A pilot study of the prevalence of leg pain among women with endometriosis

Endometriosis is the third leading cause of gynecologic hospitalization in the United States ( Eskenazi & Warner, 1997 ). Despite the high health care costs and morbidity associated with endometriosis, the etiology of endometriosis has not been fully delineated. The pathophysiology likely includes hormonal, anatomic, genetic, and immune factors. Risk may be associated with factors that increase the volume, frequency, and duration of retrograde menstruation and promote implantation and growth of endometrial plaque ( Oral & Arici, 1997 ). Women with endometriosis have been hypothesized to have a greater risk of chronic, cyclic leg pain that is independent of any referred dysmenorrheal pain. However, the prevalence of leg pain from all causes among women with endometriosis is unknown. A search of the literature revealed numerous case studies of sciatica due to endometriosis, and outcomes of surgical interventions that confirmed the origin of pain as from endometrioma on the lumbosacral plexus or intrapelvic sciatic nerve ( Binkovitz et al, 1991 ; Bjornsson, 1976 ; Denton & Sherrill, 1955 ; Descamps et al, 1995 ; Dhote et al, 1996 ; Papapietro et al, 2002 ; Takata & Takahashi, 1994 ; Torkelson et al, 1988 ; Vaisberg, 1964 ; Yekeler et al, 2004 ; Zager et al, 1998 ). Leg pain was incidentally reported by >40% of the 4000 respondents to a survey by the Endometriosis Association ( Sinaii et al, 2008 ), but specifics of the pain (location, timing, duration) were not assessed. These data suggest that endometriosis involving peripheral nerves is a common cause of leg pain in women. While the direct involvement of peripheral nerves has been referred to as “unusual” ( Binkovitz et al, 1991 ) and “rare” ( Dhote et al, 1996 ) ( Torkelson et al, 1988 ; Yekeler et al, 2004 ), under-recognition of leg pain among women with endometriosis has been cited ( Zager et al, 1998 ). This may be in part because the symptoms are similar to those often attributed to pathologies of the spinal structures, such as lumbar intervertebral discs and paraspinal muscles and joints. Manual therapists are likely to encounter patients with leg pain due to endometriosis, and need to recognize this etiological possibility. Because there had not been a formal determination of the prevalence and details of leg pain existing with endometriosis, we performed a survey designed to elucidate details about leg pain that may coexist or be caused by endometriosis.

Of the 306 mailed questionnaires, 19 were returned due to inaccurate address information. Of those who received the pilot mailing, a total of 94 women (33%) returned a completed questionnaire indicating laparoscopically confirmed endometriosis. These women ranged in age from 16 – 58 with a median age of 42. The women were primarily Caucasian (98%) and premenopausal (74%). Five women were pregnant or breast feeding at the time of questionnaire completion. The median time since diagnosis of endometriosis was 10 years (range = 1 – 33 years). A total of 48 women (51%) reported leg pain. While neither current weight nor weight at age 18 were significantly associated with risk of leg pain, we observed a borderline significant 2% increase in risk for each pound gained since age 18 (p-value, test for linear trend = 0.06; Table 1 ). In addition, as age increased, the risk of having leg pain increased (p-value, test for linear trend = 0.09). We also observed a linear association with height (p-value, test for linear trend = 0.08). No other participant characteristics were associated with the likelihood of leg pain. Forty-five of the 48 women with leg pain depicted their pain on profile diagrams ( Fig. 1 ). Pain severity encompassed the entire range, from mild to severe, and was more often reported in more than 1 region (1.8 regions +/− 1 SD). Most women (60%) reported proximal anterior leg pain. The distal anterior region was involved in 31% of women. The proximal and distal posterior regions were involved in 40%, and 47% of women, respectively. Women reported bilateral, unilateral left-, and unilateral right- sided leg pain (59%, 24%, and 17%, respectively; Table 2 ). Pain was most likely to be experienced during menstruation and just prior to the start of menses. This observation is consistent with the catamenial nature of the disease, where the symptoms result from immune mediated inflammation due to the presence of sloughed endometrial cells. Only 10% claimed that there was no relationship with their menses (i.e., they answered no to all queries). The majority of women (68%) who provided details about efforts to diminish their leg pain symptoms reported mentioning their leg pain to a clinician, and one-third of these women were referred to specialists. Nearly half of the patients were not offered any treatment option for this symptom. However, the majority of women attempted various treatments, and more than 2/3 reported some benefit.

