{"paper_id":"1b63a7f1-86f7-48ce-95f7-eb4a7c7b2f92","body_text":"Vol.:(0123456789)\nActa Neurologica Belgica (2024) 124:1263–1271 \nhttps://doi.org/10.1007/s13760-024-02484-2\nORIGINAL ARTICLE\nInvestigating migraine phenotype and dynamics in women \nwith endometriosis: an observational pilot study\nGabriele Merki‑Feld1,2  · Hanna Dietrich1 · Patrick Imesch3 · Andreas R. Gantenbein4,5 · Peter Sandor4 · \nChristoph J. Schankin6\nReceived: 25 July 2023 / Accepted: 22 January 2024 / Published online: 15 June 2024 \n© The Author(s) 2024\nAbstract\nIntroduction Migraine and endometriosis are chronic disabling pain conditions. There is evidence for a shared genetic \nbackground. Migraine phenotype and course in patients with the comorbidity are insufficient investigated. Both conditions \ncan be treated with progestins.\nMethods For this observational study we included women with migraine and endometriosis, visiting our clinic from 2015 \nto 2021. We collected available information from charts and complemented these data by a structured phone interview to \ncollect more specific information on migraine and the course of both diseases.\nResults From 344 patients fulfilling the inclusion criteria, 94 suffered from both, endometriosis and migraine. Migraine \nwith aura was reported by 41% of the patients and was associated with earlier onset of migraine (age < 17 years (OR 6.54) \nand with a history of medication overuse headache (OR 9.9, CI 1.6–59.4). Present monthly migraine frequency (1.5 ± 2.6) \nwas significantly lower than five years before the interview (2.9 ± 4.64). There was a correlation between medication overuse \nheadache and use of analgesics more than 3 days/months for dysmenorrhoea (p < 0.03). ASRM endometriosis score was not \nassociated with migraine characteristics.\nConclusions We conclude that the comorbidity of endometriosis is highly linked to migraine with aura. Migraine onset in \nthese patients was earlier. Further studies are needed to explore, if the observed decrease in migraine frequency can be attrib-\nuted to recent endometriosis surgery and to understand if early diagnosis and treatment of both conditions may contribute \nto improve the course of both conditions.\nTrial registration BASEC Nr. 2021-00285.\nKeywords Migraine · Endometriosis · Aura · Dysmenorrhea\nAbbreviations\nMO  Migraine without aura\nMA  Migraine with aura\nMO  Migraine without aura\nMOH  Medication overuse headache\nMMF  Monthly migraine frequency\nASRM  American society for reproductive medicine\nIntroduction\nBoth, endometriosis and migraine are chronic inflam-\nmatory disorders with estrogens playing a pivotal role in \nthe pathophysiology [1 –4]. Both conditions are associ-\nated with chronic pain and a high grade of disability in \nwomen during the reproductive years. Typically, symp-\ntoms decrease, when women approach menopause [5 , 6]. \n * Gabriele Merki-Feld \n Gabriele.merki@usz.ch\n1 Department of Reproductive Endocrinology, University \nHospital Zurich, 8091 Zurich, Switzerland\n2 Department of Gynaecologic Endocrinology, University \nHospital Zurich, Frauenklinikstrasse 26, 8091 Zurich, \nSwitzerland\n3 Department of Gynaecology, University Hospital Zürich, \nZurich, Switzerland\n4 Department of Neurology and Pain, ZURZACH Care, \nBad Zurzach, Switzerland\n5 Neurologie am Untertor, Bülach, Switzerland\n6 Department of Neurology, Inselspital, Bern University \nHospital, University of Bern, Bern, Switzerland\n\n1264 Acta Neurologica Belgica (2024) 124:1263–1271\nToday there is high evidence that both conditions might \nshare a common genetic background and that polymor -\nphisms of sex hormones play a crucial role [3 , 4, 7]. In a \nlarge case–control study, Yang et al. found among 20,220 \npatients with endometriosis a 1.7-fold higher prevalence \nof migraines than in controls.[8 ]. Survey-based case–con-\ntrol studies in endometriosis patients reported migraine in \n29–69% of the affected women, which is far higher than \nthe expected prevalence in the general female population \n[1, 2, 9]. Both conditions respond to treatment with the \nsynthetic progestin desogestrel, which is used continu-\nously and inhibits ovulation [10– 15].