Endometriosis as an Infectious Disease: Association with Chronic Endometritis

Objectives: Recent studies focus on immunological, infectious, and inflammatory aspects of endometriosis. Meanwhile, chronic en- dometritis (CE) is an immunological, infectious, and inflammatory disorder of the eutopic endometrium with unusual stromal plasmacyte infiltration. Mechanism: In this review article, we aimed to gain a better understanding of the relationships between endometriosis and CE. Findings in Brief : Accumulating evidence supports the idea that CE is associated with infertility of unknown etiology, repeated implantation failure in an in vitro fertilization-embryo transfer program, recurrent pregnancy loss, as well as several perinatal/neonatal complications. Endometrial biopsy/histopathologic examinations and/or hysteroscopy are required to make a definitive diagnosis of CE. Conclusions: While endometriosis has been long considered a cause of infertility, CE is also an emerging issue that may reduce fecundity in women of reproductive age. Endometriosis and CE share characteristics of endometrial proliferative nature. The potential relationships between these two diseases of the uterine lining warrant future studies.

antibiotic treatment; chronic endometritis; endometriosis; microbiota; progesterone resistance 1. Introduction Chronic endometritis (CE) is an endometrial in- flammatory disorder, which is characterized by asymp- tomatic nature and unusual Clusterof Differentiation 138(+) (CD138(+)) endometrial stromal plasmacyte (ESPC) infil- tration [1]. The major cause of CE is thought to be intrauter- ine infection represented by common bacteria (such as Es- cherichia coli , Enterococcus faecalis , Streptococcus, and Staphylococcus), Mycoplasma/Ureaplasma, and Mycobac- terium [2,3], as antibiotic treatments against these microor- ganisms are effective for the elimination of ESPCs in the affected patients [ 4,5]. Other causes such as local dysbio- sis, however, may be involved in the pathogenesis of CE [6]. Accumulating evidence support that CE is associated with infertility of unknown etiology (28%), repeated im- plantation failure in an in vitro fertilization-embryo transfer program (14%–31%), recurrent pregnancy loss (9%–13%), as well as several perinatal/neonatal complications [ 6–10]. Endometriosis involves endocrinological, genetic, and epigenetic factors in its etiology and pathogenesis [ 11]. Recent studies focus on immunological, infectious, and in- flammatory aspects of endometriosis and demonstrate the common characteristics between endometriosis and CE. This review aimed to gain a better understanding of the rela- tionships between these two infertility-associated diseases. 2. Prevalence of CE in Women with Endometriosis Studies reported that CE is identified in 3%–53% of patients with endometriosis (Table 1, Ref. [ 12–17]). These interstudy variances are due to the differences in the diag- nostic criteria (ESPC density and microscopic fields ob- served) and methodology to detect CD138(+) ESPCs (the clones, concentrations, incubation temperatures, and dura- tion of the primary antibody as well as specimen conditions) between the studies. In 2011, we first investigated the prevalence of CE in the archival full-thickness eutopic endometrial tissues of women undergoing hysterectomy due to benign uter- ine corpus diseases, such as leiomyoma, adenomyosis, and endometriosis. Histopathologic CE (defined as five CD138(+) ESPCs in 10 high power fields (HPFs), 400 mag- nification) was detected in 5.0% of the endometriosis group and 11.7% of the non-endometriosis group [ 12], although the results were inconclusive due to the small sample size. In 2014, Takebayashi et al . [ 13], retrospectively searched for CE using a larger number of the eutopic en- dometrium obtained from the hysterectomized specimens. In contrast to 27.0% of the non-endometriosis group, CE was detected in 52.9% of the endometriosis group ( p = 0.031), which is the highest number among the studies pub- lished so far. There were no relationships between CE and age, body mass index (BMI), gravidity, and parity. They further compared the prevalence of CE in women with leiomyoma and adenomyosis. According to stepwise lo- gistic regression analysis, there were no significant associ- ations between CE and these two frequent uterine benign diseases, along with carcinoma in situ of the uterine cervix. Additionally, CE was unrelated to the stage of endometrio- sis (according to the revised American Society for Repro- Table 1. Studies on the prevalence of histopathologic CE in women with