Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis

Apoptosis has been implicated in the pathogenesis of several diseases and is partly regulated by bcl-2, which blocks the apoptotic pathway and promotes cell survival. Apoptosis and bcl-2 expression were examined in paired eutopic and ectopic endometrium from women with endometriosis (n = 30 samples) or adenomyosis (n = 15 samples) and compared with control endometrium (n = 30 samples). Apoptotic cells were detected using the dUTP nick-end labelling (TUNEL) assay for DNA fragmentation; bcl-2 expression was demonstrated with a streptavidin- biotin peroxidase immunohistochemical technique. Apoptotic cells were rare in eutopic, ectopic and control endometrium; there were no significant differences between subject groups nor between eutopic and ectopic endometrium. Stromal bcl-2 expression increased in the late secretory phase in control and eutopic endometrium in endometriosis; double labelling studies revealed that most stromal bcl-2+ cells were leukocytes. Stromal bcl-2 expression in endometriotic foci was significantly increased compared with the paired eutopic endometrium, did not vary with menstrual cycle and included a significant population of non-leukocytic bcl-2+ stromal cells. In contrast, stromal bcl-2 expression in adenomyosis remained at low levels and did not show significant cyclical variation. Glandular epithelial bcl-2 expression also varied with menstrual cycle phase and peaked in the proliferative phase; in contrast, surface epithelial bcl-2 expression increased in the late secretory phase. Elevated stromal bcl-2 expression in ovarian endometriotic lesions could have implications for the growth and survival of ectopic endometrial tissue at these sites.      

Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression in endometriosis: comparison of eutopic and ectopic endometrium with normal cycling endometrium

Recent studies examining oestrogen and progesterone receptorstatus and the proliferative activity of endo-metriotic lesionshave produced conflicting reports. This study aimed to clarifythe receptor status and proliferative activity of eutopic andectopic endometrium from women with endometriosis and endometriumfrom normal women. Progesterone and oestrogen receptor expressionand proliferative activity were studied in eutopic and ectopicendometrium from 30 women with endometriosis and in endometriumfrom 30 normal cycling women using microwave-pretreated paraffin-embeddedsections stained with an avidin-biotin peroxidase technique.Progesterone and oestrogen receptor expression in the controlendo-metrium did not differ from that of eutopic endometriumfrom women with endometriosis. Oestrogen receptor expressionin ectopic endometrium increased from the proliferative to thelate secretory phase. Epithelial progesterone receptor expressiondecreased during the cycle. Oestrogen receptor expression inboth epithelium and stroma of ectopic endometrium was significantlyhigher than in eutopic endometrium throughout the cycle. Incontrast, stromal progesterone receptor expression tended tobe reduced in ectopic endometrium compared with eutopic tissue.Epithelial progesterone receptor expression was increased inectopic endometrium but only in the late secretory phase. Althoughproliferative activity in the epithelium of control and eutopicendometrium was reduced from the proliferative to the late secretoryphase, stromal activity did not vary. The proliferative activityin ectopic endometrium remained low and constant throughoutthe cycle. In the proliferative and early secretory phases,the proliferative activity of eutopic endometrium was increasedcompared with ectopic endometrium, but in the late secretoryphase, levels were comparable. These findings challenge previousreports which have suggested that oestrogen receptors are reducedin ectopic tissue. This may have clinical implications for thedevelopment of novel treatments for endometriosis.     

