{"paper_id":"4c2b8c06-e374-43df-8daa-4104ebcb6a34","body_text":"1\nRev Bras Oftalmol. 2024;83:e0040.\nORIGINAL ARTICLE\nKeywords:\nEndometriosis; Corneal \ndiseases; Corneal topography; \nLaparoscopy\nDescritores: \nEndometriose; Doenças da \ncórnea; Topografia da córnea; \nLaparoscopia\nHow to cite:\nStock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL. Corneal topographic alterations in women with \nendometriosis: data analysis in an ophthalmologic clinic. Rev Bras Oftalmol. 2024;83:e0040.\ndoi:\nhttps://doi.org/10.37039/1982.8551.20240040\nCorneal topographic alterations in women with endometriosis: \ndata analysis in an ophthalmologic clinic\nAlterações topográficas corneanas em mulheres portadoras de \nendometriose: análise de dados em uma clínica oftalmológica\nRicardo Alexandre Stock1 , Otávio Augusto Marques1 , Vitória Lovatel de Andrade1 , \n Katiussa de Werk Camboim Sampaio1 , Elcio Luiz Bonamigo1 \n1 Faculdade de Medicina, Universidade do Oeste de Santa Catarina, Joaçaba, SC, Brazil.\nReceived on:\nDec 7,2023\nAccepted on:\nMay 27, 2024\nCorresponding author: \nRicardo Alexandre Stock  \nBelotto Stock Centro Oftalmológico  \nRua Rio Branco, 589 – Centro \nCEP: 89.600-000 – Joaçaba, SC, Brazil \nE-mail ricardostockreal@gmail.com\nInstitution:  \nFaculdade de Medicina, Universidade do \nOeste de Santa Catarina, Joaçaba, SC, \nBrazil. \nConflict of interest:  \nthe authors declare no conflict of interest. \nFinancial support:  \nno financial support for this work.\nCopyright ©2024\nABSTRACT \nObjective: To verify whether there are pathological dysfunctions in the cornea of patients with \nendometriosis. \nMethods: Case-control research with a quantitative approach that compared topographic and \ntomographic examinations of the cornea of patients with a laparoscopic diagnosis of endometriosis, \nwithout the use of hormonal medications, to the control group. \nResults: We analyzed 78 eyes, 34 from the endometriosis group and 44 from the control group. The \nloss of orthogonality between the axes of the corneal curvatures was more frequent in the group with \nendometriosis (p = 0.0744). The difference between the mean keratometric measurements of the two \neyes was significantly greater in the control group (p = 0.0204). In the tomographic findings, the group \nwith endometriosis presented higher means of posterior elevation compared to the control group (p \n= 0.0060). \nConclusion: The results do not allow us to conclude that women with endometriosis have a higher risk \nof developing corneal ectasia, although the posterior elevation map demonstrated a greater posterior \ncurvature of the cornea in this group, with a statistically significant difference. However, an isolated \nincrease in the posterior elevation map does not have good diagnostic accuracy.\nRESUMO\nObjetivo: Verificar se há disfunções patológicas na córnea de pacientes portadoras de endometriose. \nMétodos: Pesquisa do tipo caso-controle de abordagem quantitativa, que comparou exames \ntopográficos e tomográficos da córnea de pacientes com diagnóstico laparoscópico de endometriose, \nsem uso de medicações hormonais, ao grupo controle. \nResultados: Foram analisados 78 olhos, 34 do grupo com endometriose e 44 do grupo controle. A \nperda da ortogonalidade entre os eixos das curvaturas corneanas foi mais frequente no grupo com \nendometriose (p = 0,0744). A diferença entre as médias das medidas ceratométricas dos dois olhos \nfoi significativamente maior no grupo controle (p = 0,0204). Nos achados tomográficos, o grupo com \nendometriose apresentou maiores médias de elevação posterior em relação ao controle (p = 0,0060). \nConclusão: Os resultados não permitem concluir que portadoras de endometriose têm maior risco \nde desenvolver ectasia corneana, embora o mapa de elevação posterior tenha demonstrado maior \ncurvatura posterior da córnea nesse grupo, com diferença estatisticamente significativa. Contudo, um \naumento isolado no mapa de elevação posterior não possui boa acurácia diagnóstica.\n\n2\nStock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL\nRev Bras Oftalmol. 2024;83:e0040.\nINTRODUCTION\nCornea is a transparent, avascular and richly innervated \nstructure that covers the front portion of the eye and is \nresponsible for approximately 75% of visual refraction.(1,2) \nCorneal ectasias, such as keratoconus, pellucid marginal \ndegeneration, and keratoglobus, are characterized, ac -\ncording to the Global Consensus on Keratoconus (2015), \nby progressive thinning and/or protrusion of the cornea \ndue to an etiopathogenesis that is still uncertain. This top-\nic deserves to be highlighted, since ectasias are becoming \nmore frequent in the world population and are related to \ndecreased visual acuity , increased deformations of the \neyeball and significant ocular morbidity .