Potential impact of COVID-19 pandemic on endometriosis : Reproductive and Developmental Medicine

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Special Issue: Adenomyosis and Endometriosis

Potential impact of COVID-19 pandemic on endometriosis

Huang, Chen-Yang1,2; Sun, Hai-Xiang1,2; Mei, Jie1,2,*

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Reproductive and Developmental Medicine 6(3):p 138-143, September 2022. | DOI: 10.1097/RD9.0000000000000015
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Abstract

Introduction

The coronavirus disease 2019 (COVID-19) has caused patients to become unable to go to medical institutions, which has an adverse impact on many chronic diseases[1]. Several studies have reported the possible impact of the COVID-19 epidemic on endometriosis (EM), such as suspending surgical treatment, canceling outpatient appointments, delaying ultrasound examination, and the psychological impact of forced self-isolation[2,3]. Here, we summarize the similarities in the pathogenesis of COVID-19 and EM, and the impact of COVID-19 on the common clinical symptoms and treatment of EM is reviewed to elaborate the comprehensive impact of the COVID-19 pandemic on EM. Our review aims to provide research ideas and directions for further exploration of the specific impact of COVID-19 on EM.

COVID-19 and pathogenesis

COVID-19 is caused by a novel coronavirus, severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2), a positive-sense single-stranded RNA virus with high infectivity and pathogenicity[4]. Angiotensin-converting enzyme 2 (ACE2), which is expressed in various tissues and cells, is the molecular target of the SARS-CoV-2 when invading target tissues[4]. Then, SARS-CoV-2 can interact with the immune system of the body, leading to individual immune system disorders, which can explain the various clinical manifestations of this disease[5].

Autopsies of patients with COVID-2019 have shown a high macrophage infiltration rate, suggesting an initial immune response of macrophages to the virus[6]. It has been reported that more than 60% of patients have a decrease in lymphocyte count (less than 1.0 × 109/L) in their peripheral blood, and this proportion could exceed 80%[7] in patients diagnosed with severe COVID-19. Moreover, neutrophilia could be detected in patients with severe COVID-19, and the neutrophils-to-lymphocytes ratio has been associated with a poor prognosis of this disease[8]. Studies have also reported that an increase in the number of monocytes could be observed in the damaged vessels of patients with COVID-19[9]. In addition, the numbers of T and natural killer (NK) cells in patients with COVID-19 significantly decreased. Simultaneously, the regulatory cell (Treg) count decreased significantly in severe COVID-19 patients[10]. These results suggest that the dual reduction of innate immunity and adaptive immunity in patients with COVID-19 significantly leads to an impaired ability of the immune system to eliminate the virus[10]. At present, it is believed that this immune response is not simply activated or inhibited but is reflected in the disorder of the body’s defense mechanism.

Studies have shown that there are significant increases in the levels of inflammatory cytokines such as interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), monocyte chemotactic protein-1 (MCP-1), C-C motif chemokine ligand 4 (CCL4), chemokine (CK), and colony stimulating factor (CSF) in patients with COVID-19[7,8]. The continuous interaction of SARS-CoV-2 with the target cells leads to the recruitment of inflammation-related cells, the continuous release of pro-inflammatory cytokines, and the continuous aggravation of the systemic inflammatory response, which is considered as the cytokine release syndrome and is commonly known as the cytokine storm (CS)[11]. Severe acute respiratory syndrome-associated coronavirus 2 only inhibits the IFN signaling pathway, specifically, the expression of IFN-1, and the secretion of chemokines is not inhibited[12], in fact, the expression of many inflammatory cytokines (IL-6, CCL-2, CCL-3, and CCL-5) is increased[11]. In addition, increased plasma IL-2 and IL-6 levels have been observed in patients with severe COVID-19[10]. After the activation of primary cytokines, CD8 + T cells, NK cells, Treg cells, and Th2 cells can secrete secondary cytokines such as IFN-γ, bidirectional regulatory protein, or IL-5 to clear the virus and inhibit inflammation[13]. Severe acute respiratory syndrome-associated coronavirus 2 repeatedly acts on super-activated T cells and produces a large number of granulocyte macrophage CSF (GM-CSF) and IL-6, which further activate CD14 + CD16 + monocytes, resulting in a CS and multi-organ dysfunction[8,14]. Therefore, SARS-CoV-2 can over-activate immune cells and inhibit negative regulation, so that the immune process will be continuously amplified, causing corresponding damage to the body[15].

