Corneal topographic alterations in women with endometriosis: data analysis in an ophthalmologic clinic

Endometriosis; Corneal diseases; Corneal topography; Laparoscopy Descritores: Endometriose; Doenças da córnea; Topografia da córnea; Laparoscopia How to cite: Stock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL. Corneal topographic alterations in women with endometriosis: data analysis in an ophthalmologic clinic. Rev Bras Oftalmol. 2024;83:e0040. doi: https://doi.org/10.37039/1982.8551.20240040 Corneal topographic alterations in women with endometriosis: data analysis in an ophthalmologic clinic Alterações topográficas corneanas em mulheres portadoras de endometriose: análise de dados em uma clínica oftalmológica Ricardo Alexandre Stock1 , Otávio Augusto Marques1 , Vitória Lovatel de Andrade1 , Katiussa de Werk Camboim Sampaio1 , Elcio Luiz Bonamigo1 1 Faculdade de Medicina, Universidade do Oeste de Santa Catarina, Joaçaba, SC, Brazil. Received on: Dec 7,2023 Accepted on: May 27, 2024 Corresponding author: Ricardo Alexandre Stock Belotto Stock Centro Oftalmológico Rua Rio Branco, 589 – Centro CEP: 89.600-000 – Joaçaba, SC, Brazil E-mail [email protected] Institution: Faculdade de Medicina, Universidade do Oeste de Santa Catarina, Joaçaba, SC, Brazil. Conflict of interest: the authors declare no conflict of interest. Financial support: no financial support for this work. Copyright ©2024

Objective: To verify whether there are pathological dysfunctions in the cornea of patients with endometriosis.

Case-control research with a quantitative approach that compared topographic and tomographic examinations of the cornea of patients with a laparoscopic diagnosis of endometriosis, without the use of hormonal medications, to the control group.

We analyzed 78 eyes, 34 from the endometriosis group and 44 from the control group. The loss of orthogonality between the axes of the corneal curvatures was more frequent in the group with endometriosis (p = 0.0744). The difference between the mean keratometric measurements of the two eyes was significantly greater in the control group (p = 0.0204). In the tomographic findings, the group with endometriosis presented higher means of posterior elevation compared to the control group (p = 0.0060).

The results do not allow us to conclude that women with endometriosis have a higher risk of developing corneal ectasia, although the posterior elevation map demonstrated a greater posterior curvature of the cornea in this group, with a statistically significant difference. However, an isolated increase in the posterior elevation map does not have good diagnostic accuracy. RESUMO Objetivo: Verificar se há disfunções patológicas na córnea de pacientes portadoras de endometriose. Métodos: Pesquisa do tipo caso-controle de abordagem quantitativa, que comparou exames topográficos e tomográficos da córnea de pacientes com diagnóstico laparoscópico de endometriose, sem uso de medicações hormonais, ao grupo controle. Resultados: Foram analisados 78 olhos, 34 do grupo com endometriose e 44 do grupo controle. A perda da ortogonalidade entre os eixos das curvaturas corneanas foi mais frequente no grupo com endometriose (p = 0,0744). A diferença entre as médias das medidas ceratométricas dos dois olhos foi significativamente maior no grupo controle (p = 0,0204). Nos achados tomográficos, o grupo com endometriose apresentou maiores médias de elevação posterior em relação ao controle (p = 0,0060). Conclusão: Os resultados não permitem concluir que portadoras de endometriose têm maior risco de desenvolver ectasia corneana, embora o mapa de elevação posterior tenha demonstrado maior curvatura posterior da córnea nesse grupo, com diferença estatisticamente significativa. Contudo, um aumento isolado no mapa de elevação posterior não possui boa acurácia diagnóstica. 2 Stock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL Rev Bras Oftalmol. 2024;83:e0040.