\nSevere dysmenorrhea without response to pain killers \nis one of the typical early symptoms in adolescents with \nendometriosis [16]. Early diagnosis of both conditions and \nspecific treatment is highly relevant to reduce the prob-\nability of developing chronic pelvic pain and possibly \ncorresponding alterations of pain response in the brain \n[17]. Women with comorbid migraine and endometriosis \nmight be at increased risk for medication overuse head -\nache (MOH), as they need to use painkillers for menstrual \nand non-menstrual pelvic pain and in addition for their \nheadaches. While several studies investigated the preva-\nlence of migraine in women with endometriosis, there is \nonly minimal knowledge on migraine characteristics in \nwomen with the comorbidity. Theoretically, endometrio-\nsis patients might be more prone to suffer from chronic \nmigraine or a higher migraine frequency. It is unknown if \nwomen with this comorbidity suffer rather from migraine \nwith aura (MA). There seems to be a genetic component \n[18]. Women during the reproductive years tend to suffer \nmore from menstrual migraine without aura (MO). With \nthe present study, we aimed to identify migraine pheno -\ntypes in women with migraine and endometriosis and the \ndynamics of migraine in these patients. In particular we \nfocused on aura, monthly migraine frequency (MMF) at \npresent during puberty and 5 years ago, age at migraine \nonset, history of medication overuse headache, use of pro-\nphylactic agents and quality of life were in our focus.\nMaterials and methods\nStudy design\nThis observational study was conducted at the Clinic for \nReproductive Endocrinology in the Department of Gynae-\ncology of the University Hospital of Zurich. Data were col-\nlected from patient records and supplemented through tel-\nephone interviews. The presented data is part of a broader \nstudy investigating the characteristics of endometriosis in \nwomen with different comorbidities.\nData collection\nPotential participants with the diagnosis of endometriosis \nand migraine were preselected by searching charts from all \nendometriosis patients treated in our outpatient clinic from \nJanuary 2015 to July 2021. Included were all premenopau-\nsal patients aged > 18 years with biopsy-confirmed endo-\nmetriosis, who in addition suffered from migraine (Fig.  1). \nDiagnosis of migraine and migraine with aura were evalu-\nated in telephone interviews using the criteria of the Inter -\nnational Classification of Headache Disorders (3rd version, \nICHD-3) of the International Headache Society to ensure the \ncorrect differentiation between migraine and other types of \nheadaches [19]. In order to increase reliability, both inter -\nviewers were trained with 50 interviews prior to start of the \nstudy. Postmenopausal women and those with adenomyosis \nor scar endometriosis were excluded. During a phone con-\ntact, we informed patients about the study and asked if they \nwere interested in participating. Those willing to partici-\npate received an information sheet and provided consent. \nDetails about the inclusion process are presented in Fig.  1. \nThe interview questions were adapted from a structured \nquestionnaire developed from the World Endometriosis \nResearch Foundation “Women’s Health Symptom Survey \nQuestionnaire” [20]. The questionnaire covers demograph-\nics, height, weight, medical conditions, operations, family \nhistory, menstruation, pregnancies, deliveries, potential \nsymptoms of endometriosis, and medication. In addition \n30 headache-specific questions, were added, including \nage at migraine onset, migraine frequency in the past (at \nage < 20 years and 5 years ago) and at present, aura, trig-\ngers, acute and prophylactic medication and disability, using \nthe Migraine Disability Assessment questionnaire (MIDAS) \n[21]. From the surgery reports, we had access to information \nabout endometriosis score (ASRM), infiltration depth, num-\nber of affected compartments, and localization [22].\nStatistical analyses\nWe performed all statistical analyses using IBM SPSS ver -\nsion 27.0.1.0. We presented categorical variables as fre-\nquencies and continuous variables as means with standard \ndeviations. For comparison of subgroups we calculated inde-\npendent sample t-tests for normally distributed variables and \nWilcoxon-Mann–Whitney test for not normally distributed \nvariables. Further, we compared categorical variables with \nChi-Square or Fisher’s exact test. Spearman`s rank correla-\ntion was used to test dependence of nonparametric measures. \nSignificance level was set at p = 0.05.\n\n1265Acta Neurologica Belgica (2024) 124:1263–1271 \nEthical approval\nThe study was approved by the ethics committee of Zürich \n(BASEC Nr. 2021-00285) and registered at clinical Trials.\ngov (NCT04816357).