EM and pathogenesis

Endometriosis is a disease in which activated endometrial glands or stroma are implanted outside of the uterine cavity. Endometriosis usually leads to the progressive exacerbation of secondary dysmenorrhea, abnormal menstruation, and even infertility[16]. Studies have suggested that there are other regulatory mechanisms leading to the occurrence and development of EM, in addition to retrograde menstruation[17,18].

Abnormal immune system function might be an important mechanism of EM [19,20]. Several studies further revealed that the following phenomena can be observed in EM patients: decreased T-cell response activity and NK cell cytotoxicity, increased polyclonal activation and antibody production of B cells, increased number and activation of peritoneal macrophages, and changes in inflammatory mediators[21]. In patients with EM, the transformation of T cells into helper T cells (Th2) increases, and the activation of systemic and local humoral reactions caused by the change of Th1/Th2 cell ratio is closely related to EM[22,23]. In addition, IL-27 triggers Th17 cells to secrete IL-10 through the c-Maf/RORγt/Blimp-1 signaling pathway, which promotes the growth and implantation of ectopic lesions[24]. Forkhead box P3 (Foxp3) was detected in the lesions of deep rectosigmoid EM/ovarian EM, and the number of Treg cells in the peritoneal fluid and endometrium of patients with EM was significantly increased, indicating that Treg cells may play a role in the immune pathogenesis of EM[23–26]. B lymphocytes may also play a role in the pathogenesis of EM by secreting autoantibodies[27], while studies have shown that NK cells in EM show reduced cytotoxicity due to increased expression of killer inhibitory receptors (KIR), resulting in immune escape of ectopic endometrium and further adhesion and invasion of the ectopic endometrium[21,28]. Neutrophils produce pro-inflammatory cytokines such as vascular endothelial growth factor (VEGF), IL-8, IL-12, C-X-C motif chemokine ligand (CXCL) 10, CXCL12, and so on, which can promote EM progression[29]. Moreover, recent studies have shown that macrophages migrate to the M2 type during EM, which may increase the local production of factors that promote angiogenesis and endometrial cell invasion[30].

Potential impacts of COVID-19 on the pathogenesis of EM

As mentioned above, the pathogenesis of COVID-19 is mainly due to a disorder of the immune system, which manifests as an abnormal number of immune cells and the release of many inflammatory factors. The occurrence and development of EM are also closely related to the immune condition of the body. Therefore, the COVID-19 pandemic may have an impact on the occurrence and development of EM, but there are no exact reports at present.

Immunity and inflammation-related impacts

In the early stages of SARS-CoV-2 infection, the number of macrophages, neutrophils, and lymphocytes slightly increase, while the number of lymphocytes significantly decrease with the progression of this disease. In addition, the number of other immune cells (such as NK cells, Treg cells, and so on) decreases significantly, and the body is in a serious immunosuppressive state[7,10]. Studies suggest that the T-cell response activity and NK cytotoxicity of patients with EM are significantly reduced, and the proportion of Th2 cells is increased, which provides the microenvironment required for immune escape for ectopic endometrium[21]. Therefore, for patients with EM, the immunosuppressive state caused by COVID-19 will help the ectopic endometrium escape the body’s clearance and may even aggravate the implantation and invasion of ectopic endometrium.

In addition to the abnormal number of immune cells, patients with COVID-19 have excessive secretion of inflammation-related cytokines, resulting in an uncontrolled systemic inflammatory response, which is called macrophage activation syndrome or CS[11]. Studies suggest that the release of immune cells increases the levels of pro-inflammatory cytokines (such as IL-1β, IL-6, and TNF) and chemokines (such as CCL-2, CCL-3, CCL-5, CCL7, and CCL12)[15]. In addition, the inflammatory response associated with EM involves a variety of immune cells (such as monocytes, macrophages, neutrophils, and T cells), which are attracted and accumulated by chemokines (such as CXCL-8, CCL-2, CCL-5, and so on). After the accumulation of immune cells, the ectopic endometrium releases a large number of pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6, and so on), which promote the invasion of ectopic lesions[31]. These chemokines and inflammatory factors are consistent with those in patients with COVID-19, suggesting that the CS in patients with COVID-19 may provide a suitable inflammatory environment for the occurrence and development of EM. An increase in VEGF has been observed in patients with COVID-19 and EM[31–33]. Therefore, COVID-19 may affect the occurrence and development of EM as angiogenesis continues.