endometriosis. Article/Ethnicity/Study pe- riod/design Prevalence of histopathologic CE in endometriosis vs control group (p-value) Age (years) in en- dometriosis vs con- trol group BMI (kg/m 2) (en- dometriosis group vs control group) Samples and preparations Detection system for ESPC/clone, concentra- tion, incubation time, and temperature of primary anti- body against CD138 Diagnostic criteria for CE Stage of endometriosis (Re- vised American Society for Reproductive Medicine clas- sification) Kitaya K et al . [ 12] /Japan/January 2002– December 2010/retrospec- tive 5.00% (1/20) vs 11.68% (25/214) (non-endometriosis, endometrial benign diseases) (p = 0.7072) Information unavail- able Information unavail- able Hysterectomy specimens Immunohistochemistry, paraffin-embedded 4- µm sections /B-A38 (Nichirei Corp., Tokyo, Japan), stock solution, 60 min, room tem- perature 5 or more ESPCs in 10 high power fields (HPFs) Information unavailable Takebayashi A et al. [13]/Ja- pan/April 2001–December 2- 012/retrospective 52.94% (18/34) vs 27.02% (10/37) (non-endometrio- sis, endometrial benign d- iseases) (p = 0.0311) 44.15, 3.65 vs 43.15, 2.75 (mean and SD) (p = 0.711) 22.08, 4.83 vs 21.60, 3.14 (mean and SD) (p = 0.940) Hysterectomy specimens Immunohistochemistry, para- ffin-embedded 4-µm sections/ B-A38, stock solution, 60 m- in, room temperature 1 or more ESPCs in 10 H- PFs (400-fold magnifica- tion) Stage I–IV No relationship between the prevalence of CE and stage Khan KN et al . [ 14] /Japan/June 2012–December 2013/retrospective 3.08% (2/65) vs 0% (0/55) (non- endometriosis, infer- tility/dysmenorrhea) (p = 0.4993) 21–51 vs 22–51 (range) Information unavail- able Curettage speci- mens Immunohistochemistry, paraffin-embedded 5- µm sections /ab34164 (Ab- cam, Tokyo, Japan), 1:200, overnight, 4 °C 1 or more ESPCs in 15 HPFs (100-fold magnifi- cation) in 3 or more sec- tions Information unavailable Cicinelli E et al . [ 16] /Italy/January 2010–June 2016/retrospective 38.46% (30/78) vs 14.10% (11/78) (non- endometriosis, endome- trial benign diseases) ( p 0.05) 27.3, 4.2 vs 27.2, 4.3 (mean and SD) ( p > 0.05) Hysterectomy specimens Immunohistochemistry, paraffin-embedded 4- µm sections /MI15 Cell Marque (Biocare Medical, Concord, CA)/not available 1 or more ESPCs in 10 HPFs (100-fold magnifi- cation) Stage IV Freitag N et al . [17]/Germany (>90% Caucasian)/January 2013– February 2017/retrospective 12.90% (8/62) vs 10.00% (5/50) (non- endometriosis, infertil- ity) (p = 0.634) 26–48 (range) Information unavail- able Pipelle suction specimens Immunohistochemistry, paraffin-embedded/Other information not available (sent to laboratory) 5 or more ESPC per mm2 section Information unavailable Khan KN et al. [ 15]/Japan/A- pril 2015–February 2017/Pro- spective, non-randomized ≥22.6% (≥12/53) Not e- xamined prior to treatment 33.4% (7/21) (Untreated e- ndometriosis) vs ≥23.4% (≥11/47) Not examined p- rior to treatment 27.3% (3/ 11) (Untreated endometri- osis) 18–51 vs 26–51 (range) Information unavail- able Curettage speci- mens Immunohistochemistry, para- ffin-embedded 5-µm sections/ ab34164, 1:200, overnight, 4 °C 1 or more ESPCs in 5 H- PFs (200-fold magnifica- tion) Stage I–IV No relationship between the prevalence of CE and stage 2 ductive Medicine classification) [ 11]. The higher preva- lence of CE in this study is due to the diagnostic criteria (defined as one CD138(+) ESPCs in 10 HPFs, 400 magni- fication). When the researchers adopted the cut-off index of 6 ESPCs in one HPF, the overall prevalence was still higher in the endometriosis group than in the non-endometriosis group (29.41% vs 5.4%, p = 0.0101). Additionally, they found that all women with endometriosis enrolled had more than 11 ESPCs in one HPF. In the same year, Khan et al. [ 14] also retrospectively compared the prevalence of CE in women with and with- out endometriosis using endometrial curettage biopsy spec- imens collected during laparoscopy. They defined CE as the presence of one or more CD138(+) ESPCs (without neu- trophils) in five non-overlapping power fields ( ×100 mag- nification) in three or more 5- µm thickness sections. CE was detected in 3.1% (2/65 patients) with endometriosis, but not in any non-endometriosis patients (no statistical dif- ference). However, the prevalence is much different from another prospective non-randomized study published in 2021 (endometriosis group 22.6%~ and non-endometriosis group 23.4%~) [ 15], even with the same sample prepa- ration and examination methods. The discrepancies be- tween the two studies may be due to the presence or ab- sence of (i) histopathologic examinations for CE