Does endometriosis increase susceptibility to COVID-19 infections? A case–control study in women of reproductive age

Background: In today’s world, coronavirus disease 2019 (COVID-19) is the most critical health problem and research is continued on studying the associated factors. But it is not clear whether endometriosis increases the risk of COVID-19.

Women who referred to the gynecology clinic were evaluated and 507 women with endometriosis (case group) were compared with 520 women without endometriosis (control group). COVID-19 infection, symptoms, exposure, hospitalization, isolation, H1N1 infection and vaccination, and past medical history of the participants were recorded and compared between the groups using IBM SPSS Statistics for Windows version 21.

Comparison between the groups represent COVID-19 infection in 3.2% of the case group and 3% of the control group (P = 0.942). The control group had a higher frequency of asymptomatic infection (95.7% vs. 94.5%; P < 0.001) and fever (1.6% vs. 0%; P = 0.004), while the frequency of rare symptoms was more common in the case group (P < 0.001). The average disease period was 14 days in both groups (P = 0.694). COVID-19 infection was cor- related with close contact (r = 0.331; P < 0.001 in the case group and r = 0.244; P 0.05).

Endometriosis does not increase the susceptibility to COVID-19 infections, but alters the manifestation of the disease. The prevalence of the disease may depend on the interaction between the virus and the individual’s immune system but further studies are required in this regard.

Endometriosis, Coronavirus, COVID-19, SARS-CoV-2, Risk factors, Immunologic factors © The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://crea- tivecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdo- main/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Coronavirus disease 2019 (COVID-19) is one of the most critical pandemics ever, resulting in about 15% mortal - ity rate in hospitalized patients [1]. As a newly emerging disease, ongoing research is running on different aspects of the disease [2]. The virus mainly affects the respiratory system, presenting with cough, difficult breathing, pneu - monia, and in severe cases, results in acute respiratory distress syndrome (ARDS), need for intensive care unit (ICU) admission, and mechanical ventilation [3]. Some cases may even be complicated by multiple organ failure (MOF) which results in death [4]. Susceptibility of specific organs to COVID-19 has provoked research towards the disease mechanisms [5], which resulted in identification of spike glycoprotein Open Access *Correspondence: [email protected] 1 Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran Full list of author information is available at the end of the article Page 2 of 7Moazzami et al. BMC Women’s Health (2021) 21:119 (S protein), one of the main structural components of SARS-CoV-2, which facilitates binding of the envelope viruses to host cells by forming homotrimers protrud - ing on the viral surface, which attracts angiotensin-con - verting enzyme 2 (ACE2) [6]. Therefore, SARS-CoV-2 can directly damage organs that express ACE2, including lungs, heart, kidneys, and intestines [7]; accordingly, the virus entry through this receptor depends on the cleavage of the S protein, which varies in different virus strains and cell types [8]. ACE2 protein is also effective in the physiol- ogy and pathology of the female reproductive system and fertility processes through production of sex hormones [9, 10], which is also affected during COVID-19 infec - tion [11]. As suggested, the renin-angiotensin system (RAS) in ovaries and angiotensin (Ang)-II and Ang [1–7] facilitate follicle development, steroid secretion, oocyte maturation, and follicle atresia, as well as steroidogenesis and ovulation [12, 13], which justifies the association of ovarian ACE2 malfunction with reproductive disorders, like polycystic ovary syndrome and ovarian hyperstimu - lation syndrome [14], uterine leiomyoma [15], as well as endometriotic lesions [16, 17]. The expression of ACE2, the SARS-CoV cellular receptor, has been also detected in the endometrial tissue [15, 18]. Although the endo - metrium has an overall low risk of COVID-19 infection, due to the low expression of ACE2 and transmembrane protease serine protease-2 (TMPRSS2), but the expres - sion of these host receptors increase at specific stages of the menstrual cycle and varies based on the woman’s age and endometrial susceptibility to the infection [19]. Previous studies on the endometrial disease have also determined the presence of ACE2 in the glandular epithe- lium, stroma, perivascular space, and endothelium [20, 21]. However, as the only study on the gene expression of SARS-CoV states, because of several limitations such as the small sample size, variability in the genetic profile of individuals and their ethnicity, and medical comorbidi - ties, the endometrial susceptibility to the virus could dif - fer based on viral cell entry mechanisms [19]. Although several animal studies have suggested the possibility of inhibition and regression of endometriotic lesions by blocking ACE II type 1 receptor (AT1R) and suggest that activation of peroxisome proliferator-activated receptor (PPAR)-g prevents vascularization and growth in murine model [22, 23]; human studies are required to determine the risk of COVID-19 infection in the endometrial tissue [24]. From the clinical perspective, it is not yet clear whether patients with thoracic endometriosis have a higher risk of pulmonary disease or COVID-19 infection [25]. An expert opinion has suggested specific treatment guide - lines, in order to reduce the susceptibility of endo - metriosis patients to COVID-19 infection [26]. As an inflammatory disease, endometriosis stimulates immune response and inflammation in the body [27], which is also a common feature of COVID-19, during which the overly vigorous immune response can result in cytokine storm [28]. So, we hypothesized that while a patient suffer - ing from this inflammatory disease (endometriosis), the patient can be more susceptible to COVID-19, compared to the normal population. As, to date, there is no evi - dence about the risk of COVID-19 infections in patients with endometriosis, the present study aimed to compare the risk of COVID-19 between women with and without endometriosis.

