{"paper_id":"932066f2-64f9-4cf8-b103-d1c4eabd57e4","body_text":"Original Article\nCorrelation between endometriosis\nand migraine features: Results from\na prospective case-control study\nAikaterini Selntigia1, Caterina Exacoustos 1, Camille Ortoleva 1,\nConsuelo Russo 1,2, Giulia Monaco 1,\nFrancesco Giuseppe Martire 2, Giuseppe Rizzo 3,\nDavid Della-Morte 4,5,6, Nicola Biagio Mercuri 4,7 and\nMaria Albanese 4,7\nAbstract\nBackground: Endometriosis and migraine frequently coexist, but only a limited number of studies have focused on\ntheir mutual association. The aim of our study was to investigate, in untreated women with comorbid endometriosis/\nadenomyosis and migraine, the correlation between headache features and endometriotic subtypes and their possible\nrelationship with pain severity and disease disability.\nMethods: Fifty women affected by endometriosis/adenomyosis and migraine matched (1:2) with 100 patients with\nendometriosis alone and 100 patients with only migraine were recruited and underwent pelvic ultrasound imaging and\nneurological examination.\nResults: Severe adenomyosis, posterior and anterior deep infiltrating endometriosis (p ¼ 0.027, p ¼ 0.0031 and\np ¼ 0.029, respectively) occurred more frequently in women with migraine. Dysmenorrhea was the most commonly\nreported symptom in women with endometriosis and migraine and the mean VAS scores of all typical endometriotic\nsymptoms were significantly higher in the presence of comorbidity. Women with both migraine and endometriosis\nreported significant higher pain intensity (p ¼ 0.004), higher monthly migraine days (p ¼ 0.042) and increased HIT\n6-scores (p ¼ 0.01), compared with those without endometriosis.\nConclusions: Our results demonstrated that the co-occurrence of migraine in untreated women with endometriosis is\nassociated with more severe gynecological infiltrations and correlated with increased pain intensity and disease disability.\nT rial Registration: Protocol number 119/21\nKeywords\nMigraine, endometriosis, adenomyosis, pain, disability, CGRP , deep infiltrating endometriosis\nDate received: 4 November 2023; revised: 5 February 2024; accepted: 7 February 2024\n1Department of Surgical Sciences, Gynecological Unit, University of\nRome T or Vergata, Rome, Italy\n2PhD Program in Medical-surgical Biotechnologies and T ranslational\nMedicine, Department Biomedicine and Prevention, University of Rome\nT or Vergata, Rome, Italy\n3Department of Biomedicine and Prevention, Obstetrics and\nGynecological Unit, University of Rome T or V ergata, Rome, Italy\n4Department of Systems Medicine, University of Rome T or Vergata,\nRome, Italy\n5Division of Internal Medicine-Hypertension, Department of Medical\nSciences, T or Vergata University Hospital, Rome, Italy\n6Department of Neurology, Evelyn F . McKnight Brain Institute, University\nof Miami Miller School of Medicine, Miami, FL, USA\n7Headache Center , Neurology Unit, T or Vergata University Hospital,\nRome, Italy\nCorresponding author:\nCaterina Exacoustos, University of Rome T or Vergata, Department of\nSurgical Sciences, Gynecological Unit, Viale Oxford, 81, 00133 Roma,\nItaly.\nEmail: caterinaexacoustos@tiscali.it\nCephalalgia\n! International Headache Society 2024\nArticle reuse guidelines:\nsagepub.com/journals-permissions\nDOI: 10.1177/03331024241235210\njournals.sagepub.com/home/cep\nCreative Commons Non Commercial CC BY -NC: This article is distributed under the terms of the Creative Commons Attribution-\nNonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and dis-\ntribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.\nsagepub.com/en-us/nam/open-access-at-sage).\n2024, Vol. 44(3) 1–9\n\n\nIntroduction\nEndometriosis and migraine represent two major\nchronic painful conditions of paramount relevance\nfor the women’s physical and mental health.\nEndometriosis is a gynecological inflammatory dis-\norder affecting up to 10–15% of women of reproduc-\ntive age and 35%–50% of infertile ones worldwide (1).\nThe disease is defined by the proliferation of endome-\ntrial tissue outside the uterus and is characterized by\nrecurrent “pain symptoms” including dysmenorrhea,\ndyspareunia, dyschezia, dysuria, and chronic pelvic\npain as well as infertility (1,2).