Local intestinal microenvironment-related impacts

It was reported in studies that Actinomycetes, Firmicutes, Verrucous microflora, Proteus, Bifidobacteria, Burkholderia, Escherichia coli, and Shigella increased significantly in the intestinal microorganisms of patients with EM, and Gardnerella decreased in the intestinal flora[34]. The immune imbalance, inflammatory response, and abnormal estrogen metabolism caused by the disorder of the intestinal microbiota may be important factors in the occurrence of EM[35]. In addition, animal experiments have confirmed that feeding fecal particles of mice with EM to other mice could promote the growth and invasion of ectopic lesions[36]. The study found that for patients with SARS-CoV-2 infection complicated by gastrointestinal symptoms, there was an intestinal microecological imbalance, which was specifically manifested in a decrease in the abundance of butyrate-producing bacteria (such as Faecalibacterium prausnitzii and Clostridium species), beneficial bacteria (such as Lactobacillus and Bifidobacteria), and an increase in some common pathogens (such as Prevotella, Enterococcus, Enterobacteriaceae, or Campylobacter)[37]. The increase in Enterobacteriaceae was similar between EM patients and SARS-CoV-2 infected patients. Intestinal microecological disorders caused by COVID-19 may promote the occurrence of EM and the further development of ectopic lesions.

Psychological status-related effects

Due to the novelty of the virus, the uncertainty of treatment methods, the lack of vaccines, and the delay of medical measures for chronic diseases, among others[38,39], COVID-19 brings great psychological pressure to the masses[18,40]. More than 45% of patients with COVID-19 have anxiety symptoms, and approximately 30% have depressive symptoms. At the same time, the results suggest that female sex is an independent risk factor for anxiety and depression in patients with COVID-19[41]. A cohort study of 14,144 patients in Switzerland showed that the risk ratios of depression and anxiety in EM patients were 1.88 (95% confidence interval [CI]: 1.78–1.99) and 2.01 (95% CI: 1.92–2.11)[42], suggesting that depression and anxiety significantly increase the risk of EM. Animal experiments revealed that exposure to psychological pressure before modeling significantly increased cell proliferation and macrophage infiltration of ectopic lesions of EM, resulting in an increase in lesion size and growth speed[43]. During the epidemic period of COVID-19, the psychological pressure on non-EM women is increased, consequently, increasing the risk of EM. However, the impact of COVID-19 on the management of EM in patients remains controversial. A study in Turkey showed that 53.63% of patients thought the management of their EM was affected by the pandemic[44], and the impact of COVID-19 on the care of people with EM was found worldwide[45]. Due to COVID-19, women with EM experience increased tension and anxiety that their diseases cannot be diagnosed and treated in time[46]. However, another study found that EM symptoms in most patients were much easier to manage, and they were more productive because of the flexibility in working hours and the increased ability to self-manage their time[47].

Gender and age-related impacts

Endometriosis is a female-specific condition; on the other hand, a study showed that there was no significant difference in the viral load and immune response of COVID-19 between the two sexes[48]. At the same time, a small number of sex-related differences have been reported in which a stronger T-cell response is observed in female patients as compared to T-cell response in male patients, which may lead to aggravation of the disease[48]. Another study showed that the antibody titer in male patients with COVID-19 was higher than that in female patients[49]. Endometriosis mostly occurs in women of gestational age (20–45 years)[50], whereas COVID-19 can occur in all age ranges. Compared to that of young patients, the adaptive immune response of patients over 65 years of age is uncoordinated[51]. Compared to that of children, adults have a stronger T-cell response to viral spinous process proteins and higher serum neutralizing antibody titers[52]. In the age group prone to EM, the COVID-19 disease was mostly mild or moderate. Therefore, immune disorders and abnormal activation of inflammatory responses are relatively limited in these age groups, and their impact on the occurrence and development of EM may be relatively limited.

Potential impacts of COVID-19 on the clinical symptoms of EM

COVID-19 may have an impact on the occurrence and development of EM but also on the typical clinical symptoms of women with EM, such as pelvic pain, emotional anxiety, and infertility.