(3) \nFurthermore, recent assumptions of an association \nbetween ectasia and increased levels of female sex hor -\nmones have aroused scientific curiosity , generating a need \nfor studies to prove such theories. (4) In this sense, studies \nhave found the presence of sexual hormone receptors, in-\ncluding estrogen, progesterone, and androgens in human \ncorneas, establishing a surprising relationship between \ncorneal and gonadotropic activity , raising the possibility \nof a relationship between ophthalmological changes and \npathologies that involve changes in the hormonal levels, \nsuch as menopause, pregnancy , endometriosis, among \nothers.(5-7) \nLikewise, it is known that a marked increase in es-\ntradiol levels can stimulate pro-inflammatory cytokines \npresent in human corneal epithelial cells, associated with \nkeratoconus and other ectatic diseases. (8) Furthermore, \nresearch has shown that men with keratoconus have in-\ncreased estradiol levels, as well as that estrogen supple-\nmentation in patients with keratoconus resulted in the \nprogression of the disease in all eyes evaluated.(9,10) In this \nsense, a case of late progression of keratoconus after ini-\ntiating therapy with the estrogen activity regulator with \ntibolone was reported.(11) Consequently , the cornea is sen-\nsitive to estrogen and the functionality of its cells can be \ninfluenced by hormonal changes. \nThus, considering that endometriosis has a high in-\ncidence in Brazil and its pathogenesis is associated with \nan increase in circulating estradiol values, through the \nanalysis of corneal topography and tomography exams, \nthe present research fits the objective of verifying wheth-\ner there are pathological dysfunctions in the cornea of pa-\ntients with endometriosis.\nMETHODS\nThis was case-control research with a quantitative \napproach that analyzed corneal tomography and \ntopography data collected using the Pentacam Oculyzer \n(Oculus, Wetzlar, Germany) and the Topolyzer (Oculus, \nWetzlar, Germany), respectively , in 34 eyes of 17 women \nwith a previous laparoscopic diagnosis of endometriosis \nand 44 eyes of 22 previously healthy women who made up \nthe control group.\nThe study began after approval of the research proj-\nect by the Ethics Committee of the institution in charge, \nenabling data collection between January 2023 and April \n2023. The study population included patients from a private \ngynecology and obstetrics clinic, located in Joaçaba (SC), \nas well as a control group. In this scenario, patients with a \nhistory of laparoscopy and a positive anatomopathological \npathology for endometriosis, without the use of hormonal \nmedications to control pain, were contacted individually , \nand were then subjected to corneal topography and tomog-\nraphy exams, after a brief explanation of the content of the \nresearch, and after signing the Free and Informed Consent \nForm (ICF) and the Image Use Acceptance Term.\nThe control group was made up of previously healthy \nwomen, without previous ophthalmological disease and \nwithout endometriosis, with an age similar to the mean \nstandard deviation found in the other group studied. To \nthis end, the ophthalmology clinic carried out a retro-\nspective analysis of the medical records of patients who \nwere candidates for refractive surgery and who had al-\nready undergone tomography and corneal topography \nexams, selecting only those who stated, during a previous \nanamnesis, that they had no previous illnesses.\nPatients who were menopausal, were taking hormon-\nal medications, were pregnant or breastfeeding during \ndata collection, or had a history of refractive eye surgery \n(laser-assisted-in-situ-keratomileusis [LASIK] and pho-\ntorefractive keratectomy [PRK]), were excluded, as well \nas those who had already diagnosed eye disease or were \non continuous use of eye drops. All test results were ana-\nlyzed by the same ophthalmologist. \nNumerical variables were compared using an un-\npaired T test. Categorical variables, such as those ob-\nserved in the presence or absence of orthogonality , were \nanalyzed using Fisher’s exact test. The data were analyzed \nusing the Python 3.9 language, using the SciPy-Stats sta-\ntistical library . The descriptive level p < 0.05 was adopted.\nRESULTS \nThe mean ages of the participants were 35.12 ± 6.76 years \nfor the control group and 31.73 ± 5.24 years for the endo-\nmetriosis group. All were female and met the study’s in-\nclusion criteria.\n\n3\nCorneal topographic alterations in women with endometriosis\nRev Bras Oftalmol. 2024;83:e0040.