Characterization of Lymphocyte Subpopulations and T Cell Activation In Endometriosis

PROBLEM: Numerous studies have characterized the lymphocyte subpopulations in normal eutopic endometrium and suggested a role for the cytokine secretory products of these lymphocytes in regulating endometrial cell proliferation and differentiation. Recent studies have shown that ectopic endometrium contains a greater concentration of scattered stromal lymphocytes than does eutopic endometrium. However, the lymphocyte subpopulations and their activation status have not been characterized in ectopic endometrium. METHODS: We performed immunohistochemical studies on serial sections of proliferative and secretory phase eutopic endometrium and ectopic endometrium obtained during the proliferative phase using monoclonal antibodies to CD4 (T helper-inducer cells), CD8 (T cytolytic-suppressor cells), CD22 (B-cells), CD56 (natural killer cells), and VLA-1 (T-cell activation marker). RESULTS: Ectopic endometrium contained significantly more scattered stromal CD4, CD8, and activated T cells than did proliferative and secretory eutopic endometrium. There were more activated T-cells in proliferative than in secretory eutopic endometrium. Ectopic endometrium contained significantly fewer NK cells than proliferative and secretory endometrium. CONCLUSIONS: These results demonstrate that (1) the increased lymphocyte population in ectopic endometrium is due to increased numbers of CD4 and CD8 cells, and (2) a greater number of activated T cells are present in ectopic endometrium as compared to eutopic endometrium. Increased concentration of stromal T cells and enhanced VLA-1 expression in ectopic endometrium suggest that cytokine products of the activated T-cells may be involved in regulating cellular processes of endometriosis tissue.     

Distribution of cyclooxygenase-2 in eutopic and ectopic endometrium in endometriosis and adenomyosis

The objective of this study was to determine the distribution of cyclooxygenase-2 (COX-2) in eutopic and ectopic endometria in endometriosis and adenomyosis. The subjects were 35 patients with endometriosis diagnosed by laparoscopy, 33 patients with histologically confirmed adenomyosis and 50 female controls with normal fecundity. Expression of COX-2 was immunohistochemically investigated in tissues from eutopic endometrium and myometrium and ectopic endometrium of the wall of ovarian chocolate cysts using polyclonal antibody. Surface epithelial cells, endometrial glandular epithelial cells or stromal cells were assessed. Cells were semi-quantitatively assessed on a scale of 1 to 5 using a nomogram created from positive cell count and the degree of staining. COX-2 expression in surface and glandular epithelia of the control group varied markedly during the menstrual cycle. It was lowest in the early proliferative phase and gradually increased thereafter. It remained high throughout the secretory phase. However, in patients with endometriosis, expression of COX-2 in glandular epithelium was higher than that in the control group, though it varied throughout the menstrual cycle. On the other hand, there was no variation in expression of COX-2 in the adenomyosis group during the menstrual cycle, and it was lower than that in the endometriosis group in all phases. Pronounced COX-2 expression was observed in glandular cells from ectopic endometrial tissue of ovarian chocolate cyst walls in all cases regardless of the menstrual phase. In summary, increased COX-2 expression in eutopic and ectopic endometria was believed to be strongly correlated with pathological abnormalities in these disorders.     

Expression of interleukin-8 receptors in endometriosis

BACKGROUND: Although the etiology of endometriosis is not well understood, chemokines and their receptors are believed to play a role in its pathogenesis. Therefore, we aimed to investigate the expression and localization of interleukin-8 (IL-8) receptors CXCR1 and CXCR2 in eutopic and ectopic endometrial tissues of women with endometriosis, and in endometrium of women without endometriosis. METHODS: Ectopic (n = 27) and homologous eutopic endometrium (n = 25) from women with endometriosis and endometrium from women without endometriosis (n = 27) were used for immunohistochemical analysis of CXCR1 and CXCR2. RESULTS: In normal endometrium, epithelial CXCR1 and CXCR2 immunostaining intensities were similar in the proliferative and secretory phase. Stromal CXCR1 expression was less then epithelial expression and did not show cyclical difference. No stromal CXCR2 expression was observed. In eutopic endometrium of women with endometriosis compared to endometrium of women without endometriosis, there was a significant increase in both proliferative and secretory phases for epithelial CXCR2 expression, and in proliferative phase for CXCR1 expression (P < 0.05). Both receptor immunoreactivities were significantly increased in the epithelial cells of ectopic endometrial tissues compared to that of normal endometrium (P < 0.05). CONCLUSIONS: These findings suggest that IL-8 and its receptors may be involved in the pathogenesis of endometriosis.     