Impacts of COVID-19 on pelvic pain of EM

Pelvic pain is the most common symptom in EM. Women with EM may experience periodic or a periodic pelvic pain such as dysmenorrhea[53], and pain-related symptoms may worsen under stress[54]. Given the added anxiety because of the pandemic, patients with EM may be more sensitive to pelvic pain from EM. Studies have found that changes in social distancing may exacerbate pain intensity during the COVID-19 pandemic[55]. On the contrary, other studies suggested that the change in social distance did not cause significant deterioration of pain intensity, and not all psychological stress aggravated chronic pain[55]. During the COVID-19 pandemic, the burden on most women was even heavier due to the increase in housework, childcare, and more study time of children at home instead of in school[56]. Thus, these may aggravate the pain symptoms of EM, which may even lead to the need for an increased dosage of painkillers[57]. Some scholars speculate that this phenomenon may also occur because COVID-19 prevents EM patients from receiving routine treatment or selective surgical treatment in hospitals[58]. Therefore, during social isolation caused by COVID-19, more patients with EM experience pain and anxiety[59]. In addition, previous studies have shown that care and concern from other people also seem to have beneficial effects in alleviating pain[60]. Social disconnection and loneliness caused by the COVID-19 pandemic affect the intensity of pain and may lead to the aggravation of pain-related symptoms[61].

Impacts of COVID-19 on infertility and assisted reproductive technology of EM

In addition to the common symptoms of pelvic pain, EM can also lead to female infertility. Patients with EM-related infertility have been under pressure from their families and themselves, and many of them require assisted reproductive technology (ART). There is no conclusive evidence that ART or pregnancy increases the risk of COVID-19. However, during the COVID-19 pandemic, it is recommended to suspend ART and postpone all non-emergency operations (such as artificial insemination and embryo transfer). Moreover, during the COVID-19 pandemic, the incidence of psychological and mental diseases has increased[62]. Infertile women in urgent need of pregnancy may be more vulnerable to negative psychosocial effects. The COVID-19 epidemic and infertility stress are both important sources of stress[63]. Some patients are unable to face the temporary closure of reproductive medicine centers, and even a small number of patients have a strong sense of despair, resulting in deterioration of health status and impairment of mental health[64]. From the perspective of female fertility, a delay in ART treatment will reduce the probability of successful pregnancy, especially in older women. In addition, the anxiety of elderly women is becomes more severe, which may adversely affect ovarian function[65]. At the same time, studies have shown that only about one-third of patients experience EM-related changes, suggesting that the impact of COVID-19 on clinical problems related to EM may be over-estimated. Patients with EM will not bear pressure similar to that of infertile patients, owing to the temporary suspension of ART treatment[3].

Conclusion

This review focuses on the potential impact of the COVID-19 pandemic on EM. The occurrence and development of COVID-19 and EM are accompanied by abnormalities in the immune system. Many inflammatory factors are released in patients with COVID-19, which may increase the risk of EM occurrence or aggravate the severity of EM. At the same time, the body of patients with COVID-19 is in a condition of severe immunosuppression, which also provides a suitable environment for ectopic endometrium to escape from clearance. Whether the impact of COVID-19 on the endometrial microenvironment can lead to the occurrence and development of EM is worthy of further investigation. On the other hand, the occurrence of COVID-19 has no association with sex and age, while EM mostly occurs in women of gestational age. These findings show that COVID-19 not only has an important impact on the occurrence and development of EM (Fig. 1) but also has a certain impact on the typical clinical symptoms of EM (Fig. 2). Mandatory isolation and increased psychological pressure during the COVID-19 pandemic may aggravate the feeling of pelvic pain from EM. For EM-infertile patients, delayed ART treatment will bring greater psychological pressure and even promote the further development of EM. In conclusion, the COVID-19 pandemic has had a significant impact on EM. During the COVID-19 pandemic, more attention should be paid to women prone to EM or with EM and effective methods should be further explore to reduce these impacts.

F1
Fig. 1.:
Potential roles of coronavirus disease 2019 (COVID-19) on the pathogenesis of endometriosis. ACE2: angiotensin-converting enzyme 2; CCL: chemokine ligand; EM: endometriosis; IL: interleukin; SARS-CoV-2: severe acute respiratory syndrome-associated coronavirus 2; TNF: tumor necrosis factor; VEGF: vascular endothelial growth factor.
F2
Fig. 2.:
Potential roles of coronavirus disease 2019 (COVID-19) on the clinical symptoms of endometriosis. ART: assisted reproductive technology; EM: endometriosis.

Acknowledgments

None.

Author contributions

C.Y.H. and J.M. contributed to concept, design, and critical discussion. C.Y.H. and H.X.S. contributed to literature search, manuscript preparation, manuscript editing, and manuscript drafting. All authors read and approved the final manuscript.

Funding(s)

This work was supported by grants from the National Natural Science Foundation of China (82071646, 81801530).

Conflicts of interest

All authors declare no conflict of interest.

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Keywords:

COVID-19; Endometriosis; Pathogenesis; Pelvic pain; Infertility

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