before la- paroscopy, (ii) preoperative administration of the oral an- tibiotic agents (levofloxacin, 500 mg, once), and/or in- tramuscular gonadotropin-releasing hormone agonist (1.88 mg per month, three times), and (iii) the difference in age of the women enrolled in the study. Again, no relationship was found between the prevalence of CE and the stage of endometriosis. In 2017, Cicinelli et al . [ 16] retrospectively com- pared the prevalence of CE in the endometrial tissues in the hysterectomized specimens of patients with and with- out endometriosis. Histopathologic CE was significantly more frequent in the stage IV endometriosis group than in the non-endometriosis group (38.5% vs 14.1%, p < 0.001). The concomitance of CE and endometriosis was observed in more than one-third of women. There were no significant associations between CE and age, BMI, and the presence of uterine leiomyoma/adenomyosis, but multiparity was found as a factor lowering the prevalence of CE in women with endometriosis. As many of these studies enrolled women undergo- ing pelvic surgery (hysterectomy or laparoscopy) and diag- nosed with endometriosis during the operation, the preva- lence of CE in women with suspected endometriosis (so- called “clinical endometriosis”) remains unknown and thus awaits further studies. 3. Microbiota in Reproductive Tract in Endometriosis and CE While there are three major theories underlying the on- set of endometriosis (i.e., retrograde menstrual blood flow, coelomic metaplasia, and Mullerian remnants), a single one is unable to explain the whole entity of the disease. Given the immunological and inflammatory natures of en- dometriosis, it is conceivable that bacterial infection and their metabolites are involved in this pathology [ 18]. Recent advances in next-generation sequencing meth- ods enabled us to analyze the local microbiota in various tissues and organs. In 2011, Human Microbiome Project revealed that the microbiota in the human vagina is domi- nated by four Lactobacillus species (L. iners, L. crispatus, L. gasseri, and L. jensenii), along with lower proportions of lactic acid bacteria, indicating the essential role of lactate in the integrity of this organ [ 19,20]. However, it remained undetermined if these results go for the whole female repro- ductive tract. In 2017, Chen et al . [ 21] comprehensively investigated the microbiota throughout the female repro- ductive tract in Chinese women of reproductive age. They demonstrated that each reproductive organ has its unique microbiota, and the local microbiota is affected by multiple factors, such as age, body temperature, menstrual cycle, fe- cundability/infertility, and anemia. Studies have demonstrated conflicting findings on the microbiota in the reproductive tract, particularly on Lacto- bacillus, in women with endometriosis. While some re- searchers reported a decrease in Lactobacillus in the en- dometrial and vaginal microbiota [ 22,23], others claimed the opposite result [ 24–26]. Interestingly, Khan et al. [ 22] found that the administration of gonadotropin-releasing hormone agonist, one of the therapeutic agents against en- dometriosis, changed the microbiota in the uterine cav- ity, resulting in a further decrease in Lactobacillus. Ad- ditionally, Le et al . [ 25], and Chang et al . [ 26] reported that surgical intervention and hormonal therapy altered the abundance of vaginal bacterial communities in the affected women with endometriosis. For example, the proportion of Lactobacillus in the vaginal microbiota was lower in pa- tients using monophasic oral contraceptives than in the non- users. The mechanisms underlying these medical interven- tions that affected the local microbiota in women with en- dometriosis remain unelucidated. Regarding other bacte- rial genera/species, the consequences are quite inconsistent among the studies [ 22–28]. These discrepancies are likely to result from the conditions for examinations such as types of local disinfectants, sampling device, and route. Taken to- gether, the bacterial genera/species and/or microbial com- munities in the female reproductive tract that are unique to endometriosis remains open so far and further studies are required. Meanwhile, studies on CE share some common find- ings on the microbiota in the reproductive tract in the af- fected women. For example, bacterial taxa such as Bifi- dobacterium, Gardnerella, Lactobacillus, Prevotella, and Streptococcus were found to be predominant in the endome- trial microbiota in women with CE [ 29–35]. By contrast, a number of studies failed to find unique bacterial gen- 3 era/species and