Study design This study was designed as a case–control study and con- ducted at Pars general hospital from May 21st to July 3rd, 2020. The study population consisted of women with his- tologic confirmation of endometriosis (extracted sample during laparoscopy), diagnosed at least a year before and maximum of 10 years before the study, compared with an age-matched control group, selected from women with - out endometriosis who referred to the gynecologic clinic for screening Pap smear test and had no complaints of any symptom related to endometriosis. All participants were asked to complete a researcher-designated check - list via email or social networks or cell phone for evalu - ation of Real-Time Polymerase Chain Reaction (rt-PCR) screening test and symptoms of COVID-19, a recent history of traveling to the high-risk areas, commitment to social distancing, relationship with a patient infected with COVID-19, positive COVID-19 rt-PCR test, his - tory of isolation due to COVID-19 infection, hospitaliza - tion due to COVID-19, H1N1 infection, and vaccination during last year, and other medical diseases. The symp - toms asked from patients included fever, sore throat, nasal congestion, cough, shortness of breath, headache, weakness and muscle pain, reduced sense of smell and/ or taste, ocular problems, and other (including gastroin - testinal, skin, hematologic, and neuronal) complications. The rt-PCR test is performed by Dacron or Rayon swabs taken from naso- or oro-pharyngeal, from any patients with suggestive symptomsDacron or Rayon swabs taken from naso- or oro-pharyngeal, from any patients with suggestive symptoms, perform the rt-PCR test. The samples were sent to the laboratory immediately, where COVID-19 nucleic acid was extracted and used for molecular detection by fluorescence probing. Patients, younger than 18 or older than 45 were excluded from the study. The sample size of the study was considered at a mini - mum of 507 in each group. For sample size calculation, we considered the prevalence of COVID-19 reported Page 3 of 7 Moazzami et al. BMC Women’s Health (2021) 21:119 by Quartuccioa et al. at 3.8; in every 1000 patients with chronic inflammatory disease due to the lack of evidence on COVID-19 in women with endometriosis) (and 2 in every 1000 in general population) [29], using the follow - ing equation and considering the power of the study at 80% and alpha error at 0.05. The researcher selected the participants according to the inclusion criteria, explained the study design and

to the eligible participants, and asked them to read and sign the written informed consent; then, the researcher included the eligible participants (who gave consent) into the study by census method. The protocol of the present study was approved by the Ethics Com - mittee of Pars Advanced and Minimally Invasive Medi - cal Manners research center, Pars Hospital, Tehran, Iran. (Code: 99G5018). Statistical analysis For describing the categorical variables, frequency (per - centage) was reported. For numeric variables, first, Kolmogorov–Smirnov test was used to assess the nor - mal distribution of data and according to the results of this test, the numeric variables were described by mean ± standard deviation (SD) or median and com - pared between the groups using independent t-test or Mann–Whitney U test, whenever the data did not appear to have normal distribution or when the assumption of equal variances was violated across the study groups. Categorical variables were, on the other hand, compared using chi-square or Fisher’s exact test. The association of variables was tested by Spearman’s correlation coeffi - cient. For the statistical analysis, the statistical software IBM SPSS Statistics for Windows version 21.0 (IBM Corp. 2012. Armonk, NY: IBM Corp.) was used. P values of 0.05 or less were considered statistically significant.