\nWith an estimated global prevalence of 14.7%,\nmigraine, on the other hand, has been considered by\nthe Global Burden of Diseases 2019 as the first leading\ncause of disability in the under 50s young women (3).\nLike endometriosis, migraine typically presents with\nepisodic moderate-to-severe headache attacks, that\ncan be associated with other manifestations such as\nlight and/or sound hypersensitivity, nausea and vomit-\ning (4).\nIn addition to clinical and epidemiological similari-\nties, the two pathologies share several risk factors\nincluding early menarche, menorrhagia, and hormonal\ndysregulation (5,6). A recent study revealed an\nhormone-dependent misregulation of plasma calcitonin\ngene-related peptide (CGRP) as a possible pathophysi-\nological similarity of this comorbidity (7).\nNotwithstanding, it is observed a missed or delayed\ncare, leading to increased levels of disability and impact-\ning negatively on all aspects of individuals’ life (8,9).\nPrevious observational epidemiological studies\nreported a mutual relationship between migraine and\nendometriosis (10,11). Some authors also noted a dif-\nferent prevalence of pain-related problems and/or dis-\nease phenotypes when migraine and endometriosis\ncoexist (12–14). However, most of these evidences are\nbased on post-surgically proven refractory endometri-\nosis and/or self-administered questionnaires for head-\nache evaluation, with mixed and heterogeneous results\n(10–14). Moreover, these previous studies do not dif-\nferentiate between women with endometriosis and\nmigraine on hormonal treatment and those without\ntreatment, which could mask the pain symptom corre-\nlated with both diseases, and are commonly used for\nmanaging endometriosis (12–14).\nIn the last years, non-invasive techniques such as\ntransvaginal ultrasound imaging (TVS) has been recog-\nnized for reliably detect the localization and severity of\nendometriotic lesions without the necessity of histolog-\nical confirmation, especially in association with other\npainful symptoms (migraine), allowing an earlier dis-\nease diagnosis (15). Growing evidence suggests a high\naccuracy (80–100%) between ultrasound findings and\nsurgical staging, that has been considered as the diag-\nnostic gold standard in the past but is limited by\nincreased operative risks with economic barriers\n(16,17). Moreover, deep infiltrating endometriosis of\nretroperitoneal spaces is identified with higher accuracy\nby imaging compared to diagnostic laparoscopy which\ndoes not investigate this localization (18–20).\nBased on this scenario, in the present study we\naimed to investigate in non-hormonal-treated women\nwith comorbid endometriosis/adenomyosis and\nmigraine (EM-MG), compared to either women with\nonly endometriosis/adenomyosis (EM-O) or women\nwith migraine alone (MG-O): a) the different subtypes\nof endometriotic lesions and severity of adenomyosis;\nb) the different migraine features; c) their possible cor-\nrelation with disease severity and disability.\nMaterials and methods\nThis prospective case-control study enrolled consecu-\ntive patients admitted to the Endometriosis Unit and\nthe Headache Center at Tor Vergata University\nHospital of Rome between January 2021 and July\n2022. Within this cohort, women with endometriosis\nwith concomitant migraine (EM-MG) were considered\ncases, meanwhile women with only endometriosis\n(EM-O) and women with migraine alone (MG-O)\nwere regarded as two different control groups.\nWomen in premenopausal age (18–50 years) and not\nunder hormonal therapy were included in the study.\nExclusion criteria were: other concomitant neurologi-\ncal and/or psychiatric disorders; other primary form of\nheadache; use of central nervous system-active medica-\ntions; pregnancy at the time of examination; incom-\nplete clinical reports; history of oncologic disease of\ngenital tract; other chronic systemic, metabolic or\nautoimmune disorders that could have affected pain’s\nevaluation (i.e. fibromyalgia, inflammatory bowel\ndiseases).\nFor each case of endometriosis with concomitant\nmigraine (EM-MG), 2 controls with a defined diagno-\nsis of migraine without endometriosis (MG-O) and a\ndefined diagnosis of endometriosis without migraine\n(EM-O) were randomly enrolled querying the electron-\nic database of both unit in the same study period.\nControls were matched for age ( þ//C0 5 years) and\nbody mass index (BMI) ( þ//C0 1).