microbial communities and/or differences in diversity and taxonomical composition in the endome- trial and vaginal microbiota between women with and with- out CE [ 36–38]. The results of the endometrial micro- biome analysis must be interpreted with precautions, as the estimated bacterial load in the vaginal cavity is shown to be 100- to 10,000-fold more than those in the uterine cavity [ 21]. No matter how local cleansing and disinfec- tion are well performed before sampling, the contamina- tion of the vaginal bacteria into endometrial bacteria is in- evitable in the course of the transvaginal procedure. In- deed, the studies using the samples obtained via the trans- peritoneo-myometrial route (laparoscopy or laparotomy) and transvaginal route disclosed quite different findings on endometrial microbiota, particularly about the compo- sitions of Lactobacillus species [ 21,39,40]. We recently reported that the vaginal microbiota in infertile women with CE is characterized by the reduction of lactic-acid- producing bacteria other than Lactobacillus, such as Strep- tococcus, Enterococcus, Atopobium, and Bifidobacterium [41]. The vaginal microbiome analysis should be noticed in future studies in this field. 4. Inflammatory Profiling of CE in Women with Endometriosis Non-pathological human endometrium contains a wide variety of leukocyte subsets. One of the physiological roles of these local leukocytes is the clearance of endome- trial cell debris shed over the course of the menstrual pe- riod. The density and proportion of endometrial leukocytes significantly fluctuate throughout the menstrual cycle. Af- ter ovulation, the subpopulations of macrophages, natural killer cells, and neutrophils increase in density in the en- dometrium [42]. This postovulatory rise of macrophages, however, is not seen in the eutopic endometrium of women with endometriosis, whereas an unusual hormonal cycle- independent global augmentation of macrophages (in par- ticular of M1 macrophages) is observed [ 43]. By contrast, in the ectopic endometrium of women with endometriosis, a large number of angiogenesis-supportive M2 macrophages are detectable in the endometriotic lesions [ 44]. These endometrial macrophages are thought to induce the pro- liferation of endometriotic cells. The postovulatory nu- merical increase of eutopic endometrial natural killer cells is maintained in women with endometriosis, but their cy- tolytic activity is impaired. In parallel, the lowered activ- ity of cytotoxic T lymphocytes, as well as the expansion of eosinophils, neutrophils, and mast cells, are reported in the peritoneal fluid in women with endometriosis [45]. Such an aberrant local immunological microenvironment is thought to allow the proliferation and survival of ectopic endome- trial tissues. Another immunological feature of the eutopic endometrium of women with endometriosis is the appear- ance of plasmacytes and CD20(+)/CD5(+)/HLA-DR(+) B cells, which are typical immunocompetent cells observed in CE, but are rare immunocompetent cells in the non- pathological eutopic endometrium [ 45]. On the contrary, endometrial immunoglobulin profiling remains undetailed. Early studies demonstrate a higher expression rate of IgG in eutopic endometrium with endometriosis compared with those without endometriosis, but subclass analysis has not been performed [46]. Meanwhile, the menstrual cycle-dependent fluctua- tion of the endometrial leukocyte subpopulations remains controversial in CE. Several studies did not find any dif- ferences [45,47], but others showed an increase in the pro- portion of local macrophages, M2 macrophages, and im- mature/mature dendritic cells [48]. Regarding mucosal im- munoglobulin expression, the densities of endometrial IgM, IgA1, IgA2, IgG1, and IgG2 subclasses were shown to be higher in CE than in non-CE and healthy controls with the predominance of IgG2+ stromal cells [ 49]. We demonstrated that several pro-inflammatory molecules involved in the selective extravasation of B cells, such as chemokines (Chemokine (C-X-C motif) ligand (CXCL1) and CXCL13) and endothelial adhesion molecule 1 (ELAM1) are aberrantly expressed in endothe- lial and epithelial cells of the endometrium in women with CE [ 47]. These pro-inflammatory molecules are induced in endometrial cells by microbial antigens such as lipopolysaccharide. In addition, the concentration of interleukin (IL)-6 and tumor necrosis factor (TNF)- α is markedly higher in the menstrual effluents of women with CE compared with those without CE [ 49]. IL-6 is known as a differentiation factor of mature B cells in various tissues. TNF- α