\nThe topographic results are shown in table 1 and fig -\nure 1.  Only the keratometric difference variable showed \nsignificant distinction. The control group showed a sig -\nnificantly greater keratometric difference compared to \nthe endometriosis group (t = 2.42; fd = 37; p = 0.0204). \nFisher’s exact test revealed an almost significant dif -\nference in the frequency of orthogonality between the \ngroups (p = 0.0744), with a higher prevalence of changes \nin the endometriosis group.\nThe data from the tomographic examination are pre-\nsented in table 2 and figure 2, which showed a statistical-\nly significant difference only in the posterior elevation \nparameter; the endometriosis group presented higher \nmeans in this variable (t = 2.87; fd = 76; p = 0.0060), com-\npared to the control group, with a measure of 9 µm of dif-\nference between the samples. \nTable 1. Topographic findings between participants who had \nendometriosis and the control group. For numerical variables, \ndata were analyzed using the t test and categorical variables \nusing Fisher’s exact test\nVariable Endometriosis Control p-value\nAge 35.12 ± 6.76 31.73 ± 5.24 0.0859\nK1 42.98 ± 1.47 43.2 ± 1.4 0.5005\nK2 44.03 ± 1.79 44.72 ± 1.19 0.4320\nMaximum K 44.78 ± 1.7 45.4 ± 1.3 0.0728\nI-S Index 0.17 ± 0.41 0.03 ± 0.575 0.2176\nOrthogonality 0.0744\nYes 28 (82.35%) 44 (100%)\nNo 6 (17.65%) 0\nDifference of the keratometric \naverage between the eyes 0.22 ± 0.15 0.46 ± 0.38 0.0204*\nMaximum K: maximum keratometry. Orthogonality: orthogonality between the k1 and k2 axes. \n* p < 0.05 between groups.  \nK1: lowest keratometric average; K2: highest keratometric average.\nA B C\n50\n45\n40\n35\n30\n25\n20\n15Keratometry\nIndex I-S\n10\n5\n0\nK1 K2 Kmax\nEndometriosis\nControl\nEndometriosis\nControl\n2.0\n1.5\n-2.0\n1.0\n0.5\n0.0\n-0.5\n-1.0\n-1.5\nKeratometric difference\nbetween eyes\nEndometriosis\nControl\n1.5\n-2.0\n1.5\n1.5 *\n1.5\n1.5\n* p < 0.05 between groups. \nK1: lowest keratometric average; K2: highest keratometric average.\nFigure 1. Comparison of topographic ophthalmological variables relative to: (A) mean and standard error of the keratometry \nmean; (B) boxplot of the I-S Index and (C) mean and standard error of the difference in the keratometry mean of the endometri-\nosis and control groups. \nA\nTachymetric map\nEndometriosis\nControl\n600\n0\n400\n200\n*\nBAnterior Elevation\nEndometriosis\nControl\n4\n0\n3\n2\n1\nC\nBack Elevation\nEndometriosis\nControl\n15\n0\n10\n5\nD\nBellin/Ambrosio Display\nEndometriosis\nControl\n2.0\n0\n1.5\n1.0\n0.5\nEndometriosis Control\n* p < 0.05 between groups.\nFigure 2. Comparisons of tomographic ophthalmological variables relating to: (A) mean and standard error of the pachymetric \nmap (B) mean and standard error of elevation and (C) posterior; (D) mean and standard error of the Bellin/Ambrósio Display mean \nfor the endometriosis and control groups.\nTable 2. Tomographic findings between participants who had \nendometriosis and the control group. For numerical variables, \ndata were analyzed using the t test\nVariable Endometriosis Control p-value\nTachymetric map 529.4 ± 2.3 522.9 ± 35.2 0.3702\nAnterior elevation 3.26 ± 2.1 3.2 ± 1.4 0.8794\nPosterior elevation 9.11 ± 5.7 6.14 ± 3.6 0.0060\nBellin/Ambrósio -D 0.43 ± 0.6 1.3 ± 0.6 0.3147\n\n4\nStock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL\nRev Bras Oftalmol. 2024;83:e0040.\nDISCUSSION\nThe gold standard for endometriosis is exploratory lap-\naroscopy with a positive result, since this disease has a \nvariable clinical course that can be confused with other \ngynecological conditions, which often cannot be differ -\nentiated by imaging tests. (12,13) That is why this inclusion \ncriterion was used in this research. The patients includ-\ned in the research were not taking hormonal medication, \nwhich allows endometriosis to be analyzed without the \npossible interference of hormonal therapies. \nEndometriosis foci grow due to the hormonal action \nof estrogen, which is why the disease is called estrogen \ndependent.(14) Exposure to estrogen in porcine corneas \ncaused an increase in thickness and a decrease in rigid-\nity , leading to the belief that hormonal exposure may be \na risk factor for corneal ectasia. (7) Variations in some bio-\nmechanical parameters of the cornea may appear during \nthe ovulation period, a phase in which there is an increase \nin estrogen, compared to the rest of the menstrual cycle \nof the same patient. (15) However, although blood levels \nof estrogen and progesterone influenced the increase in \nintraocular pressure, estrogen and progesterone did not \nconsistently modify the topography or biomechanical \nproperties of healthy corneas.