Pain and endometriosis: Etiology, impact, and therapeutics

Abstract

The association of pain and endometriosis was recognized with the first definitive published reports of this disorder. Unfortunately, the precise etiologies and pathways leading to nociception and pain symptoms in endometriosis remain poorly understood, and as a result, effective therapeutic interventions are lacking with consequent profound effects on affected women’s quality of life. In this opinion paper we summarize selected proceedings presented at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Istanbul, Turkey, and review the clinical and translational evidence of chronic pain, neurogenesis, and the pernicious impact of dyspareunia on women with symptomatic endometriosis. The effectiveness of medical treatments is critically assessed and the findings indicate that good therapeutic options are available with extant medications effective in some sub-groups of women with endometriosis, many of which are affordable globally. Nevertheless, new management strategies and drugs need to be developed to increase the options of all afflicted women to minimize and ideally eradicate painful symptoms of endometriosis. However, only by elucidating distinctions among sub-groups with specific symptoms, suggesting different mechanisms, are we likely to derive truly successful therapeutic strategies.

1. Introduction

Endometriosis affects an estimated 176 million women worldwide between the ages of 15–49 (1) negatively influencing general physical, social and mental wellbeing during their most productive years (2). Pelvic pain has long been recognized as a critical concomitant of the endometriosis syndrome. Indeed, in Sampson’s classic treatise (3), 12 of the 17 symptomatic cases he reported presented for surgery due to intolerable pain. Interestingly, as long ago as 90 years, he recognized that “there is usually nothing characteristic about the pain present in this condition, nor is there necessarily any relationship between the extent of the adhesions and the severity of pain.” This lack of correlation continues to confound modern era gynecologists (4), in large part because the mediators of painful stimuli in endometriosis are inadequately understood. In the June 2005 issue of the journal Science, a provocative and impactful publication in our field described the growth of efferent sympathetic and afferent sensory nerves into the ectopic implants of endometriosis in women and in a rat model of the disease (5). This paper by Berkley et al. (5) caught the attention of gynecologists, physiologists and neuroscientists alike, galvanizing trans-disciplinary efforts to evaluate the causes and develop new methods to ameliorate pain associated with endometriosis.

2. Symposium venue

In July 2012, a pre-congress symposium on “Pain and Endometriosis” was convened at the 28th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Istanbul, Turkey, to address this specific topic. The course represented an international collaboration between the Special Interest Group for Endometriosis and Endometrium (SIGEE) of ESHRE and the Endometriosis Special Interest Group (EndoSIG) of the American Society for Reproductive Medicine, and was organized and moderated by Professors Hilary Critchley (United Kingdom), Pamela Stratton (USA), Aydin Arici (Turkey), and Dr. Gerard Dunselman (The Netherlands). Its purpose was to consider clinical management, including accumulation of the best available evidence, and to provide mechanistic insights into the etiology of endometriosis-associated pain. A diverse, trans-disciplinary group of experts provided formal presentations. The editors of the Middle East Fertility Society Journal invited members of the World Endometriosis Society to relate some of those deliberations in this Opinion Paper.

3. Clinical and translational evidence

In her lecture entitled “Chronic pelvic pain and endometriosis: Translational evidence of the relationship and implications” Pamela Stratton, MD, Head of the Gynecology Consult Service at the National Institute for Child Health and Human Development (NICHD) in Bethesda, Maryland, USA, reviewed the clinical characteristics of chronic pelvic pain. These symptoms commonly overlap among gynecological and nongynecological syndromes, including endometriosis, pelvic adhesions, leiomyomata and inflammatory bowel disease, making the precise attribution of pain difficult (6). She described current approaches to surgical treatment of endometriosis, based on the “oncological principle” to remove visible lesions and restore normal anatomy. As noted above, severity of symptoms correlates poorly with the extent of endometriosis and pain often recurs postoperatively even in the absence of visible new lesions. In only 50% of cases is pain relief sustained for more than a year after surgery; when pain recurs sooner, concomitant adenomyosis should be suspected. In the latter case, thickness of the junctional zone by magnetic resonance imaging may be informative (7). For medical management of endometriotic pain, it was noted that hormone treatments are not effective in all women and that leuprolide (a GnRH analog) may be effective in reducing pain even if it is not of endometriosis origin. Dr. Stratton’s interesting placebo-controlled trial of raloxifene was presented. Based on its antiestrogenic effects on endometrium and breast in animal and clinical studies, it was anticipated that this SERM might effectively suppress postoperative recurrence of pain from endometriosis. But in the 47 women randomized to up to 2 years of raloxifene (180 mg/day) following laparoscopic treatment of endometriosis, there was a significantly more rapid return of pain than the 46 subjects receiving placebo (8). Other pain studies from NICHD indicated that while migraine headaches might share pathophysiological pathways with endometriosisassociated pain, their prevalence was no greater in women with than those without endometriosis (9). Complex modeling, such as the Markov method, has been used to examine the lifetime utilization and perceived benefits of medical and surgical treatments for endometriosis-related symptoms. Using cross-sectional, self-reported survey data from 1160 women responding to the 1998 US Endometriosis Association survey, more than 40% had tried three or more different medicines and had three or more surgical procedures (10). The lecture concluded with a discussion of nociception (pain sensation) and sensitization of endometriotic lesions, modified by descending central nervous system pathways. The implications of myofascial trigger points and signs of sensitization including hyperalgesia, allodynia, and decreased pain pressure thresholds (PPT) were described as part of an ongoing study at NICHD. The preliminary data indicate that sensitization to pain is common in women with endometriosis, as well as in those with chronic pelvic pain without evidence of endometriosis (11). Dr. Stratton stressed that it will be important to extend our concepts beyond the endometriotic lesion per se, taking into account the complex influences of central afferents on nociception, if we are to improve the treatment of endometriosis-associated pelvic pain.

