Pain and symptom survey results were compared with laparoscopy findings in a secondary analysis of a study investigating the use of raloxifene after surgery, to explore associations between pain location and biopsy-proven endometriosis lesion location. Neither lesions nor lesion characteristics were predictive of pain in the same anatomic locations. While dysuria predicted peritoneal lesions on the bladder, we found no association between dyspareunia and cul-de-sac or uterosacral lesions.
The strengths of our study include the systematic collection of data about pain and other symptoms, the collection of surgical data by a skilled observer in consultation with the surgical team in the operating room, and histopathologic confirmation of endometriosis for each lesion in every subject. Using the same surgical team limits interobserver variability, but may limit the generalizability of findings. Other studies acquired data on patient symptoms and surgical findings from medical records which may be incomplete. Having a dedicated research team to comprehensively catalog lesions and pain symptoms is important to evaluate relationships between pain location and lesion location or other lesion characteristics.
In two similar studies of women with DIE lesions, severe dyspareunia and painful defecation during menses was associated with posterior DIE (12
), and those with rectal or vaginal DIE lesions reported increased severity of dysmenorrhea (13
). In the retrospective study of 225 women by Fauconnier et al. (3
), severe dysmenorrhea was associated with adhesions in the pouch of Douglas, dyspareunia with uterosacral ligament DIE, lower urinary tract symptoms with bladder DIE, and gastrointestinal symptoms with bowel or vaginal DIE. Thus, DIE nodules may trigger pain and their removal may be therapeutic (3
Similar findings were reported by Vercellini et al. (4
) in a retrospective study of 1054 women undergoing surgery for pain, pelvic mass, or infertility, a strong association between posterior cul-de-sac lesions and pain at intercourse was noted. Unlike Vercellini et al, our study has too few subjects with DIE in the cul de sac to assess this association. In the Vercellini study, Endometriosis stage was weakly associated with nonmenstrual pain, pelvic symptom severity, and dysmenorrhea severity, which was of questionable significance in their large population.
Laparoscopy under local anesthesia, or conscious pain mapping, may add information to visual inspection of the pelvis in women with chronic pelvic pain (15
). While probing pelvic structures and visible pathology in a standardized fashion, subjects rate any pain on a 0–10 VAS scale. Focal tenderness may be treated with local anesthetic, re-examined, and re-scored for pain. With this technique, some subjects with pain localized to the gallbladder (16
) and appendix (17
) improved after cholecystectomy or appendectomy, respectively.
In studies of conscious pain mapping and endometriosis (18
), most women localized pain to their endometriotic lesions. However, many participants (19
), as well as 10 of 11 subjects in a similar study (20
), demonstrated generalized visceral hypersensitivity, in which all areas of the pelvis and bowel were sensitive, and pain was not completely blocked with local anesthesia.
In a prospective study, Demco et al. (21
) reported that a majority of participants had correct left-right pelvic orientation for provoked pain location during laparoscopy under conscious sedation. However, half of the cohort perceived pain on the opposite side or referred to another location. Referred pain and right-left disorientation may be altered by thalamic misinterpretation of input from the spinal cord, or by viscero-visceral or viscera-somatic convergence within the nervous system (21
). Similarly, our inability to relate lesion location with pain location may be influenced by generalized hypersensitivity. Indeed, our sub-analysis of participants with only a single endometriosis lesion noted most women had generalized pain, experiencing both ipsilateral and contralateral pain.
As opposed to other studies (4
) which combined pain and infertility cohorts, our study population was comprised exclusively of women with chronic pain. We systematically evaluated and excluded women with other causes of chronic pelvic pain, such as irritable bowel syndrome or fibromyalgia. Despite our efforts to exclude these other causes, we did not find any association between the location of pain and the location of superficial lesions. Whether other causes of pelvic pain are sought is not consistently addressed in other studies of subjects with endometriosis. Thus, endometriosis may not be the cause of pain. Further, there is tremendous heterogeneity in women with chronic pain such that the severity, associated symptoms, and initiating conditions vary from one individual to another.