\nResults\nBaseline characteristics of the 94 women with migraine \nand EM are demonstrated in Table  1. Mean age at migraine \nFig. 1  The flowchart containing the recruiting, inclusion and data collection process\nTable 1  Baseline and \nendometriosis characteristics Patients’ characteristics: Number of patients n (%)/mean ± standard \ndeviation (min–max)\nN\nAge (years) 36.4 ± 7.6 (20–53) 94\nHeight (cm) 167.3 ± 6.0 (153–184) 94\nWeight (kg) 65.2 ± 11.2 (40–120) 94\nBody mass index (kg/m2) 23.3 ± 3.8 (17–43) 94\nAge at first manifestation of migraine (years) 19.7 ± 8.4 (6–45) 88\nDepression ever 37 (39.4) 94\nMean age at menarche 12.8 ± 1.6 (8–17) 93\nCombined pill/patch/ring use at present 9 (9.6) 94\nASRM stage 94\n  1 25 (26.6)\n  2 20 (21.3)\n  3 21 (22.3)\n  4 28 (29.8)\nDepth of infiltration > 3 cm 21 (22.3) 94\nDysmenorrhea score 2/3 yes 72 (77.4) 93\n > 2 days of analgesics during menstruation 44 (46.8) 94\n\n1266 Acta Neurologica Belgica (2024) 124:1263–1271\nonset was 19.7 ± 8.4 years and mean age at menarche \n12.7 ± 1.6 years. Migraine features, including the cur -\nrent frequency, MMF five years ago and at age younger \nthan 20 years, migraine type and MIDAS score and grade \nare listed in Table  2. Altogether, the MMF was rather \nlow at present and at age < 20 years, while it was sub-\nstantially higher 5 years ago (p  < 0.01 vs frequency now; \np < 0.03 vs frequency at age  < 20 years) (Table  2). Cur -\nrently, 59% of the patients did not use any prophylactic \nagents, 37% used magnesium or riboflavin on a regular \nbasis and 3.1% used Botox or b-blockers. Pain medica-\ntion was prescribed from neurologists in 18.5%. and from \nGCPs in 35.1%. Another 35.1% of the participants bought \nthe medication in the pharmacy without prescription and \n11.3% received it from other sources. Migraine with aura \n(MA) had been reported form 41% of the women. Women \nwith MA reported more frequently unilateral attacks \n(p < 0.045. In our setting MA was associated with younger \nage at migraine onset and with a history of medication \noveruse headache (MOH) (Table  3). No associations were \nfound with ASRM stage (p  < 0.37) or depth of infiltration \nof lesions (p  < 0.45 for infiltration ≥ 3 cm).). MMF in the \npast did not differ between MA and MO patients. Women \nwith a history of MOH suffered more often from more \nthan 2 monthly attacks not now, but 5 years ago (p  = 0.05), \nwere more often triptan users (p  = 0.05) and were more \noften using more than 3 days/months analgesics for dys-\nmenorrhoea (p  < 0.04) (Table 3). MOH was not associated \nwith a personal history of depression (p  < 0.25). Endome-\ntriosis ASRM score was not associated with MA, higher \nfrequency of migraine or MOH. Patients with a history \nof MOH were also not affected by deeper infiltration of \nendometriosis lesions, what is known to be associated with \nmore pain (p  = 1.0 for infiltration ≥ 3 cm).\nTable 2  Migraine features \nin women with comorbid \nendometriosis\na Number of participants from 94 included patients\nb severe pain: pain score 3 in a pain scale from 0 to 3\nCharacteristics Number of patients n (%)/\nmean ± SD (min–max)\nN\nMigraine with aura (Yes) 39 (41.5) 94\nMigraine onset < 17 years (Yes) 39 (44.3) 94\nMigraine frequency at age under 20:  < 1 migraine attack/month 50 (56.2) 89\n1 or 2 migraine attacks/month 18 (20.2) 89\n > 2 migraine attacks/month 21 (23.6) 89\nMigraine frequency at age under 20 (Attacks/month) 1.6 ± 2.78 (0–15) 89\nMigraine frequency five years ago: (Attacks/month) 2.9 ± 4.64 (0–25) 90\nMigraine frequency five years ago:  > 2 migraine attacks/month 28 (31.1) 90\nCurrent migraine frequency: (Attacks/month) 1.5 ± 2.65 (0–15) 93\nCurrent migraine frequency:  > 2 migraine attacks/month 20 (21.5) 93\nMean duration of migraine attacks (Hours) 16.6 ± 19.1 (0.5–72) 91\nØ migraine attack duration over 9 h (Yes) 50 (54.9) 91\nStatus migraenosus ever (Yes) 22 (23.4) 94\nMigraine symptoms\nUnilateral migraine (Yes) 63 (67.0) 94\nSensitivity to light (Yes) 91 (96.8) 94\nSensitivity to noise (Yes) 63 (67.0) 94\nNausea (Yes) 83 (88.3) 94\nEmesis (Yes) 44 (46.8) 94\nTriptan for acute migraine treatment (Yes) 22 (23.7) 93\nEver MOH (Yes) 8 (8.6) 93\nMIDAS score 6.8 (13.0) 94\nMIDAS grade (migraine disability \nassessment score)\nGrade 1 (little or no disability) 60 (63.8) 94\nGrade 2 (mild disability) 15 (16.0) 94\nGrade 3 (moderate disability) 4 (4.3) 94\nGrade 4 (severe disability) 15 (16.0) 94\n\n1267Acta Neurologica Belgica (2024) 124:1263–1271 \nDiscussion\nThere is little knowledge about the course and features of \nmigraine in women who additionally suffer from comorbid \nendometriosis. Previous studies mainly focused on migraine \nprevalence in endometriosis patients, and cycle character -\nistics in patients with both, endometriosis and migraine [1 , \n2, 9, 23, 24]. Our sample included women in the middle \nof their reproductive years, recruited from an endometrio-\nsis clinic with an average BMI and typical age of migraine \nonset [25]. Mean age (36.4 years) was comparable with \nthat in other endometriosis-migraine trials, but lower than \nin the CAMEO study, which focused on non-gynaecologic \ncomorbidities. This needs consideration when interpreting \nthe results [1, 2, 24, 26, 27]. Interestingly we found an MA \nrate of 41% in patients with endometriosis. MMF was low \n(1.5 attacks), potentially related to the selection of patients \nfrom a gynaecology outpatient clinic. It is surprising, that \nthe reported MMF five years before the interview was sig-\nnificantly higher (2.9 attacks/month). Few women had ever \nexperienced MOH (8.6%) and none of the participants suf-\nfered from chronic migraine at the time of the study. Mean \nage at menarche was 12.7 years and migraine onset before \nage 17 was reported by 44.3% of participants. Endometriosis \nASRM score was not associated with MA, higher frequency \nof migraine or MOH. As a higher ASRM stage is not typi-\ncally associated with more pelvic pain, we also tested for \nassociations with depth of infiltration of the endometriosis \nlesions [28]. We also did not find an association here.