Intraepithelial leukocytes in endometriosis and adenomyosis: comparison of eutopic and ectopic endometrium with normal endometrium

Intraepithelial leukocytes (IEL) are recognized as an importantcomponent of most mucosal surfaces but have received scant attentionin the human female reproductive tract. The aim of the presentstudy was to characterize, quantify and compare IEL populationsin normal endometrium (n = 30) and in eutopic and ectopic (endometrioticor adenomyotic lesions) endometrium from women with endometriosis(n = 30) or adenomyosis (n = 15) at different menstrual cyclephases in order to assess the role of IEL in these common butpoorly understood disorders. IEL populations were examined informalin-fixed, paraffin-embedded sections using a streptavidin-biotin-peroxidasecomplex technique and quantified in relation to epithelial cellnumbers. IEL in control endometrium and eutopic endometriumin endometriosis and adenomyosis varied during the menstrualcycle, with CD45+, CD43+ and CD56+ cells increasing from theproliferative to the late secretory phase. IEL were elevatedin surface compared with glandular epithelium in the proliferativeand early secretory phases. Throughout the menstrual cycle therewere no significant differences in IEL between eutopic and ectopicendometrium in adenomyosis. Endometriotic foci, however, containedelevated levels of CD45+, CD3+ and CD8+ cells and reduced numbersof CD56+ cells compared with the corresponding eutopic endometriumand these did not vary with menstrual cycle phase. In contrast,ectopic endometrium in adenomyosis showed some cyclical changeswith CD56+ cells increasing significantly in the late secretoryphase. It is possible these differences may play a role in thepathogenesis of endometriosis and the associated complications.     

CD44s、纤维粘连蛋白表达与子宫内膜异位症发病关系的研究

目的：探讨细胞黏附分子（CAMS）纤维粘连蛋白（FN）、CD44s与子宫内膜异位症发病的关系.方法：S-P免疫组化法法检测子宫内膜异位症在位内膜（22例）、异位内膜（45例）、对照组子宫内膜（20例）进行病理组织化学观察和CD44s、FN表达的检测.结果：对照组相比子宫内膜CD44s主要表达于腺上皮细胞,FN表达于基质细胞,与对照组相比子宫内膜异位症在位子宫内膜CD44s、FN均表达于下降,差异有显著性（P〈0.05）,异位内膜组CD44s、FN表达明显降低,差异有显著性（P〈0.05）.结论：子宫内膜异位症患者从子宫内膜到异位病灶,CD44s、FN均有明显的变化,这可能与子宫内膜异位症的发生、发展、不孕有关.     

GnRHⅡ蛋白在子宫内膜异位症患者中的表达及意义

目的：检测GnRHⅡ蛋白在子宫内膜异位症患者异位子宫内膜、在位子宫内膜和正常子宫内膜中的表达情况,同时分析其表达是否与子宫内膜月经周期有关。方法：采用免疫组织化学SP法检测GnRHⅡ蛋白在异位内膜、在位内膜及正常子宫内膜组织中的表达情况,并分析和比较其表达是否有差异。结果：GnRHⅡ蛋白在子宫内膜异位症患者异位、在位子宫内膜及正常子宫内膜中均有表达,阳性表达定位于子宫内膜腺体及间质细胞的细胞质;GnRHⅡ蛋白在异位内膜、在位内膜及对照组正常内膜的表达依次增强,两两比较差异有统计学意义（P＜0.05）;GnRHⅡ蛋白在正常子宫内膜分泌期表达强于增生期（P＜0.05）,且以分泌早中期最强,显著强于增生期和分泌晚期（P＜0.01）,而异位组或在位组的分泌期与增生期比较,差异无统计学意义（P＞0.05）。结论：GnRHⅡ蛋白在子宫内膜异位症的发病中以及在人类月经生理方面可能起重要作用。     