4. Fundamental mechanisms of neurogenesis in endometriosis

As noted above, microscopic studies have documented nerve fibers in endometriotic peritoneal lesions (12–14), deep infiltrating endometriosis (15,16), and ovarian endometriomas (17). Robert Taylor, MD, PhD, Vice Chair for Research in the Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA, described the significance of interactions between the immune and neurovascular systems in endometriosis. Analyses from two independent groups demonstrated dense networks of nerve fibers in the superficial eutopic (intrauterine) endometrium of patients with endometriosis, whereas only rare nerves were found in women without disease (18–20). The histological identification of nerves has been proposed as the basis for a sensitive (>90%), minimally invasive screening tool to identify women with endometriosis (18,20,21). Moreover, differences in endometrial nerve fiber density between normal women and those with endometriosis provide a plausible explanation for the pain associated with endometriosis (20–22).

Few studies of endometrial neurogenesis in endometriosis have been undertaken, but research involving nerve growth in other aspects of mammalian physiology has identified several different neurotrophin (NT) proteins that promote neuron growth and survival. Among these, nerve growth factor (NGF) was the first identified and is the most widely studied (23). NGF has been localized in different types of endometriotic lesions (13,17). NGF, NT-3, NT-4/5 and brain-derived neurotrophic factor (BDNF) mRNA expression was identified in ovarian endometriomas and eutopic endometrium of women with Stage IV endometriosis and pain (24). Coordinated neural and vascular mitogen action, a process coined “neuroangiogenesis,” was hypothesized to provide innervation and engraftment of refluxed endometrial fragments (25). Using a clinical proteomics and immunoassay approach, significant elevations in NT-4/5 and BDNF levels, but not NGF levels, were demonstrated in eutopic endometrial homogenates from subjects with endometriosis (26). Endometrial NT-3, ciliary neurotrophic factor, glial cell derived neurotrophic factor and neurotrophin receptor p75 were detected at relatively low concentrations on the antibody microarrays. Elevated peritoneal fluid levels of NGF (27) and eutopic endometrial TrkB receptor (28), which preferentially binds NT-4/5 and BDNF, have been reported in endometriosis cases.

We postulate that the pro-inflammatory environment within the pelvis of women with endometriosis, manifested by increased recruitment (29) and accumulation (30) of activated macrophages, contributes to the neuro-angiogenic milieu. Indeed, interleukin 1β, a critical paracrine factor in endometriosis (31) also is a potent mediator of neuro-inflammation (32).

These observations have important implications, as interference with NT production within the endometrium might be targeted in the future to mitigate the pain associated with endometriosis.

5. Clinical, personal, and social impacts of pain and dyspareunia

Lone Hummelshoj, Secretary General of the World Endometriosis Society (WES) and Chief Executive of the World Endometriosis Research Foundation (WERF), summarized the first global studies conducted by WERF, investigating the impact and costs of endometriosis across a total of 16 countries on five continents (33,34). These studies found that 65% of women ultimately diagnosed with endometriosis originally presented with pain symptoms, a third of whom also complained of infertility, whereas 14% sought resolution of infertility only. Fourteen percent of women requesting tubal sterilization were found to have asymptomatic endometriosis (33). The high economic cost of the disease (~€9,600/woman-year) is comprised of 1/3 direct health care costs, and 2/3 attributed to loss of productivity indicating the significant negative impact of symptomatic endometriosis on well-being and ability to function on a day-to-day basis (34).