A total of 507 women were evaluated in the case group and 520 women in the control group. The mean ± SD of the women’s age was 29.08 ± 14.29 in the case group and 33.00 ± 7.06 in the control group (P = 0.379). The majority of the case group had stage IV endometrio - sis (N = 110, 63.2%), 17.2% had stage III (N = 30), 8% had stage II (N = 14), 11.4% had stage I endometriosis (N = 20). In the case group, 18.3% (N = 93) had a positive history of infertility. The results of comparing the COVID-19 character - istics between the case and control groups, as shown in Table  1, showed no difference between the groups in m = { z1−a/2 √ [2pq] + z1−β √ [p1q1 + p2q2] } δ2 plan terms of COVID-19 infection (P = 0.942), frequency of H1N1 vaccination, recent traveling to high-risk prov - inces, social distancing, close contact with an infected patient, as well as the frequency of performing screening test, admission and isolation due to COVID-19 (P > 0.05); but, the frequency of symptoms (P < 0.05) and H1N1 infection were significantly different between the groups (P < 0.001). As shown in Table 1, the frequency of asymp - tomatic cases and the frequency of fever was higher in the control group (P < 0.001 and 0.004, respectively), and the frequency of other symptoms was higher in the case group (P < 0.001). The average disease period was 14 days in both groups (P = 0.694). The frequency of underlying diseases is shown in Table  2. As demonstrated in this table, 80.5% in the case group and 72.3% in the control had no underlying disease (P = 0.002) and the frequency of diabetes mel - litus (P = 0.038), cardiovascular disease, hypertension, and lupus erythematosus were higher in the control (all P < 0.001; Table 2). Studying the association of the study variables with COVID-19 infection identified “close contact with a patient infected with COVID-19” as a significant risk fac- tor, both in the case (r = 0.331, P < 0.001) and the control group (r = 0.244, P 0.05; Table 3).

Comparing two groups of women with and without endometriosis showed no difference in the frequency of COVID-19 infection, which is contrary to the initial hypothesis of our study, as we assumed that patients with endometriosis, an inflammatory disease, have a greater susceptibility to COVID-19 infection, because of their baseline disorder in the immune system, as well as the evidence on the expression of ACE2 in the endometrial tissue [15, 18]. Studies have reported different diseases that can predispose the individual to COVID-19 and reported that malnutrition [30], serum parameters, such as blood group [31], and elevated plasmin(ogen) [32], as well as underlying autoimmune diseases, such as tuber - culosis [33] and lupus erythematosus [34] can increase patients’ susceptibility to COVID-19. However, as far as the authors are concerned, the risk of COVID-19 infec - tion in women with endometriosis has not been clinically evaluated, to date. The endometrial susceptibility to COVID-19 is still under investigation. Molecular investigations have shown that ACE2 is expressed in endometrial epithelial cells and stromal cells in the proliferative phase of the men - strual cycle, which increases in the secretory phase and Page 4 of 7Moazzami et al. BMC Women’s Health (2021) 21:119 affects the in  vivo decidualization, embryo implanta - tion, and placentation [18]. The expression of ACE2 has been also confirmed in the myometrium and uterine leiomyoma [15]. In another molecular genetic study, it was demonstrated that the lower expression of host pro - teases, related to SARS-CoV-2 infection, such as ACE2 and TMPRSS2 may result in a lower risk of endometrial susceptibility to COVID-19 infection, but the expres - sion of these proteins varies in different phases of the menstrual cycle and increases during implantation and in older women [19]. It is also assumed that COVID-19 can induce changes in endometrial tissue and affect the female reproductive system [12]. However, the studies available in this regard are expert opinion or molecu - lar based and the susceptibility of endometrial tissue to COVID-19 has not been confirmed in the clinical setting [24]. It has been previously demonstrated that despite the indefinite pathophysiology of endometriosis, the immune system is considered as a cause of develop - ment of endometriosis and several immunologic and inflammatory changes are observed in endometriosis [35]. The main immunologic changes in endometriotic patients include reduction of T cell reactivity, natural killer (NK) cell’s cytotoxicity, increased antibody pro - duction, macrophages polarization and augmented release of inflammatory disease [36]. The increased infiltration level of immune cells, including B cell, CD4+T cell, neutrophil, and dendritic cells as well as increased expression of ACE2 has been correlated with SARS-CoV-2 susceptibility in endometrial cancer [31]. However, such association has not been found in endo - metriosis and the results of our study showed no differ - ence in susceptibility to COVID-19 disease in women Table 1 The results of comparing the coronavirus disease characteristics between the case and control groups

