8):1563–1573. [DOI] [PubMed] [Google Scholar]
- [28].Laufer MR, Goitein L, Bush M, Cramer DW, Emans SJ. Prevalence of endometriosis in adolescent girls with chronic pelvic pain not responding to conventional therapy. J Pediatr Adolesc Gynecol 1997;10(4):199–202. [DOI] [PubMed] [Google Scholar]
- [29].Maixner W, Fillingim RB, Williams DA, Smith SB, Slade GD. Overlapping Chronic Pain Conditions: Implications for Diagnosis and Classification. J Pain 2016;17(9 Suppl):T93–t107. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [30].Missmer SA. Why so null? Methodologic necessities to advance endometriosis discovery. Paediatr Perinat Epidemiol 2019;33(1):26–27. [DOI] [PubMed] [Google Scholar]
- [31].Nisenblat V, Bossuyt PM, Farquhar C, Johnson N, Hull ML. Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev 2016;2(2):Cd009591. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [32].Nnoaham KE, Hummelshoj L, Webster P, d’Hooghe T, de Cicco Nardone F, de Cicco Nardone C, Jenkinson C, Kennedy SH, Zondervan KT. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011;96(2):366–373.e368. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [33].Phan VT, Stratton P, Tandon HK, Sinaii N, Aredo JV, Karp BI, Merideth MA, Shah JP. Widespread myofascial dysfunction and sensitisation in women with endometriosis-associated chronic pelvic pain: A cross-sectional study. Eur J Pain 2021;25(4):831–840. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [34].Rothman KJ GSLTL. Modern epidemiology. 2008.
- [35].Sasamoto N, Farland LV, Vitonis AF, Harris HR, DiVasta AD, Laufer MR, Terry KL, Missmer SA. In utero and early life exposures in relation to endometriosis in adolescents and young adults. Eur J Obstet Gynecol Reprod Biol 2020;252:393–398. [DOI] [PubMed] [Google Scholar]
- [36].Schliep KC, Mumford SL, Peterson CM, Chen Z, Johnstone EB, Sharp HT, Stanford JB, Hammoud AO, Sun L, Buck Louis GM. Pain typology and incident endometriosis. Hum Reprod 2015;30(10):2427–2438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [37].Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K, Missmer SA. Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol 2018;51:1–15. [DOI] [PubMed] [Google Scholar]
- [38].Shah DK, Missmer SA. Scientific investigation of endometriosis among adolescents. J Pediatr Adolesc Gynecol 2011;24(5 Suppl):S18–19. [DOI] [PubMed] [Google Scholar]
- [39].Shum LK, Bedaiwy MA, Allaire C, Williams C, Noga H, Albert A, Lisonkova S, Yong PJ. Deep Dyspareunia and Sexual Quality of Life in Women With Endometriosis. Sex Med 2018;6(3):224–233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [40].Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P. High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Hum Reprod 2002;17(10):2715–2724. [DOI] [PubMed] [Google Scholar]
- [41].Smorgick N, Marsh CA, As-Sanie S, Smith YR, Quint EH. Prevalence of pain syndromes, mood conditions, and asthma in adolescents and young women with endometriosis. J Pediatr Adolesc Gynecol 2013;26(3):171–175. [DOI] [PubMed] [Google Scholar]
- [42].Stuparich MA, Donnellan NM, Sanfilippo JS. Endometriosis in the Adolescent Patient. Semin Reprod Med 2017;35(1):102–109. [DOI] [PubMed] [Google Scholar]
- [43].Tsonis O, Barmpalia Z, Gkrozou F, Chandraharan E, Pandey S, Siafaka V, Paschopoulos M. Endometriosis in adolescence: Early manifestation of the traditional disease or a unique variant? Eur J Obstet Gynecol Reprod Biol 2020;247:238–243. [DOI] [PubMed] [Google Scholar]
- [44].Vercellini P, Somigliana E, Consonni D, Frattaruolo MP, De Giorgi O, Fedele L. Surgical versus medical treatment for endometriosis-associated severe deep dyspareunia: I. Effect on pain during intercourse and patient satisfaction. Hum Reprod 2012;27(12):3450–3459. [DOI] [PubMed] [Google Scholar]
- [45].Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, Giudice LC, Stratton P, Adamson GD, Becker CM, Zondervan KT, Missmer SA. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril 2014;102(5):1223–1232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [46].Wolfe F, Butler SH, Fitzcharles M, Häuser W, Katz RL, Mease PJ, Rasker JJ, Russell AS, Russell IJ, Walitt B. Revised chronic widespread pain criteria: development from and integration with fibromyalgia criteria. Scand J Pain 2019;20(1):77–86. [DOI] [PubMed] [Google Scholar]
- [47].Yosef A, Allaire C, Williams C, Ahmed AG, Al-Hussaini T, Abdellah MS, Wong F, Lisonkova S, Yong PJ. Multifactorial contributors to the severity of chronic pelvic pain in women. Am J Obstet Gynecol 2016;215(6):760.e761–760.e714. [DOI] [PubMed] [Google Scholar]
- [48].Zondervan KT, Yudkin PL, Vessey MP, Jenkinson CP, Dawes MG, Barlow DH, Kennedy SH. Chronic pelvic pain in the community--symptoms, investigations, and diagnoses. Am J Obstet Gynecol 2001;184(6):1149–1155. [DOI] [PubMed] [Google Scholar]
- [49].Zondervan KT, Cardon LR, Kennedy SH. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod 2002;17(6):1415–1423. [DOI] [PubMed] [Google Scholar]
- [50].Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020;382(13):1244–1256. [DOI] [PubMed] [Google Scholar]
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