Cornea is a transparent, avascular and richly innervated structure that covers the front portion of the eye and is responsible for approximately 75% of visual refraction.(1,2) Corneal ectasias, such as keratoconus, pellucid marginal degeneration, and keratoglobus, are characterized, ac - cording to the Global Consensus on Keratoconus (2015), by progressive thinning and/or protrusion of the cornea due to an etiopathogenesis that is still uncertain. This top- ic deserves to be highlighted, since ectasias are becoming more frequent in the world population and are related to decreased visual acuity , increased deformations of the eyeball and significant ocular morbidity .(3) Furthermore, recent assumptions of an association between ectasia and increased levels of female sex hor - mones have aroused scientific curiosity , generating a need for studies to prove such theories. (4) In this sense, studies have found the presence of sexual hormone receptors, in- cluding estrogen, progesterone, and androgens in human corneas, establishing a surprising relationship between corneal and gonadotropic activity , raising the possibility of a relationship between ophthalmological changes and pathologies that involve changes in the hormonal levels, such as menopause, pregnancy , endometriosis, among others.(5-7) Likewise, it is known that a marked increase in es- tradiol levels can stimulate pro-inflammatory cytokines present in human corneal epithelial cells, associated with keratoconus and other ectatic diseases. (8) Furthermore, research has shown that men with keratoconus have in- creased estradiol levels, as well as that estrogen supple- mentation in patients with keratoconus resulted in the progression of the disease in all eyes evaluated.(9,10) In this sense, a case of late progression of keratoconus after ini- tiating therapy with the estrogen activity regulator with tibolone was reported.(11) Consequently , the cornea is sen- sitive to estrogen and the functionality of its cells can be influenced by hormonal changes.  Thus, considering that endometriosis has a high in- cidence in Brazil and its pathogenesis is associated with an increase in circulating estradiol values, through the analysis of corneal topography and tomography exams, the present research fits the objective of verifying wheth- er there are pathological dysfunctions in the cornea of pa- tients with endometriosis.

This was case-control research with a quantitative approach that analyzed corneal tomography and topography data collected using the Pentacam Oculyzer (Oculus, Wetzlar, Germany) and the Topolyzer (Oculus, Wetzlar, Germany), respectively , in 34 eyes of 17 women with a previous laparoscopic diagnosis of endometriosis and 44 eyes of 22 previously healthy women who made up the control group. The study began after approval of the research proj- ect by the Ethics Committee of the institution in charge, enabling data collection between January 2023 and April 2023. The study population included patients from a private gynecology and obstetrics clinic, located in Joaçaba (SC), as well as a control group. In this scenario, patients with a history of laparoscopy and a positive anatomopathological pathology for endometriosis, without the use of hormonal medications to control pain, were contacted individually , and were then subjected to corneal topography and tomog- raphy exams, after a brief explanation of the content of the research, and after signing the Free and Informed Consent Form (ICF) and the Image Use Acceptance Term. The control group was made up of previously healthy women, without previous ophthalmological disease and without endometriosis, with an age similar to the mean standard deviation found in the other group studied. To this end, the ophthalmology clinic carried out a retro- spective analysis of the medical records of patients who were candidates for refractive surgery and who had al- ready undergone tomography and corneal topography exams, selecting only those who stated, during a previous anamnesis, that they had no previous illnesses. Patients who were menopausal, were taking hormon- al medications, were pregnant or breastfeeding during data collection, or had a history of refractive eye surgery (laser-assisted-in-situ-keratomileusis [LASIK] and pho- torefractive keratectomy [PRK]), were excluded, as well as those who had already diagnosed eye disease or were on continuous use of eye drops. All test results were ana- lyzed by the same ophthalmologist. Numerical variables were compared using an un- paired T test. Categorical variables, such as those ob- served in the presence or absence of orthogonality , were analyzed using Fisher’s exact test. The data were analyzed using the Python 3.9 language, using the SciPy-Stats sta- tistical library . The descriptive level p < 0.05 was adopted.