The macrophage stimulating protein/RON system: a potential novel target for prevention and treatment of endometriosis

Our recent DNA microarray analysis using tissue obtained by laser capture microdissection (LCM) identified up-regulation of RON (a tyrosine kinase receptor) during the late secretory phase in eutopic endometrial epithelial cells from patients with deep endometriosis compared with control endometrium from women with macroscopically normal pelvic cavities. In the present study, we further investigated mRNA expression of RON and its ligand, macrophage stimulating protein (MSP), in deep endometriotic lesions, eutopic endometrium from patients with deep endometriosis and control endometrium by using LCM and quantitative real-time RT-PCR. MSP mRNA expression in endometrial epithelial cells was significantly up-regulated in endometriosis patients during the late secretory phase compared with expression in controls. Furthermore, we detected up-regulation of MSP mRNA in ectopic endometrial epithelial cells compared with matched eutopic endometrial epithelial cells within the same patients regardless of the menstrual phase. MSP has an intrinsically dual functional nature through its receptor RON-it is a trophic cytokine preventing apoptosis and a scatter factor promoting invasion, both of which may be necessary for the initial development and growth of endometriosis. The present findings suggest that the MSP/RON system may be involved in the pathophysiology of endometriosis.     

Estrogen metabolizing enzymes in endometrium and endometriosis

BACKGROUND: Estradiol (E(2)) is an important promoter of the growth of both eutopic and ectopic endometrium. The findings with regard to the expression and activity of steroidogenic enzymes in endometrium of controls, in endometrium of endometriosis patients and in endometriotic lesions are not consistent. METHODS: In this study, we have looked at the mRNA expression and protein levels of a range of steroidogenic enzymes [aromatase, 17beta-hydroxysteroid dehydrogenases (17beta-HSD) type 1, 2 and 4, estrogen sulfotransferase (EST) and steroid sulfatase (STS)] in eutopic and ectopic endometrium of patients (n = 14) with deep-infiltrative endometriosis as well as in disease-free endometrium (n = 48) using real-time PCR and immunocytochemistry. In addition, we evaluated their menstrual cycle-related expression patterns, and investigated their steroid responsiveness in explant cultures. RESULTS: Aromatase and 17beta-HSD type 1 mRNA levels were extremely low in normal human endometrium, while mRNAs for types 2 and 4 17beta-HSD, EST and STS were readily detectable. Only 17beta-HSD type 2 and EST genes showed sensitivity to progesterone in normal endometrium. Types 1 and 2 17beta-HSD and STS protein was detected in normal endometrium using new polyclonal antibodies. CONCLUSIONS: In endometriosis lesions, the balance is tilted in favor of enzymes producing E(2). This is due to a suppression of types 2 and 4 17beta-HSD, and an increased expression of aromatase and type 1 17beta-HSD in ectopic endometrium.     

Cell Proliferation and apoptosis: Detection of apoptosis in human endometriotic tissues

To clarify whether apoptosis is involved in endometriosis, weobtained eutopic endometrial tissues along with endometriotictissues from the uterus (adenomyosis) (n = 12) and from theovary (n = 12) from patients undergoing gynaecological surgery.Apoptosis-induced DNA fragmentation was detected by the TdT-mediateddUTP-biotin nick-end labelling method, and immunostaining witha monoclonal antibody against the Fas, Le^y or B-cell leukaemia/lymphoma-2(bcl-2) was also performed using the same tissue section. Analysisshowed that apoptosis was occurring in all the samples of ovarianendometriotic tissue but in only two of the 12 adenomyotic andin five of the 24 eutopic endometrial tissue samples. In noneof these cases was apoptosis correlated with phases of the menstrualcycle. The expression of bcl-2 in the eutopic endometrial andadenomyotic tissues was limited to the proliferative phase,and was observed in only one of the 12 cases of ovarian endometriosis.Fas and Le^y were expressed randomly across a wide range in boththe eutopic and ectopic endometrial tissues. These results suggestthat the features of ovarian endometriosis are different fromthose of adenomyosis and eutopic endometrium in terms of theinvolvement of apoptosis. In addition, the regulatory mechanisminvolved in ovarian endometriosis may differ from that in otherendometrial cells. adenomyosis/apoptosis/bcl-2/DNA fragmentation/endometriosis     