In this cross-sectional pilot study among women with endometriosis, we observed that the prevalence of self-reported leg pain was 51%. The prevalence of leg pain among a comparable group of women is not known, but the few studies available estimate the point and lifetime prevalence of sciatic pain from all etiologies to be 2–5% and 2.5 – 21%, respectively ( Hofmann et al, 2002 ; Riihimaki et al, 1994 ; Videman et al, 2005 ; Younes et al, 2006 ). These data support that endometriosis is a prominent cause of radiating leg pain. It is acknowledged that the population observed in this pilot study may not be generalizable. Members of the Endometriosis Association are a self-selected group of women who have chosen to join a support group and pay annual dues, and their diagnosis, medical details, and experience of endometriosis are strictly self-reported. While these support group member women may represent those with more endometriosis-related sequelae ( Sinaii et al, 2008 ), these data were limited to respondents who reported laparoscopic confirmation of endometriosis, and therefore are more reliable than self-reports alone ( Missmer et al, 2004 ). Given the many causes of leg pain, it is unknown what proportion of our subjects had leg pain due to endometriosis directly affecting one or more peripheral nerve, and what proportion had pain due to co-existing pathologies. It was also not possible to identify cases of referred pain. While we plan to perform examinations of such women in the future, such differential diagnosis is often not possible. However, even if the true proportion of women who suffer from leg pain directly related to an endometriotic lesion affecting a peripheral nerve is much lower than 51%, and given that endometriosis among women of reproductive age is estimated to be as great as 10% ( Eskenazi & Warner, 1997 ), leg pain with endometriosis represents a significant public health concern. Further studies including control groups and physical examinations are warranted based on these initial observations. The variability of the pain distributions supports the hypothesis that leg pain associated with endometriosis can affect many different and even multiple nerves in the same woman. Most nerves to the lower limbs pass through the abdominal and pelvic cavities, only separated from the intraperitoneal space by the peritoneum. Inflammatory endometrioma that are attached to the peritoneum in close proximity to a nerve are likely to inflame the nerve and the axons it contains, and indeed show a predilection for nerves ( Anaf et al, 2004 ; Anaf et al, 2000 ). Such a neuritis could cause local or radiating pain; this is supported by data from rat models ( Bove & Light, 1997 ; Bove et al, 2003 ; Bove et al, 2009 ; Sauer et al, 1999 ). It is also possible that nerve inflammation due to endometriosis leads to abdominal and pelvic pain as well as leg pain, by affecting the nerves supplying the viscera. Finally, afferent activity in these nerves could be sufficient to form what has been called the “peripheral generator” ( Gracely et al, 1992 ; Hedo et al, 1999 ). In this concept, the nociceptive afferent signals from a pathology induce and then maintain a form of spinal cord or higher center sensitization, which then can lead to the perception of pain in areas that are neurologically remote from the location of the pathology, i.e. are innervated by different nerves. Thus, the pain or other sensations could be perceived in a much wider distribution than would seem appropriate to the pathology. While the sample size for this pilot study is relatively small, these data yield the first quantification of the leg pain experience of women with endometriosis. We hypothesize that this symptom, though prevalent, may elude clinical detection, and indeed may be masked by referred dysmenorrheal pain. It is possible that women do not make the connection between their abdominal / pelvic pain and their leg pain, or are not forthcoming in discussing this with their physician ( Zager et al, 1998 ). Moreover, because non-pelvic pain associated with endometriosis is not well described in the literature, it is also possible that physicians and other therapists do not customarily ask details about such symptoms. The etiology of radiating leg pain is often obscure. When a patient presents with radiating leg pain, most clinicians look for pathologies of the musculoskeletal system, such as altered spinal mechanics or focal muscle hypertonicities (“trigger points”), which can lead to similar symptoms. The initial findings reported here support the concept that endometriosis that directly involves nerves should also be considered in women with endometriosis. While there may not be pathognomonic symptoms aside from the radiating pain distribution, neurological and orthopedic examinations should prove consistent with peripheral nerve involvement. Our goal is that the results of this pilot study will lead to improved diagnostic awareness of this prevalent consequence of endometriosis.

This research was approved by the Institutional Review Board of the Beth Israel Deaconess Medical Center. The Endometriosis Association is a national support group in the United States that is focused on progress in treatment and research of endometriosis. A total of 306 members with the disease who resided in the geographic vicinity of Boston, Massachusetts were mailed a 4-page questionnaire to be completed and returned in a postage paid envelope. The time allowed from initial mailing to receipt of the final questionnaire was 3 months. No repeat mailings or other methods to increase response rate were employed. Because endometriosis is sufficiently validated by self reporting when a woman reports laparoscopic confirmation ( Missmer et al, 2004 ), the first question asked was whether endometriosis had been confirmed laparoscopically. Women who did not report laparoscopic confirmation were not asked to complete the questionnaire and were not included in the results. The questionnaire then asked details of demographic and anthropometric characteristics, reproductive history, and pain symptoms. Those who reported suffering from leg pain were asked to provide details of their pain including clinical help sought and treatments attempted. In addition, they completed pain drawings. Analysis of the pain diagrams was performed with acknowledgment of the limitations regarding the determination of the involved nerve(s), which is difficult even during clinical evaluation, particularly when deep pain is involved. As previously performed ( Bove et al, 2005 ), we subdivided the leg into 4 regions: proximal anterior (hip to knee), distal anterior (knee to foot), proximal posterior, and distal posterior. Respondent marks within these boundaries were counted as noting presence of pain in this region of the leg. Using SAS Statistical Software Version 8.2 (SAS Institute Inc., Cary, NC), we compared the distribution of demographic, anthropometric, dietary intake, and reproductive history characteristics between women with laparoscopically confirmed endometriosis who did and did not report experiencing leg pain. Unconditional logistic regression was used to calculate the crude and multivariable odds ratios (OR) and 95% confidence intervals (CI) that are presented as estimates of the relative risk ( Rothman & Greenland, 1998 ). In the final models, we included all variables that were observed to be significantly associated with leg pain as potential confounders. We conducted tests for trend in ordinal categorical exposures by creating an ordinal variable in which the median value or midpoint of each category was assigned to all participants in that group and then calculated a Wald statistic ( Lemeshow & Hosmer, 1989 ). Statistical significance was placed at the 0.10 level.