A particular strength of our study was the histologic confirmation of laparoscopic diagnoses of endometriosis, occurring in two-thirds of biopsies in this cohort (23
). Visual diagnosis of endometriosis by laparoscopy has poor sensitivity and specificity. A “positive” finding on laparoscopy is incorrect in up to half of cases (25
), while biopsy of normal-appearing peritoneum has shown endometriosis in 6% of women with no visible lesions (26
). Visual diagnosis may be challenging because of the differing color, size, and morphology of peritoneal lesions (23
). Only 75.6% and 72.9% of women in studies by Fauconnier et al. (3
) and Vercellini et al. (4
), respectively, had biopsy-confirmed endometriosis. The possible miscategorization of up to one-fourth of subjects as having endometriosis, when they may not actually have the disease, may hamper inferring any association or lack of association between lesions and pain.
The inherent limitations of our study include possible selection bias and study design limitations. Most subjects were self-referred and only had minimal or mild disease at surgery. The study goal was to treat women with complete excision of all lesions at laparoscopy. Since bowel resections were not performed in this study; our findings are not generalizable to women with extensive disease involving the bladder, ureters, and bowel. All subjects underwent excision of all suspicious lesions, but some lesions may have been missed even with careful inspection. Secondly, there may be inaccuracies in translating how women ascribe their pain to a pelvic region, as well as in how lesion characteristics and location were recorded. We attempted to overcome these potential inaccuracies by defining anatomic regions broadly.
Third, the analysis was restricted to biopsy-proven endometriosis; whether some lesions were innervated while others were not was not studied here. Fourth, this analysis only estimated the relationship between pain and biopsy-proven endometriosis; the relationship between pain and adhesions or other non-endometriotic lesions was not considered. While adhesions were recorded, we were unable to infer whether adhesions related to endometriosis or prior surgery caused pain. Finally, since this study investigated secondary outcomes of a larger clinical trial, it may not be adequately powered (aggregate power yielded 65% using a two-sided alpha of 0.05) for the observed results, thus inflating the type 2 error. However, type 1 error was minimized by correcting p-values for multiple comparisons. This study had insufficient power to assess the relationship between deeply infiltrating lesions and pelvic pain.
The inconsistency of the relation between the presence or severity of pain with endometriosis lesion location, extent of disease, and lesion characteristics also emphasizes that pelvic pain is a symptom which may also arise in the setting of other regional pain syndromes such as migraines (27
), irritable bowel syndrome, painful bladder syndrome, and fibromyalgia (22
). These diseases each engage the nervous system in one of several mechanisms (22
). Most of our subjects, including those with a single endometriosis lesion, experienced diffuse pain which may reflect central nervous system sensitization. The fact that patients experience a region of pain in the setting of endometriosis may, in fact, be the reason why lesion location is not
correlated with pain symptoms.
Sensitization is a form of neural plasticity that includes allodynia, hyperalgesia, and a lowered pain pressure threshold affecting multiple adjacent spinal cord segments. Bajaj et al. (30
) has reported central sensitization and generalized hypersensitivity in women diagnosed with endometriosis, compared to healthy volunteers. “Generalized visceral hypersensitivity” described in conscious pain mapping studies also suggests sensitization. Possible mechanisms suggested by Stratton and Berkley (22
) include incomplete resection of lesions, which may activate nociceptor activity after surgery, as well as damage to peripheral axons of nociceptor (pain receptor) afferents during surgery, which in turn initiates visceral pain which can persist or is easily reinitiated after surgery.
Overall, we did not find a statistically significant relationship between pain location and the location of superficial endometriosis lesions. This raises questions about how these lesions relate to pain. Referred pain, inconsistent innervation of lesions, and viscero-viscero and viscero-somatic convergence may result in pain that does not map to endometriosis lesions and endometriomas. The interaction between lesions, local nerve fibers, and the central nervous system may be more significant than the existence of endometriosis lesions in any particular anatomic location. Improving treatment of women with endometriosis-related pain will likely require a better understanding of these pain mechanisms to determine whether they are initiated and perpetuated by inflammatory or other neuropathic mechanisms, and to determine the role hormones may play in such mechanisms. This may lead to insights into which patients may benefit from surgery, and may aid in tailoring hormonal or other treatments.