\nAll participants were evaluated at the time of enroll-\nment by a gynecologist who confirmed the diagnosis of\nendometriosis based on the combination of clinical\nsymptoms and transvaginal ultrasound imaging\n(TVS), as previously reported and validated (15).\nThey were also examined by a headache expert neurol-\nogist, to confirm the diagnosis of migraine according to\n2 Cephalalgia\n\nthe International Classification of Headache Disorders\n3rd edition (ICHD-3) (21).\nThe study was conducted in respect of Helsinki rules\nand all subjects signed a written consent before being\nincluded in the study. The Internal Committee of the\nUniversity Hospital Tor Vergata approved the study\nwith protocol number 119/21. The study database is\navailable from the Corresponding Author on reason-\nable request.\nGynecological evaluation\nFor each patient, a detailed clinical history was assessed,\ncollecting the following: date of birth and age at time of\nenrollment, body mass index (BMI Kg/m\n2), age of men-\narche, menstrual cycle characteristics, last menstrual\nperiod, parity, delivery modality, primary or secondary\ninfertility, previous surgical interventions, other diseases,\nongoing medications. Infertility was defined as no preg-\nnancy after 12 months of intercourses. The following\npainful symptoms, compatible with endometriotic\nlesions and adenomyosis, were collected and scored\naccording to a standard visual analogue scale (VAS):\ndysmenorrhea, dyspareunia, dyschezia, dysuria, chronic\npelvic pain (CPP) intended as an unpleasant sensation\nexperienced by the patient outside the menstrual cycle\nfor at least 7 days and in 6 consecutive months. Bowel\nfunctional symptoms included symptoms such as consti-\npation, cyclic diarrhea, non-cyclical diffuse abdominal\npain, nonspecific gastrointestinal symptoms, nausea,\nand vomiting during the menstrual period. The\namount and duration of menstrual bleeding and any\nepisodes of intermenstrual bleeding were also investigat-\ned, asking patients to subjectively rate their menstrual\nflow (as being “poor”, “normal”, “abundant”). This\nsubjective evaluation is reported as reliable and compa-\nrable to the pictorial blood loss analysis chart (PBCA)\nscore (22).\nUltrasound imaging\nThe ultrasound examination was performed using a\nVoluson E6 or E8 device (GE Healthcare, Zipf,\nAustria) with a transvaginal probe. In pre-sexually\nactive patients, the vaginal probe was used transrectally\nto evaluate the pelvic organs with the same accuracy of\nthe transvaginal approach. Ultrasound examinations\nperformed only transabdominally were not considered\nin this study. A two- and three-dimensional (2D and\n3D) ultrasound with grey scale and power Doppler for\nassessment of the pelvis was performed. Scans evaluat-\ned the uterus, the adnexa, the pouch of Douglas, all\nother pelvic organs and sites. Endometriosis features\nwere always carefully scanned using a previously pub-\nlished ultrasound mapping system (23). The ultrasound\ndiagnosis of ovarian endometrioma was defined by the\npresence of a persistent unilocular or multilocular (less\nthan five locules) cyst characterized by a homogeneous\nlow-level echogenicity (ground glass echogenicity) of\nthe cyst fluid and absent or moderate vascularization\nof the cystic walls (24). The diagnosis of deep infiltrat-\ning endometriosis (DIE) was made if at least one struc-\nture in the anterior, posterior or lateral compartments\nshowed the presence of an abnormal retroperitoneal\nhypoechoic linear or nodular thickening with irregular\ncontours and no or few Doppler signals, according to\npreviously validated criteria (18–22). We reported the\nDIE localization in relation to the pelvic compartment:\nanterior (bladder, vescico-uterin septum), posterior\n(rectum, torus posterior vaginal fornix, RVS) and lat-\neral (bilateral USL parametria, ureters). Sonographic\nfindings of uterine adenomyosis were also recorded and\nits diagnosis was made when at least one direct imaging\nmorphological sign was present according to MUSA\ncriteria (24–26). Adenomyosis was classified as mild,\nmoderate, or severe according to our recently published\nclassification scoring system (26,27). According to\navailable ESHRE Guidelines, these TVS direct features\ncan be considered diagnostic and do not require a sur-\ngical confirmation (15).