Transcriptional expression of survivin and its splice variants in endometriosis

Survivin is a novel inhibitor of apoptosis (IAP), and the two splice variants of survivin (survivin-2B and survivin-EX3) have been identified. Gene expression levels of survivin, survivin-2B and survivin-EX3 in 56 ectopic (16 peritoneal red and 16 peritoneal black lesions and 24 ovarian endometriomata) and 13 eutopic endometrial tissues surgically obtained from 42 women with endometriosis (group A) were compared with those in 16 control eutopic endometrium from 16 women without endometriosis (group B) by quantitative RT-PCR analysis. Survivin mRNA expression levels in ectopic endometriotic tissues were significantly higher than those in eutopic endometrium of groups A and B over the whole cycle. Red peritoneal lesions had higher gene expression levels of survivin than black lesions. In contrast, all tissue samples examined showed relatively lower gene expression levels of survivin-2B and survivin-EX3. No cyclic variation was found in survivin and the two splice variants, both in ectopic and in eutopic endometrium. Although there was no significant difference in the ratio of survivin-2B/survivin between ectopic and eutopic endometrium, the ratio of survivin-EX3/survivin in peritoneal endometriotic lesions was significantly higher than that of eutopic endometrium of groups A and B. These results suggest that survivin and survivin-EX3 may be closely linked to escape from apoptosis and the development of endometriosis.     

Apoptosis in human endometrium and endometriosis

Apoptosis plays a critical role in maintaining tissue homeostasis and represents a normal function to eliminate excess or dysfunctional cells. Accumulated evidence suggests that apoptosis helps to maintain cellular homeostasis during the menstrual cycle by eliminating senescent cells from the functional layer of the uterine endometrium during the late secretory and menstrual phase of the cycle. The BCL-2 family and Fas/FasL system have been extensively studied in human endometrium and endometriotic tissues. Eutopic endometrium from women with endometriosis reportedly has some fundamental differences compared with normal endometrium of women without endometriosis. The differences could contribute to the survival of regurgitating endometrial cells into the peritoneal cavity and the development of endometriosis. One mechanism that recently gained a lot of interest is the finding that apoptosis appeared in eutopic and ectopic endometrium of patients with endometriosis. This study is a current review of the literature focused on the physiological role of apoptosis in normal endometrium and the alterations in regulation of apoptosis in eutopic and ectopic endometrium from women with endometriosis. Similarities in characteristics of endometriosis at a molecular level with gynaecological tumours are also discussed. Finally, the role of apoptosis in the treatment of endometriosis is reviewed to link the basic research findings into clinical applications.     

血管内皮生长因子在子宫内膜异位症发病中的作用

目的探讨血管内皮生长因子(vascularendothelialgrowthfactor,VEGF)在子宫内膜异位症(endometriosis,EM)发病中的作用。方法应用免疫组织化学方法并结合图像分析技术。结果正常子宫内膜和EM在位内膜腺上皮细胞的VEGF随月经周期呈现规律性变化,分泌期腺上皮VEGF蛋白表达量显著高于增殖期(P<0.05)。在增殖期,EM在位子宫内膜腺上皮VEGF的表达与正常子宫内膜相比无明显差别,但在分泌期,EM在位子宫内膜腺上皮细胞中VEGF的表达强度明显高于正常子宫内膜(P<0.01)。EM在位内膜腺上皮的VEGF含量显著高于同组卵巢子宫内膜异位囊肿的异位腺上皮(P<0.01)。结论表明VEGF的表达异常与EM的发病有关。     