The mean ages of the participants were 35.12 ± 6.76 years for the control group and 31.73 ± 5.24 years for the endo- metriosis group. All were female and met the study’s in- clusion criteria. 3 Corneal topographic alterations in women with endometriosis Rev Bras Oftalmol. 2024;83:e0040. The topographic results are shown in table 1 and fig - ure 1. Only the keratometric difference variable showed significant distinction. The control group showed a sig - nificantly greater keratometric difference compared to the endometriosis group (t = 2.42; fd = 37; p = 0.0204). Fisher’s exact test revealed an almost significant dif - ference in the frequency of orthogonality between the groups (p = 0.0744), with a higher prevalence of changes in the endometriosis group. The data from the tomographic examination are pre- sented in table 2 and figure 2, which showed a statistical- ly significant difference only in the posterior elevation parameter; the endometriosis group presented higher means in this variable (t = 2.87; fd = 76; p = 0.0060), com- pared to the control group, with a measure of 9 µm of dif- ference between the samples.  Table 1. Topographic findings between participants who had endometriosis and the control group. For numerical variables, data were analyzed using the t test and categorical variables using Fisher’s exact test Variable Endometriosis Control p-value Age 35.12 ± 6.76 31.73 ± 5.24 0.0859 K1 42.98 ± 1.47 43.2 ± 1.4 0.5005 K2 44.03 ± 1.79 44.72 ± 1.19 0.4320 Maximum K 44.78 ± 1.7 45.4 ± 1.3 0.0728 I-S Index 0.17 ± 0.41 0.03 ± 0.575 0.2176 Orthogonality 0.0744 Yes 28 (82.35%) 44 (100%) No 6 (17.65%) 0 Difference of the keratometric average between the eyes 0.22 ± 0.15 0.46 ± 0.38 0.0204* Maximum K: maximum keratometry. Orthogonality: orthogonality between the k1 and k2 axes. * p < 0.05 between groups. K1: lowest keratometric average; K2: highest keratometric average. A B C 50 45 40 35 30 25 20 15Keratometry Index I-S 10 5 0 K1 K2 Kmax Endometriosis Control Endometriosis Control 2.0 1.5 -2.0 1.0 0.5 0.0 -0.5 -1.0 -1.5 Keratometric difference between eyes Endometriosis Control 1.5 -2.0 1.5 1.5 * 1.5 1.5 * p < 0.05 between groups. K1: lowest keratometric average; K2: highest keratometric average. Figure 1. Comparison of topographic ophthalmological variables relative to: (A) mean and standard error of the keratometry mean; (B) boxplot of the I-S Index and (C) mean and standard error of the difference in the keratometry mean of the endometri- osis and control groups. A Tachymetric map Endometriosis Control 600 0 400 200 * BAnterior Elevation Endometriosis Control 4 0 3 2 1 C Back Elevation Endometriosis Control 15 0 10 5 D Bellin/Ambrosio Display Endometriosis Control 2.0 0 1.5 1.0 0.5 Endometriosis Control * p < 0.05 between groups. Figure 2. Comparisons of tomographic ophthalmological variables relating to: (A) mean and standard error of the pachymetric map (B) mean and standard error of elevation and (C) posterior; (D) mean and standard error of the Bellin/Ambrósio Display mean for the endometriosis and control groups. Table 2. Tomographic findings between participants who had endometriosis and the control group. For numerical variables, data were analyzed using the t test Variable Endometriosis Control p-value Tachymetric map 529.4 ± 2.3 522.9 ± 35.2 0.3702 Anterior elevation 3.26 ± 2.1 3.2 ± 1.4 0.8794 Posterior elevation 9.11 ± 5.7 6.14 ± 3.6 0.0060 Bellin/Ambrósio -D 0.43 ± 0.6 1.3 ± 0.6 0.3147 4 Stock RA, Marques OA, Andrade VL, Sampaio KW, Bonamigo EL Rev Bras Oftalmol. 2024;83:e0040.