\nNeurological examination\nPatients were assessed by a headache expert neurologist\nwith a face-to-face interview using a semi-structured\nquestionnaire addressing clinical migraine characteris-\ntic, previous and current acute and preventive migraine\ntreatments, comorbidities, and concomitant medica-\ntions. All patients were asked to fill a prospective head-\nache diary. The following parameters were collected:\nage at migraine onset and duration, monthly migraine\ndays (MMDs); monthly days of painkillers intake\n(MPIs), intensity and duration of the headache\nattack, presence of associated symptoms (i.e. aura,\ncutaneous allodynia). Patients were also asked to rate\npain severity using the Visual Analogue Scale (VAS) of\nthe monthly most painful attack. According to the\nICHD-3 criteria, patients were categorized as having:\npure menstrual migraine (defined as migraine occurring\nexclusively on day 1 /C6 2 of menstruation); menstrually-\nrelated migraine defined as migraine occurring on day\n1 /C6 2 of menstruation and additionally at other times of\nthe cycle) or non-menstrual migraine (20). Migraine\ndisability was measured using the next validated stan-\ndard self-reported questionnaires: the Headache\nImpact Test (HIT-6) and the Migraine Disability\nAssessment Scale (MIDAS) (28,29). A detailed physical\nand neurological exam has been carried out to exclude\npresence of focal neurological deficit and/or secondary\ncauses of headache.\nSelntigia et al. 3\n\nStatistical analysis\nThe sample size was based on the following consider-\nations, matching the comorbid women by 1:2 with each\ncontrol group. Assuming a drop-out rate of 10% and a\nstatistical power of 0.9 at a significance level of a ¼ 0.05\n(two-tailed) using the Kruskal–Wallis analysis of vari-\nance (ANOVA), we planned to enroll a final sample\nsize of at least 50 cases (EM-MG), and respectively\nmatched 1:2, 100 controls with only endometriosis\n(EM-O) and 100 patients with migraine alone (MG-O).\nStatistical analysis was performed using the\nStatistical Package for the Social Sciences (SPSS\nv.15.0; SPSS, Inc., Chicago, IL). For population char-\nacteristics all continuous variables were expressed in\nterms of mean /C6 SD, while categorical variables were\nindicated in terms of frequency and percentage. The\nstatistical analysis initially assessed the general charac-\nteristics, prevalence of symptoms of endometriosis/\nadenomyosis and migraine, and transvaginal ultra-\nsound findings of the study population EM-MG.\nGeneral characteristics of EM-MG were compared\nwith the two control groups: EM-O and MG-O.\nPrevalence rate of different types of endometriosis/\nadenomyosis and endometriosic symptoms have been\ncompared between the study population and the con-\ntrol group EM-O. Prevalence rate of different migraine\nphenotypes and the impact on patient’s quality of life\nhas been calculated between the study population and\nthe control group MG-O. The characteristics between\ngroups were compared using the independent samples\nt-test for continuous variables and chi-square tests for\ncategorical variables. Fisher exact test was used to\ncompare prevalence and a p < 0.05 was considered sta-\ntistically significant.\nResults\nThe final sample consisted of 50 patients (mean age\n33.46 /C6 8.98) suffering from both endometriosis/adeno-\nmyosis and migraine (EM-MG) and two control groups\nof 100 women each one: EM-O (endometriosis/adeno-\nmyosis without migraine) and MG-O (patients\nwith migraine without endometriosis/adenomyosis).\nThe general characteristics of these three groups are\nreported in Table 1. In most patients (45/50, 90%),\nendometriosis was diagnosed after the migraine onset,\nwith a mean time lag of at least 12 years. The remaining\n10% of women received the diagnosis at the same age\n(2/50) or before (3/50) migraine presentation.\nThe comparison between EM-MG patients and\nEM-O control group is shown in Table 2. Mean VAS\nscores of all typical endometriotic symptoms (dysmen-\norrhea, dyspareunia, dyschezia, dysuria) were signifi-\ncantly higher in endometriotic women with migraine\nthan in those without migraine. Dysmenorrhea was\nthe most common symptom (94% vs 76%, p ¼ 0.007,\nTable 2), reported during TVS in women with migraine\nthan in those without migraine. Moreover, bowel\nsymptoms (28% vs 2%, p < 0.0001) and heavy men-\nstrual bleeding (66% vs 46%, p ¼ 0.02) were more fre-\nquent in cases than controls. Only the incidence of\ninfertility was similar in these two groups.