Endometrial leptin and leptin receptor expression in women with severe/moderate endometriosis

The leptin system has been implicated in reproductive function, acting at endocrine and paracrine levels. Recently, deregulation of this gene family has been linked to endometrial changes caused by endometriosis. In the present study, we compare the expression of leptin receptor mRNA during the pre-receptive (LH+2) and receptive (LH+9) phases in the eutopic endometrium from patients with severe/moderate endometriosis (n = 30) versus fertile controls (n = 12). In each patient, two endometrial samples were obtained at LH+2 and LH+9 in their natural cycles. When real-time quantitative fluorescent PCR was performed, an up-regulation of OB-RL and all the isoforms investigated was observed at LH+9 versus LH+2 in patients with and without endometriosis. However, no difference was found in the expression pattern of the total leptin receptor OB-RT, or in its long OB-RL and soluble HuB219.3 forms when the eutopic endometria of patients with severe/moderate endometriosis and fertile controls were compared. By means of in situ hybridization, total leptin receptor mRNA was localized in the luminal epithelium and the glands of the endometrium. The immunohistochemical analysis of the long form of leptin receptor was also performed in order to confirm these findings at the protein level. Finally, we have also shown similar leptin mRNA expression in both the control group and patients with endometriosis. In conclusion, we have not identified differences in the endometrial expression and localization of leptin and the leptin receptor when comparing the eutopic endometrium of women with severe/moderate endometriosis and fertile controls.     

整合素β3在子宫内膜异位症与子宫内膜癌中的表达及生物学行为相关性研究

目的研究整合素β3（beta3 integrin）在子宫内膜异位症、子宫内膜癌中的表达,探讨其表达与子宫内膜异位症发生及子宫内膜异位症和子宫内膜癌生物学行为的相关性。方法采用免疫组织化学方法检测10例子宫内膜异位症在位内膜、异位内膜,10例子宫内膜癌,10例对照组正常子宫内膜整合素β3的表达。结果整合素β3在子宫内膜异位症在位内膜组的表达显著低于对照组（P〈0.05）,在异位内膜组中的表达显著高于在位内膜组及对照组（P〈0.05、P〈0.05）;整合素β3在子宫内膜癌组中的表达显著高于对照组（P〈0.05）;整合素β3在子宫内膜异位症异位内膜组中的表达与子宫内膜癌组中的表达差异无显著性（P〉0.05）。结论整合素β3的异常表达可能与子宫内膜异位症的发生有关;且可能与子宫内膜异位症具有和子宫内膜癌相似的生物学行为有关。     

Endometriosis results from the dislocation of basal endometrium

BACKGROUND: The hypothesis is tested that both adenomyotic and endometriotic lesions are derived from basal endometrium. METHODS: Normal uteri and uteri with adenomyosis obtained by hysterectomy, excised endometriotic lesions and menstrual blood of women with and without endometriosis were used. Estrogen receptor (ER), progesterone receptor (PR), progesterone receptor B isoform (PR(B)) and P450 aromatase (P450A) immunohistochemistry was performed with the use of specific monoclonal antibodies. RESULTS: With respect to the parameters studied there was a fundamental difference between the cyclical patterns of the basalis and the functionalis of the eutopic endometrium. The endometrium of endometriotic and adenomyotic lesions mimicked the cyclical pattern of the basalis. The peristromal muscular tissue of endometriotic and adenomyotic lesions displayed the same cyclical pattern of ER and PR expression as the archimyometrium. There was a significantly higher prevalence of fragments of shed basalis in menstrual blood of women with endometriosis than in healthy controls. CONCLUSIONS: These data suggest that ectopic endometrial lesions result from dislocation of basal endometrium. Dislocated basal endometrium has stem cell character resulting in the ectopic formation of all archimetrial components such as epithelial and stromal endometrium as well as peristromal muscular tissue.     

