Comment on ''Correlation between endometriosis and migraine features: Results from a prospective case-control study''

from a prospective case-control study’‘ We read with great interest the recently published article by Selntigia et al. 1 The paper concludes that patients with co-occurrence of both endometriosis and migraine (EM-MG) have higher pain intensity compared to patients with endometriosis only (EM-O) or migraine only (MG-O) and also the patients with both endometriosis and migraine has more severe gynaecological in filtrations compared to endometriosis only patients. However, we have several concerns regarding the overly assertive con- clusions, methodology, and statistical and power analysis of the study. One primary issue is the study’s broad strokes in conclud- ing that EM-MG patients suffer from more severe endometri- osis/adenomyosis compared to those with endometriosis alone. This simpli fication overlooks the complexity of disease severity and the distinct classification systems for ade- nomyosis and deep in filtrating endometriosis (DIE). By equating the presence of adenomyosis or DIE with “more severe gynecological infiltrations” without a systematic com- parison of endometrioma, DIE, and other lesions, the study fails to accurately capture disease severity. Furthermore, the similar frequency of DIE and endometrioma between the EM-MG and EM-O groups undermines the claim of inher- ently greater disease severity in the comorbid group, espe- cially without a comparative analysis of severity. Secondly, the study ’s emphasis on the signi ficance of the CGRP pathway is notable, yet it may overextend its con- clusions. The increased pain intensity observed in patients with both endometriosis and migraine, as opposed to those with just one condition, can be attributed to a variety of factors including hormonal changes, chronic in flammation, altered pain sensitivity, genetic factors, psychological distress, fatigue, and both peripheral and central sensitization, along with delayed diagnosis and treatment 2. Therefore, focusing extensively on the CGRP pathway and asserting its targeting efficacy without direct pathophysiological evidence might exceed the study’s scope and be overly conclusive. Thirdly, while the study points to a relationship between increased migraine pain scores and speci fic endometriosis subtypes (DIE and adenomyosis), it lacks direct correlation analysis to substantiate this association. The study ’s methodology also presents several notable issues. Initially, the approach is hindered by sampling bias due to its observational design and patient recruitment from two distinct departments: endometriosis and head- ache. The selection criteria for patients with both endomet- riosis and migraine (EM-MG) lack clarity, particularly regarding their initial clinic of presentation. This oversight introduces potential biases, as symptoms and severity reported by EM-MG patients could be skewed based on whether they first sought treatment at the endometriosis or headache clinic. Furthermore, treatment biases may exist; EM-only patients not receiving hormonal treatments likely represent milder cases, while the hesitancy of clini- cians to use hormonal treatments in EM-MG patients, espe- cially those with migraine with aura, might mean this group disproportionately represents more severe endometriosis cases. Additionally, the study ’s protocol speci fies that each EM-MG case was matched with two control patients from each of the EM-O and MG-O cohorts based on a strict BMI matching criterion of ±1 unit range. However, the actual reported mean BMI differences between the EM-MG group and the control groups exceed this thresh- old, with variations of up to 2 BMI units. This variation indicates a deviation from the described matching process and raises concerns about the study ’s methodological adherence and the reliability of its comparative analysis. Lastly, the study ’s power analysis is compromised due to the absence of an effect size, crucial for assessing the ability to identify meaningful differences, and incorrectly employing the Kruskal-Wallis test for two-group compari- sons. Moreover, the statistical analysis presents concerns, as demonstrated by mean VAS scores (inherently non- negative) having standard deviations larger than the means, indicating a non-normal distribution. This issue raises concerns about the appropriateness of utilizing t-tests for data analysis, suggesting a need for non- parametric tests or methods such as logarithmic transforma- tions to ensure a normal distribution for precise analysis. In conclusion, while this study contributes to the under- standing of the comorbidity between endometriosis and migraine, these concerns highlight the need for cautious Creative Commons Non Commercial CC BY -NC: This article is distributed under the terms of the Creative Commons Attribution- NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and dis- tribution of the work without further permission provided the original work is attributed as speci fied on the SAGE and Open Access page (https://us. sagepub.com/en-us/nam/open-access-at-sage). Letter to the Editor Cephalalgia 2024, Vol. 44(5) 1 –2 © International Headache Society 2024 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/03331024241254824 journals.sagepub.com/home/cep interpretation of the findings and call for further research to address the complex relationship between these conditions more comprehensively.

1. Selntigia A, Exacoustos C and Ortoleva C et al. Correlation between endometriosis and migraine features: Results from a prospective case-control study. Cephalalgia 2024; 44: 3331024241235210. 2024/03/04. DOI: 10.1177/03331024241235210. 2. Morotti M, Vincent K and Becker CM. Mechanisms of pain in endometriosis.European Journal of Obstetrics & Gynecology and Reproductive Biology 2017; 209: 8 –13. DOI: 10.1016/j. ejogrb.2016.07.497. Utku AKGOR 1 and Onur INCE 1 1Department of Obstetrics and Gynecology, 64005Faculty of Medicine, Hacettepe University, Ankara, Turkey. Corresponding authors: Utku Akgör, Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, 06230 Ankara, Turkey. Email: + 905495197799 2 Cephalalgia 44(5)