of: aChi square test, bFisher’s exact test Variable Categories Case group (N = 507) Control group (N = 520) p-value Number Percent Number Percent H1N1 infection No 462 91.1 490 2.0 < 0.001a Yes 44 8.7 10 2.0 H1N1 vaccine No 488 96.3 495 97.4 0.212a Yes 18 3.6 13 2.6 Travel No 470 92.7 370 69.7 0.059a Yes 36 7.1 24 4.5 Social distancing No 397 78.3 267 67.8 0.256a Yes 109 21.5 127 32.2 Close contact No 475 93.7 358 91.8 0.979a Yes 31 6.1 32 8.2 COVID-19 infection No 490 96.6 515 97 0.942a Yes 16 3.2 16 3 symptoms None 479 94.5 508 95.7 < 0.001a Fever 0 0 8 1.6 0.004b Sore throat 7 1.4 6 1.2 0.745a Nasal congestion 8 1.6 2 0.4 0.050a Cough 7 1.4 6 1.2 0.747a Shortness of breath 8 1.6 6 1.2 0.558a Headache 4 0.8 3 0.6 0.486a Weakness and muscle pain 5 1.0 13 2.6 0.094a Reduced sense of smell and/or taste 9 1.8 7 1.4 0.622a Ocular problems 4 0.8 1 0.2 0.179b Other 11 2.2 0 0 < 0.001b Screening No 477 94.1 476 89.6 0.137a Yes 29 5.7 42 7.9 Admission No 505 99.6 520 100 0.494b Yes 1 0.2 0 0 Isolation No 493 97.2 420 97.2 0.790a Yes 13 2.6 12 2.8 Page 5 of 7 Moazzami et al. BMC Women’s Health (2021) 21:119 with endometriosis, the underlying reason requires fur - ther investigations. In the current study, it was found that the frequency of COVID-19 symptoms differed between women with and without endometriosis; endometriotic women had a lower frequency of asymptomatic and febrile infec - tion, but higher frequency of other symptoms, including gastrointestinal, dermatologic, hematologic, and neu - ronal disorders. Keeping in mind that the difference in the symptoms may, also, be related to the difference in the underlying diseases of the patients and the medica - tions they use [37], our results suggest that more atten - tion should be paid to women with endometriosis for diagnosis of COVID-19 infection, as they mainly do not present common symptoms, which can make diagno - sis difficult [38]. COVID-19 infection interferes with the antigen-presenting cells in the immune system and cre - ates bilayer vesicles, which can block the expression of Pattern Recognition Receptor (PRR) and, as a result, the patient’s innate immune system does not recognize them and continue to proliferate within the vesicle, they also, disable the production of Type I interferon as one of the most important antiviral factors so it will develop as an asymptomatic disease in some cases [39]. Asymptomatic COVID-19 is considered the Achilles’ heel for disease control, due to the strong infectivity and transmission during this period, and the major role of asymptomatic carriers in the person-to-person disease transmission [40]. We suppose that the different clinical presentation of COVID-19 in women with endometriosis in the pre - sent study can be attributed to the altered immune inter - actions in endometriosis [41, 42], similar to the different disease characteristics of COVID-19 in other immune- mediated inflammatory diseases/conditions, such as rheumatoid arthritis, psoriatic arthritis, ankylosing spon - dylitis, psoriasis, inflammatory bowel disease [43], and pregnancy [44]. Further molecular studies are required to understand the exact mechanism of this finding. We also analyzed factors associated with COVID-19 infection and the results revealed that close contact with a patient infected with COVID-19 was the only risk fac - tor in both groups that resulted in a slightly increased chance (0.3- and 0.2-folds higher odds in the case and Table 2 The results of comparing the frequency of underlying diseases between the study groups