\nConsidering the specific localization of endometriotic\nlesions and the different types of adenomyosis, we\nobserved a higher percentage of severe adenomyosis\nin the study group EM-MG compared with the control\ngroup EM-O (14% vs 4%, p ¼ 0.027). Posterior and\nanterior DIE occurred more frequently in women\nwith migraine EM-MG (48% and 10%, respectively)\nthan in those without migraine EM-O (30% and 2%,\np ¼ 0.0031 and 0.029, respectively). The incidence of\nother phenotypes of endometriosis was similar between\ncases and controls (p > 0.05) (Table 2).\nThe migraine features of women with and without\nendometriosis (EM-MG versus MG-O) are summa-\nrized in Table 3. Both groups of patients had a long\nhistory of migraine (a long migraine duration), com-\nmonly starting before the age of 18 years old.\nCompared to women with only migraine (MG-O),\nthose with EM-MG reported significant higher pain\nintensity (8.44 /C6 1.18 vs 7.74 /C6 1.47, p ¼ 0.004) and\nhigher monthly migraine days (MMDs 6.68 /C6 4.01 vs\n5.44 /C6 3.21, p ¼ 0.042). Monthly days with analgesic\nuse tended to be higher in cases than in controls, with-\nout reaching the statistical significance (MPIs 4.88 /C6\n4.47 vs 4.12 /C6 3.36, NS). Women mostly used\nT able 1. Demographic data.\nParameter\nStudy group EM-MG\nn ¼ 50\nControl group EM-O\nn ¼ 100\nControl group MG-O\nn ¼ 100\nAge (years) mean /C6 SD 33.46 /C6 8.98 32.94 /C6 5.49 33.60 /C6 8.26\nBody Mass Index (BMI) mean /C6 SD 20.99 /C6 6.34 22.08 /C6 3.43 22.96 /C6 3.88\nAge at menarche (years) mean /C6 SD 12.06 /C6 1.53 12.22 /C6 1.39 11.80 /C6 1.38\nParity n (%) 14 (28%) 24 (24%) 25 (25%)\nTime since endometriosis diagnosis (years) mean /C6 SD 2.1 /C6 4.38 2.14 /C6 3.91 NA\nTime since migraine onset (years) mean /C6 SD 15.42 /C6 11.05 NA 15.76 /C6 10.03\n4 Cephalalgia\n\nnon-steroidal anti-inflammatory drugs (NSAID) as\nacute medication, often self-administered without med-\nical advice and at different dosage recommended for\nmigraine. Only 4/50 EM-MG patients (8%) preferred\ntriptans for acute migraine management, that had been\nprescribed by a previous headache specialist, as few\nof them were already examined previously by\na neurologist and were recruited on their first visit in\nout headache center. In contrast, no women with\nmigraine alone reported the use of prophylactic head-\nache treatments, choosing non-pharmacological strate-\ngies such as nutraceuticals, osteopathy and acupuncture.\nOf the EM-MG group, 20% (10/50) had pure men-\nstrual migraine, 46% (23/50) had menstrually-related\nT able 2. Characteristics of women with endometriosis/adenomyosis.\nWith MIGRAINE\n(study group EM-MG)\nn ¼ 50\nWithout MIGRAINE\n(control group EM-O)\nn ¼ 100 P value 95% CI\nEndometriosis symptoms\nDysmenorrhea (VAS) mean /C6 SD 8.08 /C6 2.44 6.24 /C6 3.72 0.002 0.69 to 2.99\nDyspareunia (VAS) mean /C6 SD 4.92 /C6 3.18 3.70 /C6 3.56 0.042 0.04 to 2.40\nDyschezia (VAS) mean /C6 SD 2.48 /C6 3.59 1.08 /C6 2.52 0.006 0.40 to 2.40\nDysuria (VAS) mean /C6 SD 0.52 /C6 2.13 0 0.015 0.10 to 0.94\nDysmenorrhea n (%) 47 (94%) 76 (76%) 0.007 5.44 to 28.04\nDyspareunia n (%) 35 (70%) 56 (56%) 0.099 /C0 2.61 to 28.63\nDyschezia n (%) 17 (34%) 16 (16%) 0.001 3.70 to 33.05\nDysuria n (%) 6 (12%) 0 0.0004 4.62 to 23.80\nBowel symptoms n (%) 14 (28%) 2 (2%) <0.0001 0.14 to 0.40\nHeavy menstrual bleeding n (%) 33 (66%) 46 (46%) 0.02 0.03 to 0.35\nInfertility (primary/secondary) n (%) 8 (16%) 14 (14%) 0.745 0.09 to 0.15\nEndometriosis ultrasound findings\nEndometrioma n (%) 17 (34%) 26 (26%) 0.309 /C0 0.07 to 0.24\nDeep Infiltrated Endometriosis (DIE) n (%) 41 (82%) 76 (76%) 0.405 /C0 0.09 to 0.18\nPosterior DIE n (%) 24 (48%) 30 (30%) 0.031 0.017 to 0.34\nAnterior DIE n (%) 5 (10%) 2 (2%) 0.029 0.005 to 0.19\nLateral DIE n (%) 36 (72%) 62 (62%) 0.226 /C0 0.06 to 0.24\nAdenomyosis n (%) 30 (60%) 64 (64%) 0.634 /C0 0.12 to 0.20\nMild n (%) 8 (16%) 14 (14%) 0.745 /C0 0.09 to 0.16\nModerate n (%) 18 (36%) 42 (42%) 0.481 /C0 0.11 to 0.21\nSevere n (%) 7 (14%) 4 (4%) 0.027 0.08 to 0.22\nEndometriosis þ Adenomyosis n (%) 24 (48%) 44 (44%) 0.644 /C0 0.12 to 0.21\nT able 3. Characteristics of women with migraine.