The gold standard for endometriosis is exploratory lap- aroscopy with a positive result, since this disease has a variable clinical course that can be confused with other gynecological conditions, which often cannot be differ - entiated by imaging tests. (12,13) That is why this inclusion criterion was used in this research. The patients includ- ed in the research were not taking hormonal medication, which allows endometriosis to be analyzed without the possible interference of hormonal therapies. Endometriosis foci grow due to the hormonal action of estrogen, which is why the disease is called estrogen dependent.(14) Exposure to estrogen in porcine corneas caused an increase in thickness and a decrease in rigid- ity , leading to the belief that hormonal exposure may be a risk factor for corneal ectasia. (7) Variations in some bio- mechanical parameters of the cornea may appear during the ovulation period, a phase in which there is an increase in estrogen, compared to the rest of the menstrual cycle of the same patient. (15) However, although blood levels of estrogen and progesterone influenced the increase in intraocular pressure, estrogen and progesterone did not consistently modify the topography or biomechanical properties of healthy corneas.(16) In the present research, it was noted that only the dif- ference between the average keratometric measurements of the two eyes showed a significant difference. The con- trol group showed a significantly greater difference be- tween the mean keratometric measurements of the two eyes compared to the endometriosis group (t = 2.42; fd = 37; p = 0.0204). Fisher’s exact test revealed an almost sig- nificant difference in the frequency of orthogonality be- tween the groups (p = 0.0744), with a higher prevalence of changes in the endometriosis group. The Placido rings corneal topography presents some relevant indices for detecting keratoconus: Central K (central curvature); I-S values (inferior-superior dioptric asymmetry); and SRAX (relative inclination of the steep- est radial axes above and below the horizontal meridian). In these parameters, a central K greater than 47.20 D, I-S index greater than 1.2 and the SRAX index above 21° iden- tified 98% of patients with KC.(17) Different curvatures be- tween the two eyes can also be an indication of corneal disease. The I-S index has a strong relationship with the diag - nosis of corneal ectasia, especially at values above 1.2. (18) In this context, the mean I-S indexes of the endometriosis group (0.17 ± 0.41) were higher than the mean I-S indexes of the control group (0.03 ± 0.575), this difference being not statistically significant (p = 0.2176). Therefore, it is not possible to confirm a concrete relationship between the I-S index and endometriosis; however, we observed a slight increase in the averages in this group, which can be con- sidered a risk factor for the development of corneal ectasia. The use of tomography (Pentacam) increases the specificity and sensitivity to differentiate normal corneas from those that are diseased and susceptible to ectasia.(19) There are reports in the literature that demonstrate pa- tients with topography exams within normal parameters, but changes in the tomographic exam, demonstrating an earlier detection of corneal diseases.(20) Therefore, a tomographic examination was also carried out, with the data represented in table 2, which showed a statistical difference only in the posterior eleva- tion parameter, with the endometriosis group presenting higher means in this variable (t = 2.87; fd = 76; p = 0.0060), compared to the control group, with a difference of 9 µm between the samples. Studies demonstrate that the radius of posterior cor - neal curvature makes it possible to detect corneal disease in its earliest phase, compared to topography (17,21). It is known that posterior elevation of the cornea is an early sign of keratoconus; therefore, this parameter should al- ways be evaluated, especially during refractive surgeries, to avoid post-LASIK corneal ectasia.(22) In relation to the Belin/Ambrosio Enhanced Display (BAD) index, the ideal cutoff point to differentiate kerato- conus from normal eyes would be 1.6. (23) This parameter was slightly increased in the group of patients with en- dometriosis, but not significantly (p = 0.3147). There was no statistically significant difference in the other tomo- graphic parameters analyzed. Finally , it is worth highlighting that keratoconus is di- agnosed based on a set of clinical signs, such as: Munson sign, which is the protrusion of the lower eyelid when looking down, and decreased vision, in addition to as- pects considered by the ABCD of Belin: (A) the radius of the anterior corneal curvature; (B) the radius of the poste- rior corneal curvature; (C) corneal pachymetry at the thin- nest point; and (D) visual acuity . Therefore, the change in an isolated parameter in such exams does not constitute a diagnosis of corneal ectasia, requiring a set of factors to improve diagnostic accuracy .(17)

Although the cornea carries sex hormone receptors and can therefore be affected by systemic diseases that involve changes in the levels of circulating sex hormones, based 5 Corneal topographic alterations in women with endometriosis Rev Bras Oftalmol. 2024;83:e0040. on the sample studied, it cannot be said that the presence of endometriosis confirmed by surgery is a predisposing factor of corneal ectasia. However, among all the data that generate suspicion for corneal disease, there was a statistically significant dif- ference in the posterior elevation map of those with endo- metriosis. It is known that increased posterior curvature of the cornea is an early sign of keratoconus, but that just one altered parameter alone does not have good diag - nostic accuracy . This study had the limitation of a small sample and still scarce literature regarding this probable relationship between endometriosis and corneal ectasia.

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