raises estrogen biosynthesis in endometrial glandular cells, which may drive the uterine lining to the proliferative phenotype that may cause the occurrence of endometrial micropolyposis, a hysteroscopic finding that is often seen in CE [ 50,51]. Although it remains fully elucidated if these hypothe- ses apply to the eutopic endometrium of endometriosis, studies suggest that these unusual plasmacytes and B cells are potentially involved in the proliferation and survival of the other endometrial cell components. For example, the endometrium with local polyps and micropolyps own proliferative nature and contains a larger number of ES- PCs than the non-pathologic endometrium [ 52]. One of the histopathological characteristics of CE is delayed endome- trial differentiation in the mid-secretory phase, when blasto- cysts start to implant in this mucosal tissue. We found that approximately one-third of the endometrium with CE ex- hibit “out-of-phase” morphology, such as pseudostratifica- tion and mitotic nuclei in both glandular and surface epithe- lial cells [47]. Additionally, the expression levels of the an- tiapoptotic genes (BCL2 and BAX ), proliferation-associated nuclear marker (Ki-67), and ovarian steroid receptors (es- trogen receptor-α, and -β, progesterone receptor-A, and -B) are unusually upregulated in the secretory phase endometr- 4 Table 2. Studies on the use of metronidazole against CE. Article/Ethnicity/Study pe- riod/Study design Dose Indications Age (years) BMI (kg/m2) Samples/Detection system for ESPC/clone, dilution, incu- bation time, and temperature of primary antibody against CD138 Diagnostic criteria for CE The cure rate of histopathologic CE Johnston-MacAnanny EB et al ., [ 58] /United States/January 2001– December 2007/Retro- spective 1000 mg/day, 14 days (500 mg, twice) in combination with ciprofloxacin 1000 mg/day, 14 days RIF (two failed ET cy- cles), second-line against doxycycline-resistant CE 34.50, 3.27 (mean and SD) Information unavail- able Pipelle suction specimens/ Immunohistochemistry, paraffin-embedded sec- tions/MI15 Cell Marque (Biocare Medical, Concord, CA)/not available Biocare Medical, Concord, CA) /1:100 dilution/60 min/Room air? 1 or more ESPCs in 1 HPF observed 100% (3/3) McQueen DB et al . [ 8] /United States (Cau- casian and African- American)/July 2004– February 2012/Prospective 1000 mg/day, 14 days (500 mg, twice) in combina- tion with or ofloxacin 800 mg/day, 14 days Recurrent pregnancy loss, first-line 22.08, 4.83 (mean and SD) 25.8, 6.4, 20–47 (mean, SD and range) Not detailed Not detailed 73.1% (19/26) Y ang R et al . [ 62] /Chi- nese/January 2009–January 2010/Prospective 1000 mg/day, 14 days (500 mg, twice) in combina- tion with levofloxacin 500 mg/day, 14 days RIF (three failed ET cy- cles or 6 or more high- quality transferred em- bryos), first-line Not detailed (Two combined studies are reported in one article) Not detailed (Two combined studies are reported in one article) Pipelle suction specimens/ Im- munohistochemistry 1 or more ESPCs in the section observed Not re-examined Tersoglio AE et al . [59] /Argentina/2010– 2013/Prospective 1000 mg/day, 14 days (500 mg, twice) in combination with ciprofloxacin 1000 mg/day, 14 days and prece- dent 200 mg/day doxycycline along with prednisone 4–8 mg/day RIF (two or more failed ET cycles), first-line 36, 4.08 (mean and SD) Information unavail- able Not detailed 1 or more ESPCs in 1 HPF observed 64.3% (9/14) Kitaya K et al . [10]/Japan/November 2011–July 2014/Prospective 500 mg/day, 14 days (250 mg, twice) in combination with ciprofloxacin 400 mg/day, 14 days RIF (three or more 6 or more high-quality trans- ferred embryos and/or blastocysts), second-line against doxycycline- resistant CE 38.1, 3.8 (mean and SD) 21.1, 1.9 (mean and SD) Curette biopsy speci- mens/Immunohistochemistry, paraffin-embedded 4- µm sec- tions /B-A38 (Nichirei Corp., Tokyo, Japan), stock solution, 60 min, room temperature endometrial stromal plasmacyte density index (sum of ESPC counts divided by the number of HPF evaluated) 0.25 or more 88.9% (8/9) Gay C et al. [ 63]/France/Jan- uary 2013–January 2018/Re- trospective 1000 mg/day, 14 days (500 mg, twice) in combination with doxycycline 200 mg/d- ay, 14 days (Antibiotic was chosen according to antibio- gram if bacteria were ident- ified.) Recurrent pregnancy loss, first-line 33 (9) 24 (3) Pipelle suction specimens/Imm- unohistochemistry, not detailed 1 or more ESPCs in 1 H- PF observed Not detailed median and (in- terquartile range) median and (in- terquartile range) 5 ium with CE [ 53–56]. Meanwhile, the expression of the genes potentially associated with embryo receptivity ( in- terleukin 11 (IL11), Chemokine Ligand 4 (CCL4) , insulin- like growth factors 1 (IGF1) , and caspase 8 (CASP8) ) and decidualization ( prolactin (PRL) and Insulin-like growth factor-binding protein 1 (IGFBP1)) are impaired in this pe- riod [53,56]. These findings indicate that the endometrium with CE is unable to respond correctly to ovarian steroids and mod- ulate its component cells into a receptive phenotype, impli- cating the potential relationship between progesterone re- sistance and CE, which is also seen in endometriosis [ 57]. 