A serious challenge in endometriosis is that the age of onset of menstrual pain is early and there is a significant delay (7–11 years (2,33)) before the average woman with the disease is diagnosed. Yet, among adolescents who complain of dysmenorrhea, approximately 70% eventually are diagnosed with endometriosis, so this symptom warrants special attention in young women (35,36). On average, women have seen seven health care professionals before referral to a specialist and initiation of treatment (33). This delay is due partly to a lack of awareness of endometriosis in adolescents, social taboos shrouding conditions involving the sexual organs, and the fact that many women, as well as primary care providers, are not familiar with the boundaries of normal and abnormal menstrual health (37).

In an ongoing WERF analysis, ~56% of questionnaire responders reported pain with sexual relations and among those, close to 54% limited or avoided intercourse altogether (de Graaff et al., unpublished results). Similar rates have been reported recently in other studies. In a questionnaire-based survey of 21,746 women in eight countries, 50% of women responded that the effect of pain on their sex lives was the single most important impact of endometriosis over the previous 12 months (38). In a 15-year follow up study, more than half of the women interviewed reported that the symptoms of endometriosis had negatively impacted their intimate relationships in some cases precipitating infidelity and divorce (39). Among the most severely debilitating pain symptoms is dyspareunia, which can deprive women and their partners of their sexual and reproductive rights (40), and focus on this specific symptoms is a high priority for the World Endometriosis Society (41).

Dyspareunia affects young women in their most sexually active years and consequently contributes negatively to fertility and pain, factors with the greatest impact on both physical and mental components of health-related quality of life (de Graaff et al., unpublished results). The accurate diagnosis of the existence of dyspareunia and causes of sexual dysfunction can be a challenge in women who find it difficult to disclose personal and intimate information. Representatives from the World Endometriosis Society have called for the assessment of dyspareunia from a broad clinical perspective, considering its profound psychological and interpersonal consequences. (41)

6. Effective medical treatment of endometriosis-associated pain

Paolo Vercellini, MD, Associate Professor at the Istituto Ostetrico Ginecologico “Luigi Mangiagalli” of the University of Milan, Italy, and President of WES, closed the symposium with a lecture on the medical treatment of endometriosis pain. In his introductory remarks he emphasized the point that available pharmacological agents for endometriosis are not cytoreductive, but only cytostatic and that upon restoration of ovulation and recrudescence of estradiol levels, quiescent ectopic and eutopic endometrium resume metabolic activity. His contention, well supported by the literature, was that potent drugs administered only for a few months due to poor tolerability, severe metabolic side-effects or high costs, were of less benefit to women than well-tolerated, inexpensive medications (such as combination oral contraceptive pills [OCPs] or progestin-only pills) that are safer to use long-term. Moreover, in head-to-head comparisons, the cheaper drugs were as effective (42). For women in whom cyclic OCPs did not provide adequate relief, switching to continuous OCP use resulted in ~50% decrease in visual analog scale dysmenorrhea scores and a significant improvement in overall satisfaction (43). Comparison of a continuous ethinyl estradiol and cyproterone acetate-containing combination with norethindrone acetate (2.5 mg/day) in a one-year study conducted in women with rectovaginal lesions, showed similar and dramatic relief of menstrual and non-menstrual pain as well as of dyspareunia (44). In particular, low-dose oral norethindrone acetate was associated with higher amenorrhea and patient satisfaction rates. This treatment strategy appears to be effective in reducing endometriosis recurrence as well. After conservative surgical treatment for ovarian endometriomas, cyclic low-dose, monophasic oral contraceptive containing ethinyl-estradiol (0.02 mg) and desogestrel (0.15 mg) was prescribed for a median follow-up of 28 months. Ultrasonographic evidence of recurrent endometriomas was 16% in the OCP-treated group compared to 49% in a control group that elected not to take OCPs postoperatively (P < 0.001) (45). A recent meta-analysis using the same postsurgical study design corroborated the original findings (46).

7. Conclusion

In summary, it was stressed that the general principles for evaluating the effectiveness of endometriosis treatment should be no different than those of other chronic inflammatory disorders, and specific metrics are in development to precisely understand the healthcare, quality of life and opportunity costs associated with the pains of endometriosis (34). From a research perspective, it is becoming increasingly important to recognize and identify specific characteristics and symptoms associated with endometriosis-related pain and not to lump all presentations together as an undifferentiated syndrome. Important distinctions among sub-groups with specific symptoms suggest different mechanisms; only by elucidating these are we likely to derive successful therapeutic strategies for the millions who struggle with painful symptoms on a daily basis (41).