\nMMF in our trial was lower than in population-based \nstudies [26, 27, 29]. We expected higher frequencies in \nwomen with two disabling pain comorbidities, especially as \nwe see in our clinic for hormonal migraines rather patients \nhighly affected by both conditions. The CAMEO study \nreported a MMF of 3.5 days for slightly older patients with \nother types of comorbidities in a huge sample representative \nfor the US population [26]. For MMF at age < 20 years, our \ndata are in accordance with findings from a diary -based \nstudy including migraine patients without endometriosis \nusing combined hormonal contraceptives in a setting in \nSwitzerland. In the latter study, MMF rose to 4.2 monthly \nattacks until mean age 26.5 years [30].\nThe decline of MMF during the reproductive years in \nour study is unusual [26, 31]. This decline compared to the \nfrequency 5 years ago was probably not related to the new \nstart of prophylactic agents, as the number of women using \npharmaceutical products for headache prevention at the time \nof the interview was very low (3.2%). Therefore, we sug-\ngest that recent endometriosis surgery and treatment might \nplay a pivotal role in the observed reduction. Improvement \nof one pain condition might exert a positive effect on the \ncourse of the second pain condition [17]. Long-term studies \nin migraine patients suffering from endometriosis are neces-\nsary to improve our understanding of the impact of endome-\ntriosis surgery and treatment on the course of migraine. Up \nto date, most studies addressing comorbidities of migraine \nfocus on cardiovascular conditions, psychic conditions, and \nautoimmune disease but not on endometriosis [26, 32, 33].\nOur patients reported a relatively long duration of \nmigraine attacks with 16.6 h. In a recent Italian multicenter \nstudy, around 50% of the migraine patients suffered from \nmigraine episodes lasting less than 24 h, while the mean \nduration in the CAMEO setting was 27.7 h [ 26, 34]. The \nduration of attacks might be related to insufficient response \nto acute medication. Only 18% of the patients in our set-\nting had ever seen a neurologist to receive a prescription, \nand triptan use in this setting of an endometriosis clinic was \nrather low. Triptans would not reduce pain associated with \nendometriosis, what could contribute to the preferred use of \nother types of analgesics in patients with both conditions.\nTwo trials with patients recruited from a gynaecologic \ncenter did not report MA data and typical migraines features \nfor the subgroup of patients with both, endometriosis and \nmigraine patients [2 , 35]. In comparison to the MA preva-\nlence in population-based studies (5–6%), we found a much \nhigher prevalence (41.5%) [34, 36, 37]. This finding is very \nTable 3  Correlations for MA \nand MOH\na Migraine frequency in migraine days per month\nMA Correlation \ncoefficient\nn 95% confidence \ninterval of odds \nratio\np-value\nFirst manifestation of migraine under 17 years old 0.331 88 0.124, 0.510 0.002\nCurrent migraine  frequencya − 0.069 93 − 0.275, 0.143 0.511\nMedication overuse headache 0.206 93 − 0.004, 0.398 0.048\nMOH\nMore than 2 attacks/month 0.033 92 − 0.179, 0.242 0.754\nMore than 2 attacks/month five years ago 0.220 89 0.006, 0.415 0.038\nTriptan use 0.224 92 0.014, 0.415 0.032\nMore than 3 days/months analgesics for dysmenorrhoea 0.226 94 0.017, 0.416 0.029\n\n1268 Acta Neurologica Belgica (2024) 124:1263–1271\nmuch in line with the results from Ferrero, who also studied \nmigraine features in more detail in women recruited from an \nendometriosis-clinic [38]. The strengths of our trial with a \nsmaller sample size is the inclusion of only patients with sur-\ngically confirmed endometriosis and collection of migraine \ndata not with a questionnaire but in interviews performed by \nneurologists. Ferrero et al. found a MA prevalence of 35% \nand a slightly higher migraine frequency with 44.7 attacks/\nyear [38]. The higher MMF in this trial, performed more \nthan 15 years ago, could be related to the high percentage \nof combined hormonal contraceptive (CHC) users (25.6%). \nToday