\nWith ENDOMETRIOSIS\n(study group EM-MG)\nn ¼ 50\nWithout ENDOMETRIOSIS\n(control group MG-O)\nn ¼ 100 P value 95% CI\nMigraine parameters\nDisease duration (years) mean /C6 SD 15.42 /C6 11.05 15.76 /C6 10.03 0.850 /C0 3.89 to 3.21\nPain intensity (VAS) mean /C6 SD 8.44 /C6 1.18 7.74 /C6 1.47 0.004 0.23 to 1.17\nMonthly migraine days (MMDs) mean /C6 SD 6.68 /C6 4.01 5.44 /C6 3.21 0.042 0.04 to 2.44\nMonthly painkillers intake (MPIs) mean /C6 SD 4.88 /C6 4.47 4.12 /C6 3.36 0.246 /C0 0.53 to 2.05\nMigraine with aura n (%) 8 (16%) 28 (28%) 0.106 /C0 0.02 to 0.24\nCutaneous allodynia n (%) 12 (24%) 16 (16%) 0.237 /C0 0.05 to 0.22\nMenstrual migraine subtypes\nPure menstrual migraine n (%) 10 (20%) 19 (19%) 0.88 /C0 11.39 to 15.56\nMenstrually-related migraine n (%) 23 (46%) 48 (48%) 0.82 /C0 14.61 to 18.23\nNon-menstrual migraine n (%) 17 (34%) 33 (33%) 0.90 /C0 14.09 to 17.21\nMigraine disability\nHIT -6 score mean/C6 SD 62.33 /C6 9.44 57.38 /C6 11.83 0.010 1.15 to 8.75\nMIDAS score mean /C6 SD 19.27 /C6 13.82 19.22 /C6 23.32 0.169 /C0 7.02 to 7.12\nSelntigia et al. 5\n\nmigraine and the remaining 17 patients (34%) had non-\nmenstrual migraine. These percentages were similar to\nthe MG-O control group.\nThe presence of migraine aura and/or cutaneous\nallodynia did not significantly differ between the two\ngroups of patients (p > 0.05). HIT-6 score was signifi-\ncantly increased in the EM-MG group compared to the\ncontrol group MG-O (62.33 /C6 9.44 vs 57.38 /C6 11.83,\np ¼ 0.01), meanwhile the MIDAS values were similar\nbetween them (see Table 3).\nDiscussion\nThis multidisciplinary study investigated the bidirec-\ntional relationship between a non-invasive diagnosed\nendometriosis and assessment of migraine in premeno-\npausal female patients not on hormonal therapies.\nEM-MG group presented more severe symptoms and\nmore frequent painful days than EM-O or MG-O.\nThese alterations were more prominent in the presence\nof adenomyosis and/or deep endometriosis subtypes,\nand did correspond to personal perception of discom-\nfort, with further negative effects on activities of daily\nlife. Migraine onset together with dysmenorrhea often\nstarted in adolescence and preceded the diagnosis of\nendometriosis by several years, becoming underesti-\nmated and undertreated, with a possible delay in\nbetter pain management.\nAlthough endometriosis and migraine commonly\nco-occur in women of reproductive age (5,6), data\nexploring the specific correlation between the two dis-\norders are not consistent across the studies, most prob-\nably due to the different methods of disease evaluation\nand high variability of patient cohorts (10–14).\nMaitrot-Mantelet and colleagues found a higher prev-\nalence of ovarian endometrioma and deeply infiltrating\nendometriosis (DIE) in women with associated\nmigraine compared to those without migraine (12). In\ncontrast, Pasquini et al. showed no difference of endo-\nmetriosis phenotypes between female patients with and\nwithout migraine (13). The main limitation of their\nstudies was that these alterations were observed\nmostly in women with post-surgically proven drug-\nresistant endometriosis, by using self-administered\nheadache reports and/or without considering the influ-\nence of hormonal contraceptive treatments on pain\nperception. Surgical laparoscopy has long been consid-\nered the gold standard for diagnosing endometriosis,\nbut it is limited by increased operative risk, high finan-\ncial costs, failure to evaluate the retroperitoneal spaces\nand underestimation of DIE (16,17). Recently, the\nEuropean Society of Human Reproduction and\nEmbryology guidelines recognized non-invasive\ntechniques including TVS, as a valid tool for an earlier\ndiagnosis of endometriosis in young patients, particu-\nlarly in the presence of other suspected pain diseases\nsuch as migraine, without the necessity of laparoscopic/\nhistological confirmation and with high accuracy\n(80–100%) compared to surgical staging (15,18–20).\nIn our case-control study, we confirmed a substan-\ntial correlation between migraine and endometriosis,\ndemonstrating a difference in both the intensity of all\ntypical painful symptoms and the disease severity\nbetween EM-MG and the other 2 groups. In fact, the\nVAS scores were significantly higher in women with\nassociated endometriosis and migraine compared\nto women with only one of the two disorders.