Urocortin 2 and urocortin 3 in endometriosis: evidence for a possible role in inflammatory response

Urocortin 2 (Ucn 2) and urocortin 3 (Ucn 3) are neuropeptides expressed by human endometrium. This study evaluated (i) the expression of Ucn 2 and Ucn 3 mRNA in endometriotic lesions and in endometrium of women with endometriosis; (ii) the effect of Ucn 2 and Ucn 3 on cytokines secretion from cultured endometrial stromal cells. Endometriotic tissue was collected from endometrioma (n=39); endometrial specimens were obtained from women with (n=39) and without (n=41) endometriosis throughout menstrual cycle. Tissue specimens were analysed for Ucn 2 and Ucn 3 mRNA expression and peptide localization; the effects of Ucn 2 or Ucn 3 on tumour necrosis factor (TNF-α) and interleukin (IL-4) secretion from cultured endometrial stromal cells was studied. Ucn 2 and Ucn 3 mRNA expression and localization were assessed by RT-PCR and by immuohistochemistry, respectively; cytokines secretion were measured by ELISA. Results showed that endometriotic tissue expressed both Ucn 2 and Ucn 3, with Ucn 3 expression higher in ectopic than in eutopic endometrium. Endometrial Ucn 2 mRNA expression in controls showed peak values at early proliferative phase, while in endometriotic patients low expression and no significant changes throughout menstrual cycle were observed. Endometrial Ucn 3 mRNA expression was highest in late secretory phase in controls, while in endometriotic patients low levels and no menstrual-cycle-related changes were found. When added to cultured endometrial cell cultures, Ucn 2 significantly increased TNF-α (P<0.01) and IL-4 (P<0.001), while Ucn 3 induced an increase of IL-4 secretion (P<0.01). In conclusion, endometriotic tissue expressed and localized Ucn 2 and Ucn 3; patients with endometriosis showed Ucn 2 and Ucn 3 mRNA expression in eutopic endometrium lower than in control group, with no endometrial cycle-related changes. Ucn 2 and Ucn 3-modulated TNF-α and IL-4 secretion from culture endometrial cells. These data suggest a possible involvement of Ucn 2 and Ucn 3 in the mechanisms of endometriosis.     

Hormonal stimulation for IVF treatment positively affects the CD56bright/CD56dim NK cell ratio of the endometrium during the window of implantation

The effects of hormone stimulation for IVF treatment on endometrial receptivity remain controversial. Since CD56(bright) natural killer (NK) cells in the endometrium positively contribute to implantation and decidualization whereas CD56(dim) NK cells are negatively associated with reproduction, shifts in the balance between those cells will affect receptivity. Therefore, we compared the leukocyte composition in the endometrium of IVF women (n=20) with non-pregnant women (n=18) in a natural cycle, as a parameter for endometrial quality. Biopsies were obtained 7 days after ovulation. Histological dating of the endometrium showed no increased endometrial advancement after IVF treatment as compared to the control group. Flow cytometric analysis of leukocyte subsets showed that hormonal stimulation positively affected the CD56(bright)/CD56(dim) ratio in the endometrium by a relative decrease in the cytotoxic CD56(dim)CD16(+) NK cell numbers. The relative number of T-cells remained unaffected, while the number of non-T and non-NK cells (i.e. B-cells and macrophages) was higher in the IVF group. These effects were restricted to the endometrium and not observed in peripheral blood. Within the CD56(bright) population we could identify a distinct subset of NK cells (CD56(superbright)) that was unique for the endometrium. We conclude that hormonal stimulation for IVF treatment positively affects the CD56(bright)/CD56(dim) ratio of the endometrium during the window of implantation and does not affect endometrial advancement.