it is better known among neurologists and gynaecolo-\ngists, that CHCs should not be used in MA patients. In addi-\ntion, CHC use for endometriosis treatment is less common. \nConsidering the high genetic background with sex hormone \nreceptor polymorphisms in endometriosis-migraine patients, \nwe suggest that we have a special subgroup of migraineurs, \nwith different migraine features, especially more frequent \naura [3 , 4]. Factors associated with MA in our trial were \nmigraine onset at an earlier age ( ≤ 17 years) and a history of \nMOH. Earlier age at migraine onset might also be an indica-\ntor for a stronger genetic background. The pathophysiology \nof MA is by far not complete understood. One of the lead-\ning theories is that aura phenomena are linked to cortical \nspreading depression (CSD). Hormone fluctuations during \nthe menstrual cycle, especially estrogen fluctuations might \nplay a role in the development of CSD [39]. Endometrio-\nsis lesions may release estradiol. Sandweiss et al. found, \nthat rats, after a 17-β-estradiol injection, developed signifi-\ncantly more CSD episodes over a 12-h recording period. Pre-\nadministration of an estrogen receptor antagonist blocked \nCSD events and pain behaviors [40]. However, the low \namounts of estrogen released locally from endometriosis \nlesions are minimal in comparison to the cyclic estrogen \nproduction in the ovaries. Endometriosis patients have regu-\nlar cycles and do not differ from other healthy young women \nwith regard to estrogen levels or fluctuations. Therefore, it \nseems unlikely, that the high prevalence of aura in endome-\ntriosis patients is generated from the estrogen release from \nendometriosis lesions.\nNone of our patients suffered from chronic migraine, \nwhich would have an expected prevalence in the female \npopulation of around 1.3% and might be even higher in \nwomen with comorbidities [26, 41]. We cannot exclude that \nwith age some of our participants might develop chronic \nmigraine in the future. In a small sample of endometriosis \npatients recruited from a tertiary headache center who were \nof similar age, Tietjen et al. found chronic migraine in 40% \nof women [35]. The reason for such differences is unclear \nbut might be explained with differing recruitment-strategies.\nChronic pain conditions, more severe headache, psychic \nconditions and triptan use have been shown to be associated \nwith a higher risk or medication overuse headaches (MOH) \n[32, 42–44]. MOH prevalence in the general population \nof migraineurs is 1–2%. It was 11.9% in a study including \npatients with non-gynaecologic comorbidities and much \nhigher in trials conducted in headache clinics (50–72%) [26, \n42, 45–47]. In our trial 8.6% of the participants reported to \nhave ever experienced MOH. Surprising for us in this setting \nof women with two disabling pain conditions was, that at \npresent none of the participants suffered from MOH. Spe -\ncial features of a history of MOH in our trial include more \nmigraine attacks 5 years ago, migraine with aura, use of \ntriptans (OR 4.9) and use of more pain killers to treat pelvic \npain during the menstrual bleeding (Table  3). Use of pain \nkillers for other conditions than migraine may contribute to \nthe risk of developing MOH [48]. Again, we raise the theory, \nthat the low MOH rate could be related to the improvement \nof endometriosis pain after surgery and treatment. Future \nprospective studies should focus on this point. The location \nfor recruitment, i.e. headache clinic, gynaecologic setting, \nor general population, has to be taken into account when \ncomparing results with other studies.\nMIDAS score in our trial did not differ substantially from \nthe CAMEO study (6.0 and 6.8). A MIDAS grade indicat-\ning moderate or severe disability in 20% of the women is of \nconcern and reflects severe suffering in a subgroup of our \nsample.\nAltogether, we observed in contrast to the normal course \nof migraine in women during the reproductive years a \ndecrease in migraine frequency in our sample. If this \nimprovement is causally related to endometriosis surgery, \nhas to be investigated in further prospective studies. We con-\nfirm that the prevalence of MA is higher than expected from \nthe general population. Migraine with aura, early migraine \nonset and episodic migraine have been shown to be asso-\nciated with a positive family history [18, 49]. Therefore \nand based on the knowledge that endometriosis-migraine \npatients share common sex-hormone specific polymor -\nphisms, we postulate a potential shared genetic background \nas reason for the high prevalence of MA. In comparison to \nstudies with endometriosis-migraine patients recruited from \nheadache clinics, we found much lower MMF, a lower MOH \nrate and no patients with chronic migraine. This might indi-\ncate that there are two subtypes and phenotypes of women \nwith both conditions. On the one hand, those with endome-\ntriosis pain as the major burden and less migraines and on \nthe other hand patients with migraine as the major burden, \nwho would suffer from a higher MMF and more often from \nchronic migraines.