\nFurthermore, migraine and pain manifestations were\nmore prevalent in advanced endometriosis, especially\nwhen coexisting with severe adenomyosis and deep\ninfiltrating types. These results are in line with those\nof Wu et al, who suggested that moderate-severe stages\nof endometriosis, in particular of adenomyosis, were\nsignificantly associated with the presence of migraine\nin women undergoing surgery (13). In this light, pain\nand its features may be an early indicator of comorbid\ndisorders and more complicated disease course, sup-\nporting the importance of a concurrent gynecological\nultrasound screening in women with migraine and, on\nthe contrary, of the clinical migraine search in patients\nwith endometriosis.\nFocusing on the different pelvic involvement of\nectopic tissues by ultrasound imaging, we also reported\nthat endometriosic patients with migraine had consid-\nerably higher prevalence of both posterior (p ¼ 0.031)\nand anterior (p ¼ 0.029) deeply infiltrating phenotypes\nthan those without migraine. Previous preclinical evi-\ndence highlighted that CGRP-positive sensory nerve\nfibers are more abundant around lesions of deep endo-\nmetriosis and create a pro-inflammatory state (28).\nThis micro-environment is able to promote the survival\nand progression of endometrial cells and to trigger\npainful symptoms due to heightened levels of neuro-\npeptides (29,30). At the same time, the release of\nCGRP and the so-called neurogenic inflammation in\nthe trigeminovascular system are also independently\ncrucial for migraine generation (30,31). Thus, we spec-\nulate that in comorbid women, severe adenomyosis and\nDIE might potentiate both abdominal symptoms and\nheadache due to most pronounced CGRP release com-\npared to patients EM-O or MG-O. This hypothesis is\nalso supported by the fact that only 8% of our\nEM-MG used triptans, a migraine-specific acute ther-\napy acting as potent agonists of 5-HT receptors that\nappear to be co-expressed with CGRP in trigeminocer-\nvical ganglion cells (31). Human CGRP levels were\n6 Cephalalgia\n\nreduced by triptans, coincident with pain relief, at both\ncentral and peripheral afferent terminals (31,32).\nConsequently, we suggest that the scarce triptan use\nin our comorbid women who are hormonal-drug free,\nmight further enhance the inflammatory setting CGRP-\nmediated and its persistent excitotoxic activities both in\nthe uterus and in the brain, sustaining more painful and\nfrequent attacks through a self-perpetuating vicious\ncircle (Figure 1). Interestingly, a recent study demon-\nstrated that in women with the comorbidity of migraine\nand endometriosis CGRP levels rise, with the drop of\nestrogens, during menstruation. While, in healthy\nfemales decrease of CGRP during the menstrual\nperiod was observed (7). However, other shared patho-\ngenetic mechanisms should be considered in the strict\ncomplex relationship between migraine and endometri-\nosis, including the genetic ones (6).\nNo difference between cases and controls was noted\nconcerning the prevalence of cutaneous allodynia. We\nhave no reliable explanation for this finding, probably\nbiased by the small number of women with chronic\nmigraine included in the study (MMDs /C21 15 in the last\nthree months), of which allodynia is a common\nmarker of disease progression (33). Other factors that\nhave been reported to increase the likelihood of having\nallodynia during migraine episodes are: high body\nmass index, headache-specific features such as high fre-\nquency of aura attacks, and comorbidity with\ndepression and anxiety, that were not present in our\ncohort of patients (32).\nAdditionally, our EM-MG patients exhibited higher\nHIT-6 scores than MG-O, pointing that the disease\nglobal burden could increase when both conditions\noccur together. On the other hand, the MIDAS\nvalues were similar among groups of women.\nAlthough HIT-6 and MIDAS are complimentary in\nmeasuring migraine-related disability, they also show\nsome substantial differences (28–34).