of: aChi-square test, bFisher’s exact test Case group (N = 507) Control group (N = 520) p-value Frequency Percent Frequency Percent None 408 80.5 376 72.3 0.002a Thyroid disease 5 0.98 3 0.57 0.501b Diabetes mellitus 11 2.2 23 4.6 0.038a Cardiovascular disease 2 0.4 36 7.2 < 0.001a Hypertension 13 2.6 42 8.4 < 0.001a Asthma 1 0.2 6 1.2 0.124b Allergy 13 2.6 23 4.6 0.057a Cancer 5 1.0 11 2.2 0.097a Sinusitis 6 1.2 2 0.4 0.173b Lupus erythema- tosus 2 0.4 6 1.2 0.156b Rheumatoid arthritis 4 0.8 26 5.2 < 0.001b Other 18 3.6 24 4.8 0.314a Table 3 The association of COVID-19 infections with the study variables in each study group COVID-19-positive cases in the case group (N = 16) COVID-19-positive cases in the control group (N = 16) N (%) Pearson’s coefficient p value N (%) Pearson’s coefficient p value Underlying diseases Diabetes mellitus – 0.108 0.611 1 (6.2%) 0.202 0.533 Cardiovascular disease – 1 (6.2%) Hypertension – 2 (12.5%) Asthma – 1 (6.2%) Allergy – 1 (6.2%) Rheumatoid arthritis 2 (12.5%) 1 (6.2%) Thyroid disease 5 (31%) 0.032 0.471 3 (18.6%) 0.026 0.588 Admission due to COVID-19 1 (6.2%) 0.246 < 0.001 0 – – H1N1 vaccination 1 (6.2%) 0.026 0.445 13 (81.2%) 0.026 0.554 Travel 1 (6.2%) 0.006 1.000 4 (25%) 0.803 0.465 Social distancing 5 (31%) 0.043 0.355 4 (25%) 0.089 0.510 Close contact 8 (50%) 0.331 < 0.001 6 (37.5%) 0.244 < 0.001 Page 6 of 7Moazzami et al. BMC Women’s Health (2021) 21:119 control groups, respectively), while other variables such as social distancing, traveling, underlying diseases, thy - roid disorders, and endometriosis stage were not associ - ated with COVID-19 infection. As suggested, preventive measures should be considered by everyone to reduce contact with an infected person (possibly in the incuba - tion or asymptomatic period) to reduce the transmission rate and the prevalence of this epidemic [45, 46], which requires increasing the knowledge and awareness of the general population about the necessary precautions to be taken during the current outbreak [47]. The limitations of the present study include the cross- sectional nature of the study and lack of follow-up. Therefore, we could only suggest associations, rather than the causal relationship between the study variables. Furthermore, we matched the control group in terms of age with the case group and selected women were from the same medical center; however, differences in other characteristics between the groups may affect the results. Also, we recruited participants by census method and the nonrandomized patient selection increases the chance of confounders on the results. For sample size calculation, we could not use the statistics of our own region, as pub - lished data was not available at the time of sample size calculation and we had to estimate the real prevalence based on the available evidence.

The results of the present study suggested that endome - triosis does not increase the susceptibility to COVID- 19 infection, but it changes the presenting symptoms; although more homogenous groups are required for defi- nite conclusions. It is thus suggested to pay more atten - tion for accurate diagnosis of COVID-19 in women with endometriosis. Since the exact mechanism of infection with this virus in these patients is not fully understood, the most important task at present is to eliminate the transmission cycle, for which identifying the predispos - ing factors can help diagnose high-risk patients. Abbreviations COVID-19 infection: Coronavirus disease 2019; ARDS: Acute respiratory distress syndrome; ICU: Intensive care unit; MOF: Multiple organ failure; ACE2: Angiotensin-converting enzyme 2; TMPRSS2: Transmembrane protease serine protease-2; rt-PCR: Real-time polymerase chain reaction; SD: Standard deviation; NK: Natural killer; PRR: Pattern recognition receptor; CT: Computed tomography.

The authors of the present study sincerely thank patients who answered the questions very carefully and with patience in the critical ere of COVID-19. Authors’ contributions Study concept and design: SC and BM, Data collection: SS and MMZ, drafting the manuscript FJ, MA, and DS, critical revision of the manuscript: FJ, SC, ZSM, SS, and MMZ, Statistical Analysis: MAP and FK. All of the authors have given final approval of the submitted and revised versions and have agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately inves- tigated, resolved, and the resolution documented in the literature. All authors read and approved the final manuscript. Funding This study is supported by, Pars General hospital, Tehran, Iran. The funder had a role in data collection, but had no role in decision to publish, or preparation of the manuscript. Availability of data and materials The corresponding author, Shahla Chaichian, can be contacted if someone wants to request the data. Declarations Ethics approval and consent to participate The protocol of the present study was approved by the Ethics Committee of Pars Advanced and Minimally Invasive Medical Manners research center, Pars Hospital, Tehran, Iran. (Code: 99G5018). Written informed consent was obtained from the participants. Consent for publication Not applicable. Competing interests The authors of the present study declare that they have no competing interests. Author details 1 Pars Advanced and Minimally Invasive Medical Manners Research Center, Pars Hospital, Tehran, Iran. 2 Pediatric Urology and Regenerative Medicine Research Center, Section of Tissue Engineering and Stem Cells Therapy, Chil- dren’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 3 PhD Student in Epidemiology, Department of Epidemiology and Biosta- tistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. Received: 3 August 2020 Accepted: 16 March 2021

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