\nStrength and limitations\nMigraine features might differ between patients recruited \nfrom a gynaecologic clinic or a headache center. Our results \napply to women who visited a specialised endometriosis \n\n1269Acta Neurologica Belgica (2024) 124:1263–1271 \nclinic. Women recruited from a gynaecologic center with \nendometriosis pain as their major burden might suffer from \nless severe migraines than those recruited at headache cent-\ners. Only a subset had ever consulted a neurologist for their \nheadache problem. Endometriosis was the more disabling \ncondition for our participants. A limitation of this trial is \nthe lack of a control group. Furthermore, we cannot exclude \nthat there might be some recall bias related to interview data \naddressing events very long ago like age at menarche or \nmigraine onset. Strength of the study include the sample \nsize and the collection of migraine data through personal \ntelephone interviews performed by specialists. In addition, \nthe diagnosis of endometriosis was histologic confirmed and \nlocalization and ASRM score provided detailed information \non the stage and phenotype of the condition.\nConclusion\nWe conclude that the comorbidity of endometriosis maybe \nlinked to MA, while MMF is rather low. Further studies \nare needed to explore, if the observed decrease in MMF at \npresent in comparison to MMF 5 years ago, can be attrib-\nuted to recent endometriosis surgery. ASRM score was not \nassociated with any of the migraine features, nor was deep \ninfiltration of the lesions.\nAcknowledgements We thank Chiara Knobel and Lea Portmann for \ndata collection and performance of the interviews. Further we thank \nall patients who agreed to be part of this project.\nAuthors contributions GSM: Conceptualized and organized the study. \nPerformed the acquisition of analysis and interpretation the data, wrote \nthe the abstract and introduction and main parts of the discussion; \nrevised the final manuscript. HD: Contributed to development of the \ninterview, supervised correct data entry, supported statistical analyses \nand interpretation of the data. PI: Contributed to data interpretation and \ncritical discussion of the data. PS: Contributed to data interpretation \nand critical discussion of the data. AG: Contributed to data interpreta-\ntion and critical discussion of the data. CS: Contributed to statistics and \ninterpretation of the data and main parts of the discussion. All authors \nhave approved the submitted version of the manuscript and have agreed \nto be personally accountable for the author's own contributions and to \nensure that questions related to the accuracy or integrity of any part of \nthe work, even ones in which the author was not personally involved, \nare appropriately investigated, resolved, and the resolution documented \nin the literature.\nFunding Open access funding provided by University of Zurich.\nData availability The datasets used and/or analysed during the cur -\nrent study are available from the corresponding author on reasonable \nrequest.\nDeclarations \nConflict of interest GSM: Reports fee for advisory board and presen-\ntations for/from Novartis, Eli Lilly, Almirall Lundbeck. CJS: Reports \nfees for consulting, advisory boards, presentations, and travel support \nfor/from Novartis, Eli Lilly, TEVA Pharmaceuticals, Pfizer, Allergan, \nAbbvie, Almirall, Amgen, Lundbeck, MindMed, Grünenthal. He is \npart-time-employee at Zynnon. He has received research support from \nSwiss Heart Foundation, Eye on Vision Foundation, Baasch-Medicus \nFoundation, German Migraine and Headache Society, Visual Snow \nSyndrome Germany e.V. ARG has received honoraria for speaking or \nconsulting from Amgen, Abbvie, Allergan, Biomed, Curatis, EliLilly, \nLundbeck, Novartis, Sanofi and TEVA. PS has received honoraria for \nadvisory boards from Novartis, Eli Lilly, Almirall. HD declares no CO. \nPI declares no COI.