\nThe HIT-6 depends more on headache severity and\nexplores patients’ impressions on how migraine is\naffecting them (28,34). The total score is obtained by\nsumming the weighted responses to all six questions\nand a value of /C21 60 reflects a greater disability, as\nreported only in our EM-MG patients (28,34). Unlike\nthe HIT-6, MIDAS is basically a function of migraine\nfrequency and relies on concrete variables (i.e., days of\nwork or school missed) (30,35). A score /C21 11 is a marker\nof negative impact of migraine on various aspects of\nwomen’s lives, with pain that can be disabling and\ncompromising family, work, school and social relation-\nships (29,34). Although been pathological in our women\nwith migraine, the mean MIDAS score was similar\nbetween patients with and without endometriosis.\nConsequently, we cannot exclude that it is also somehow\nrelated to the societal normalization of women’s\npain and stigma around menstrual issues (35).\nFigure 1. Mutual relationship between migraine and deep infiltrating endometriosis/adenomyosis.\nSelntigia et al. 7\n\nWomen often feel ashamed of their condition and the\ntaboo around topics like menstruation or painful sex\ncan prevent them from taking time off from work, seek-\ning help or discussing symptoms with and receiving sup-\nport from friends, family, employer and colleagues (9,35).\nMany may be suffering in silence at work, resulting in loss\nof significant productivity and in missed or delayed diag-\nnosis and treatment. This phenomenon might account for\nthe very high percentage of EM-MG patients in our\nsample (46/50, 92%) who self-medicate pain without\nspecialist-care for several years before being diagnosed.\nOur data were limited by the non-quantitative\nmeasurement of inflammatory, genetic and hormonal\nmediators for exploring their direct impact on the phe-\nnotype and severity of the two clustering conditions.\nFurther studies are needed to certify this association,\nto fully assess their changes in female patients and to\ndevelop more individualized therapeutic plans.\nConclusions\nOur findings further confirm the comorbidity of endo-\nmetriosis and migraine and indicate that pain intensity\nis correlated with disease severity and disability. A\ndetail evaluation of pain problems, clinically and by\nusing non-invasive techniques such as TVS, may repre-\nsent a powerful tool for earlier diagnosis and an oppor-\ntunity to monitor disease course, to prevent\nchronicization and to reduce socio-economic burden,\nthe main unmet needs of affected women. This is of\nparticular relevance in relation to innovative available\npharmacological classes of drugs targeting the CGRP\npathways (i.e monoclonal antibodies anti-CGRP,\nantagonists of CGRP receptors and/or agonists of the\n5-HT1F receptor) (36), that have recently revolution-\nized the migraine management and may also be bene-\nficial for comorbid endometriosis.\nClinical implications\n Women with endometriosis and migraine presented more severe symptoms and more frequent painful days\nthan patients with only endometriosis and/or migraine alone.\n These alterations were more prevalent in the presence of adenomyosis and/or deep endometriosis subtypes,\nleading to increased levels of disability.\n Early diagnosis of migraine and endometriosis (and of their association), clinically and by using non-\ninvasive ultrasound techniques, could significantly improve the patient management and overall health\nstatus.\nAuthor contributions\nAS: ultrasonographic scan, design and conceptualized study and\ninterpreted data; CE: ultrasonographic scan and revised the\nmanuscript for intellectual content; CR: ultrasonographic scan;\nCO: role in technological e xecution; IM: role in tec hnological\nexecution; GM: ultrasonographic scan; FGM: revised the man-\nuscript for intellectual content; NBM: revised the manuscript for\nintellectual content; MA: clinical neurological examination and\nrevised the manuscript for intellectual content.\nAll the authors discussed the results and commented on the\nmanuscript.\nDeclaration of conflicting interests\nThe authors declared no potential conflicts of interest with\nrespect to the research, authorship, and/or publication of this\narticle.\nFunding\nThe authors received no financial support for the research,\nauthorship, and/or publication of this article.\nReferences\n1. 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