(16)\nIn the present research, it was noted that only the dif-\nference between the average keratometric measurements \nof the two eyes showed a significant difference. The con-\ntrol group showed a significantly greater difference be-\ntween the mean keratometric measurements of the two \neyes compared to the endometriosis group (t = 2.42; fd = \n37; p = 0.0204). Fisher’s exact test revealed an almost sig-\nnificant difference in the frequency of orthogonality be-\ntween the groups (p = 0.0744), with a higher prevalence of \nchanges in the endometriosis group. \nThe Placido rings corneal topography presents some \nrelevant indices for detecting keratoconus: Central K \n(central curvature); I-S values (inferior-superior dioptric \nasymmetry); and SRAX (relative inclination of the steep-\nest radial axes above and below the horizontal meridian). \nIn these parameters, a central K greater than 47.20 D, I-S \nindex greater than 1.2 and the SRAX index above 21° iden-\ntified 98% of patients with KC.(17) Different curvatures be-\ntween the two eyes can also be an indication of corneal \ndisease.\nThe I-S index has a strong relationship with the diag -\nnosis of corneal ectasia, especially at values above 1.2. (18) \nIn this context, the mean I-S indexes of the endometriosis \ngroup (0.17 ± 0.41) were higher than the mean I-S indexes \nof the control group (0.03 ± 0.575), this difference being \nnot statistically significant (p = 0.2176). Therefore, it is not \npossible to confirm a concrete relationship between the I-S \nindex and endometriosis; however, we observed a slight \nincrease in the averages in this group, which can be con-\nsidered a risk factor for the development of corneal ectasia.\nThe use of tomography (Pentacam) increases the \nspecificity and sensitivity to differentiate normal corneas \nfrom those that are diseased and susceptible to ectasia.(19) \nThere are reports in the literature that demonstrate pa-\ntients with topography exams within normal parameters, \nbut changes in the tomographic exam, demonstrating an \nearlier detection of corneal diseases.(20) \nTherefore, a tomographic examination was also \ncarried out, with the data represented in table 2, which \nshowed a statistical difference only in the posterior eleva-\ntion parameter, with the endometriosis group presenting \nhigher means in this variable (t = 2.87; fd = 76; p = 0.0060), \ncompared to the control group, with a difference of 9 µm \nbetween the samples.\nStudies demonstrate that the radius of posterior cor -\nneal curvature makes it possible to detect corneal disease \nin its earliest phase, compared to topography (17,21). It is \nknown that posterior elevation of the cornea is an early \nsign of keratoconus; therefore, this parameter should al-\nways be evaluated, especially during refractive surgeries, \nto avoid post-LASIK corneal ectasia.(22) \nIn relation to the Belin/Ambrosio Enhanced Display \n(BAD) index, the ideal cutoff point to differentiate kerato-\nconus from normal eyes would be 1.6. (23) This parameter \nwas slightly increased in the group of patients with en-\ndometriosis, but not significantly (p = 0.3147). There was \nno statistically significant difference in the other tomo-\ngraphic parameters analyzed.\nFinally , it is worth highlighting that keratoconus is di-\nagnosed based on a set of clinical signs, such as: Munson \nsign, which is the protrusion of the lower eyelid when \nlooking down, and decreased vision, in addition to as-\npects considered by the ABCD of Belin: (A) the radius of \nthe anterior corneal curvature; (B) the radius of the poste-\nrior corneal curvature; (C) corneal pachymetry at the thin-\nnest point; and (D) visual acuity . Therefore, the change in \nan isolated parameter in such exams does not constitute \na diagnosis of corneal ectasia, requiring a set of factors to \nimprove diagnostic accuracy .(17)\nCONCLUSION\nAlthough the cornea carries sex hormone receptors and \ncan therefore be affected by systemic diseases that involve \nchanges in the levels of circulating sex hormones, based \n\n5\nCorneal topographic alterations in women with endometriosis\nRev Bras Oftalmol. 2024;83:e0040.\non the sample studied, it cannot be said that the presence \nof endometriosis confirmed by surgery is a predisposing \nfactor of corneal ectasia.\nHowever, among all the data that generate suspicion \nfor corneal disease, there was a statistically significant dif-\nference in the posterior elevation map of those with endo-\nmetriosis. It is known that increased posterior curvature \nof the cornea is an early sign of keratoconus, but that just \none altered parameter alone does not have good diag -\nnostic accuracy . 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