\nOpen Access This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article’s Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article’s Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a \ncopy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nReferences\n 1. Wu Y, Wang H, Chen S, Lin Y, Xie X, Zhong G, Zhang Q (2021) \nMigraine is more prevalent in advanced-stage endometriosis, \nespecially when co-occuring with adenomoysis. Front Endocrinol \n(Lausanne) 12:814474\n 2. Maitrot-Mantelet L, Hugon-Rodin J, Vatel M, Marcellin L, San-\ntulli P, Chapron C, Plu-Bureau G (2020) Migraine in relation with \nendometriosis phenotypes: results from a French case-control \nstudy. Cephalalgia 40(6):606–613\n 3. Adewuyi EO, Sapkota Y, International Endogene Consortium I, \nandMe Research T, International Headache Genetics Consortium \nI, Auta A, Yoshihara K, Nyegaard M, Griffiths LR, Montgomery \nGW et al (2020) Shared molecular genetic mechanisms underlie \nendometriosis and migraine comorbidity. Genes (Basel) 11(3)\n 4. van der Vaart JF, Merki-Feld GS (2022) Sex hormone-related \npolymorphisms in endometriosis and migraine: a narrative review. \nWomens Health (Lond) 18:17455057221111316\n 5. Mattsson P (2003) Hormonal factors in migraine: a population-\nbased study of women aged 40 to 74 years. Headache 43(1):27–35\n 6. Wang SJ, Fuh JL, Lu SR, Juang KD, Wang PH (2003) \nMigraine prevalence during menopausal transition. Headache \n43(5):470–478\n 7. Nyholt DR, Gillespie NG, Merikangas KR, Treloar SA, Martin \nNG, Montgomery GW (2009) Common genetic influences under-\nlie comorbidity of migraine and endometriosis. Genet Epidemiol \n33(2):105–113\n 8. Yang MH, Wang PH, Wang SJ, Sun WZ, Oyang YJ, Fuh JL \n(2012) Women with endometriosis are more likely to suffer from \nmigraines: a population-based study. PLoS ONE 7(3):e33941\n 9. Miller JA, Missmer SA, Vitonis AF, Sarda V, Laufer MR, DiVasta \nAD (2018) Prevalence of migraines in adolescents with endome-\ntriosis. Fertil Steril 109(4):685–690\n 10. Merki-Feld GS, Imthurn B, Langner R, Sandor PS, Ganten-\nbein AR (2013) Headache frequency and intensity in female \nmigraineurs using desogestrel-only contraception: a retrospective \npilot diary study. Cephalalgia 33(5):340–346\n 11. Merki-Feld GS, Imthurn B, Langner R, Seifert B, Gantenbein \nAR (2015) Positive effects of the progestin desogestrel 75 mug \n\n1270 Acta Neurologica Belgica (2024) 124:1263–1271\non migraine frequency and use of acute medication are sustained \nover a treatment period of 180 days. J Headache Pain 16:522\n 12. Sacco S, Merki-Feld GS, Karen L, Aegidius E, Bitzer J, Canon-\nico M, Gantenbein AR, Kurth T, Lampl C, Lidegaard O, Anne \nMacGregor E et al (2018) Effect of exogenous estrogens and pro-\ngestogens on the course of migraine during reproductive age: a \nconsensus statement by the European headache federation (EHF) \nand the European society of contraception and reproductive health \n(ESCRH). J Headache Pain 19(1):76\n 13. Casper RF (2017) Progestin-only pills may be a better first-line \ntreatment for endometriosis than combined estrogen-progestin \ncontraceptive pills. Fertil Steril 107(3):533–536\n 14. Nappi RE, Sances G, Allais G, Terreno E, Benedetto C, Vac-\ncaro V, Polatti F, Facchinetti F (2011) Effects of an estrogen-free, \ndesogestrel-containing oral contraceptive in women with migraine \nwith aura: a prospective diary-based pilot study. Contraception \n83(3):223–228\n 15. Morotti M, Remorgida V, Venturini PL, Ferrero S (2014) Pro-\ngestogen-only contraceptive pill compared with combined oral \ncontraceptive in the treatment of pain symptoms caused by endo-\nmetriosis in patients with migraine without aura. Eur J Obstet \nGynecol Reprod Biol 179:63–68\n 16. Liakopoulou MK, Tsarna E, Eleftheriades A, Arapaki A, Tout-\noudaki K, Christopoulos P (2022) Medical and behavioral aspects \nof adolescent endometriosis: a review of the literature. Children \n(Basel) 9(3):384\n 17. Karp BI, Sinaii N, Nieman LK, Silberstein SD, Stratton P (2011) \nMigraine in women with chronic pelvic pain with and without \nendometriosis. Fertil Steril 95(3):895–899\n 18. de Boer I, Terwindt GM, van den Maagdenberg A (2020) Genetics \nof migraine aura: an update. J Headache Pain 21(1):64\n 19. Headache Classification Committee of the International Headache \nSociety (IHS) The International Classification of Headache Dis-\norders, 3rd edition. Cephalalgia 2018, 38(1):1–211\n 20. World Endometriosis Research Foundation. Women`s Health Sur-\nvey Questionniare\n 21. Stewart WF, Lipton RB, Dowson AJ, Sawyer J (2001) Develop-\nment and testing of the migraine disability assessment (MIDAS) \nquestionnaire to assess headache-related disability. Neurology \n56(6 Suppl 1):S20-28\n 22. Revised American Society for Reproductive Medicine classifica-\ntion of endometriosis (1996) Fertil Steril, 67(5):817–821\n 23. Spierings EL, Padamsee A (2015) Menstrual-cycle and menstru-\nation disorders in episodic vs chronic migraine: an exploratory \nstudy. Pain Med 16(7):1426–1432\n 24. Tietjen GE, Bushnell CD, Herial NA, Utley C, White L, Hafeez F \n(2007) Endometriosis is associated with prevalence of comorbid \nconditions in migraine. Headache 47(7):1069–1078\n 25. Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fan-\nning KM, Serrano D, Lipton RB (2013) Sex differences in the \nprevalence, symptoms, and associated features of migraine, prob-\nable migraine and other severe headache: results of the American \nmigraine prevalence and prevention (AMPP) study. Headache \n53(8):1278–1299\n 26. Lipton RB, Fanning KM, Buse DC, Martin VT, Hohaia LB, \nAdams AM, Reed ML, Goadsby PJ (2019) Migraine progression \nin subgroups of migraine based on comorbidities: results of the \nCaMEO Study. Neurology 93(24):e2224–e2236\n 27. Aegidius K, Zwart JA, Hagen K, Schei B, Stovner LJ (2006) Oral \ncontraceptives and increased headache prevalence: the Head-\nHUNT Study. Neurology 66(3):349–353\n 28. Fauconnier A, Chapron C, Dubuisson JB, Vieira M, Dousset B, \nBreart G (2002) Relation between pain symptoms and the ana -\ntomic location of deep infiltrating endometriosis. Fertil Steril \n78(4):719–726\n 29. Katsarava Z, Mania M, Lampl C, Herberhold J, Steiner TJ (2018) \nPoor medical care for people with migraine in Europe—evidence \nfrom the Eurolight study. J Headache Pain 19(1):10\n 30. Merki-Feld GS, Sandor PS, Nappi RE, Pohl H, Schankin C (2022) \nClinical features of migraine with onset prior to or during start \nof combined hormonal contraception: a prospective cohort study. \nActa Neurol Belg 122(2):401–409\n 31. Burch RC, Buse DC, Lipton RB (2019) Migraine: epidemiology, \nburden, and comorbidity. Neurol Clin 37(4):631–649\n 32. Katsarava Z, Buse DC, Manack AN, Lipton RB (2012) Defining \nthe differences between episodic migraine and chronic migraine. \nCurr Pain Headache Rep 16(1):86–92\n 33. Nicodemo M, Cevoli S, Giannini G, Cortelli P (2012) Comor -\nbidity in perimenstrual migraine. Curr Pain Headache Rep \n16(5):477–483\n 34. Barbanti P, Egeo G, Aurilia C, Fiorentini G, Proietti S, Tomino \nC, Bonassi S (2022) Italian migraine registry study G: the first \nreport of the Italian migraine registry (I-GRAINE). Neurol Sci \n43(9):5725–5728\n 35. Tietjen GE, Conway A, Utley C, Gunning WT, Herial NA (2006) \nMigraine is associated with menorrhagia and endometriosis. \nHeadache 46(3):422–428\n 36. Kurth T, Rist PM, Ridker PM, Kotler G, Bubes V, Buring JE \n(2020) Association of migraine with aura and other risk fac-\ntors with incident cardiovascular disease in women. JAMA \n323(22):2281–2289\n 37. Rasmussen BK (1995) Epidemiology of migraine. Biomed Phar-\nmacother 49(10):452–455\n 38. Ferrero S, Pretta S, Bertoldi S, Anserini P, Remorgida V, Del \nSette M, Gandolfo C, Ragni N (2004) Increased frequency of \nmigraine among women with endometriosis. Hum Reprod \n19(12):2927–2932\n 39. Grafstein B (1956) Mechanism of spreading cortical depression. \nJ Neurophysiol 19(2):154–171\n 40. Sandweiss AJ, Cottier KE, McIntosh MI, Dussor G, Davis TP, \nVanderah TW, Largent-Milnes TM (2017) 17-beta-estradiol \ninduces spreading depression and pain behavior in alert female \nrats. Oncotarget 8(69):114109–114122\n 41. Lipton RB, Silberstein SD (2015) Episodic and chronic migraine \nheadache: breaking down barriers to optimal treatment and pre-\nvention. Headache 55(Suppl 2):103–122\n 42. Diener HC, Dodick D, Evers S, Holle D, Jensen RH, Lipton RB, \nPorreca F, Silberstein S, Schwedt T (2019) Pathophysiology, pre-\nvention, and treatment of medication overuse headache. Lancet \nNeurol 18(9):891–902\n 43. Park HK, Chu MK, Oh SY, Moon HS, Song TJ, Lee MJ, Kang JJ, \nHong Y, Cho SJ, Investigators R (2022) Interim analysis of the \nregistry for load and management of medication overuse headache \n(RELEASE): a multicenter, comprehensive medication overuse \nheadache registry. Cephalalgia 42(6):455–465\n 44. Schwedt TJ, Alam A, Reed ML, Fanning KM, Munjal S, Buse \nDC, Dodick DW, Lipton RB (2018) Factors associated with acute \nmedication overuse in people with migraine: results from the 2017 \nmigraine in America symptoms and treatment (MAST) study. J \nHeadache Pain 19(1):38\n 45. Jonsson P, Hedenrud T, Linde M (2011) Epidemiology of medica-\ntion overuse headache in the general Swedish population. Cepha-\nlalgia 31(9):1015–1022\n 46. Calhoun A, Ford S (2008) Elimination of menstrual-related \nmigraine beneficially impacts chronification and medication over-\nuse. Headache 48(8):1186–1193\n 47. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ, Lipton RB \n(2004) Transformed migraine and medication overuse in a tertiary \nheadache centre–clinical characteristics and treatment outcomes. \nCephalalgia 24(6):483–490\n\n1271Acta Neurologica Belgica (2024) 124:1263–1271 \n 48. Schmid CW, Maurer K, Schmid DM, Alon E, Spahn DR, Gan-\ntenbein AR, Sandor PS (2013) Prevalence of medication overuse \nheadache in an interdisciplinary pain clinic. J Headache Pain 14:4\n 49. Pelzer N, Louter MA, van Zwet EW, Nyholt DR, Ferrari MD, \nvan den Maagdenberg AM, Haan J, Terwindt GM (2019) Linking \nmigraine frequency with family history of migraine. Cephalalgia \n39(2):229–236\nPublisher's Note Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}