5. Antibiotic Treatment against CE and Endometriosis As a bacterial infectious disease, antibiotic treatments have been utilized in the treatment of CE. Indeed, recent studies demonstrated that antibiotic treatments are supe- rior to follow-up observations in the cure rate of CE [ 4,5]. Additionally, some studies suggest an improved live birth rate in subsequent embryo transfer cycles after the cure of CE, although there are no published randomized controlled studies [ 7,9,58–60]. Considering the broad antibacterial spectrum covering from common bacteria to mycoplasma, the antibiotic agents such as oral doxycycline, fluoro- quinolones (ofloxacin, levofloxacin, and ciprofloxacin), ni- troimidazole (tinidazole and metronidazole) have been pre- ferred in the treatment against CE [7,9,58–63]. Meanwhile, some studies adopted an antibiogram-oriented choice of an- tibiotic agents [ 6]. Antibiotic resistance is a global prob- lem in the treatment of bacterial infectious diseases. CE is no exception anymore. We recently demonstrated the in- crease in multi-drug-resistant CE in infertile women with a history of repeated implantation failure (7.8% of whole CE cases), along with the effectiveness of azithromycin or moxifloxacin against multi-drug-resistant CE [ 37]. Although there is currently no literature that demon- strated the effectiveness and safety of antibiotic treatment against endometriosis in humans, animal studies suggest the potential of some antibiotic agents, particularly metronida- zole, which has been utilized for the treatment of CE (Ta- ble 2, Ref. [ 8,10,58,59,62,63]), as a promising therapeutic drug against endometriosis. Using a mouse model, Chadchan et al . [ 64] investi- gated the effect of 21-day oral water-solubilized adminis- tration of the broad-spectrum antibiotics (0.5 mg/mL van- comycin, 1 mg/mL neomycin, 1 mg/mL metronidazole, and 1 mg/mL ampicillin, V ancomycin, Neomycin, Metronida- zole, and Ampicillin (VNMA)) on endometriosis lesions. Of them, metronidazole significantly reduced the volumes and weights of the ectopic endometriosis lesions, along with amelioration of pelvic inflammatory responses (sup- pression of macrophage proliferation and production of cy- tokines such as IL-1 β, IL-6, and TNF- α). Interestingly, oral administration of feces from mice with endometriosis exacerbates the growth and inflammation of the endometri- otic lesions in metronidazole-treated mice, indicating a key role of gut bacteria in the promotion and progression of en- dometriosis in these mice. Furthermore, Lu et al. [ 65] re- ported the effectiveness of the vaginal administration of the VNMA mixture (once every 3 days for 21 days) via an ab- sorbable gel sponge on endometriosis lesions. While the disorder of the vaginal microbiota potentially promoted the progression of endometriosis, antibiotic treatment was ca- pable of reducing the volume of the endometriotic lesions via regulation of the nuclear factor-kappa B signaling path- way. Thus, antibiotic treatment can be a potential therapeu- tic option against endometriosis, although more basic stud- ies are required prior to application to humans. 6. Conclusions While endometriosis has been long considered a cause of infertility, CE is also an emerging issue that may reduce fecundity in women of reproductive age [ 66]. Endometrio- sis and CE share characteristics of endometrial prolifer- ative nature. Like endometrial polyps being often seen in endometriosis, endometrial micropolyposis is frequently complicated with CE [ 17,67]. The potential relationships between these two diseases of the uterine lining warrant fu- ture studies. Author Contributions KK wrote the manuscript. TM and MM were involved in the discussion of the contents. All authors read and ap- proved the final manuscript. Ethics Approval and Consent to Participate Not applicable. Acknowledgment Not applicable. Funding This research received no external funding. Conflict of Interest The authors declare no conflict of interest.

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