Hum. Reprod. Advance Access originally published online on December 1, 2008
Human Reproduction 2009 24(2):325-332; doi:10.1093/humrep/den393
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Macrophage expression in endometrium of women with and without endometriosis
1 Department of Obstetrics and Gynaecology, Queen Elizabeth II Research Institute for Mothers and Infants, Sydney 2006, Australia 2 Department of Pathology, The University of Sydney, Sydney 2006, Australia
3 Correspondence address. E-mail: m.berbic{at}usyd.edu.au
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Abstract |
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BACKGROUND: Endometriosis is an inflammatory condition, characterized by the presence of endometrial-like tissue outside the uterus. The immune system provides a defence mechanism in response to foreign pathogens, and macrophages play important roles in this response. Activation of macrophages has been reported in peritoneal fluid and ectopic endometriotic lesions; however, controversy exists regarding the composition and function of macrophage populations in eutopic endometrium of women with and without endometriosis. This study aimed to quantify macrophages in eutopic endometrium of women with and without endometriosis, during the early, mid and late proliferative and menstrual phases of the cycle.
METHODS: Paraffin-embedded endometrial curettage blocks were selected from pathology archives. Seventy-six specimens from women with and without endometriosis were analysed using standard immunohistochemical techniques with CD68-PGM1 (phosphoglucomutase 1) clone antibody. Macrophages were counted according to their morphology over several fields of view.
RESULTS: A significant increase in macrophage cell numbers was shown in eutopic endometrium in women with endometriosis (mean ± SD, 182.7 ± 72.9/mm2) during all stages of the proliferative phase compared with normal controls (101.6 ± 53.4/mm2; P < 0.001). Significant increase in macrophage density occurred in the control group during the mid-menstrual phase, Days 3–4 (P < 0.01), which was not observed in women with endometriosis.
CONCLUSIONS: This study further supports an association between immune changes in eutopic endometrium and presence of endometriosis. However, it remains uncertain if eutopic immune changes are primary or secondary occurrences.
Key words: macrophage/endometrium/endometriosis/CD68/immunology
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Introduction |
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Endometriosis is characterized by the presence of endometrial-like tissue outside the uterine cavity (ectopic endometrium), often causing pain and infertility (Matalliotakis et al., 2003
). Predisposing factors of genetic and environmental origin, as well as defective immune response, may allow the endometrial cells to persist within the peritoneal cavity of some women (Sharpe-Timms et al., 2001; Dmowski and Braun, 2004; Lebovic et al., 2004). These viable endometrial cells may attach to the serosa, establish a new blood supply and continue to proliferate in the form of endometriotic lesions (Healy et al., 1998; Taylor et al., 2002).
It has been widely documented that endometriosis, as an inflammatory disease, induces an immune response, leading to both cellular and humoral immune changes. Many studies have focused on the role of immune cells and have provided evidence regarding the important roles they play in facilitating the development and maintenance of endometriotic lesions, as well as modulating pain mechanisms and endometriosis-associated infertility (Braun and Dmowski, 1998; Jones et al., 1998; Gazvani et al., 2002; Matarese et al., 2003). Macrophages are tissue residing leukocytes which play crucial roles in the immune response (Freitas, 2003).
Numerous studies (Oosterlynck et al., 1993; Lebovic et al., 2002; Hever et al., 2007) have shown that macrophages in the peritoneum are highly active in patients with endometriosis, where they are believed to mediate and exacerbate inflammation and sustain the disease (Vinatier et al., 1996; Taylor et al., 1997; Lebovic et al., 2002; Taylor et al., 2002; Kyama et al., 2003; Wu and Ho, 2003). Increased activation of macrophages, along with increased secretion and synthesis of different pro-inflammatory mediators; cytokines (Taylor et al., 1997), tumour necrosis factor-
, interleukins (IL-1, -2, -6, -8, -10) (Lebovic et al., 2002; Taylor et al., 2002; Wu and Ho, 2003), RANTES (regulated upon activation, normal T-cell expressed and secreted) (Wu and Ho, 2003; Lebovic et al., 2004), platelet activating factors, fibroblast growth factors, hepatocyte growth factor (HGF) macrophage-derived growth factor, vascular endothelial growth factor, angiogenesis factor and fibronectine (Vinatier et al., 1996; Donnez et al., 1998; Taylor et al., 2002; Kyama et al., 2003; Khan et al., 2004) have been reported to be elevated at ectopic sites in women with endometriosis compared with peritoneum or peritoneal fluid of normal controls. Thus, it is likely that their effects may facilitate establishment and maintenance of endometriosis (Vinatier et al., 1996; Lebovic et al., 2002; Taylor et al., 2002; Kyama et al., 2003; Siristatisis et al., 2006).
A relatively small number of studies have investigated the changes in the immune response within the eutopic endometrium of women with and without endometriosis, with controversial findings (Klentzeris et al., 1995; Jones et al., 1996; Ota et al., 1996). Surprisingly, it remains unclear if distinct immune cell populations are altered within the eutopic tissue in endometriosis.
Thus, the purpose of our study has been to compare macrophage density in the functional layer of endometrium between women with and without endometriosis during the early, mid and late proliferative and menstrual phases of the menstrual cycle. It is likely that at this time, macrophage's key functions may be significantly affected by endometriosis. Macrophages play their most crucial roles in terms of inflammatory endometrial destruction, repair and regeneration (Salamonsen and Lathbury, 2000) during menstrual and proliferative phases of the cycle. At this stage, in endometriosis, viable endometrial fragments may escape immune surveillance and implant at ectopic sites. To our knowledge, macrophages within the eutopic endometrium of women with and without endometriosis during the time of menstruation have not been compared previously. In addition to this, controversy exists in the literature as to whether proliferative phase macrophages are increased (Khan et al., 2004) or decreased (Braun et al., 2002) in eutopic endometrium of women with endometriosis.
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This study was approved by the Human Ethics Committees of the Southwest Sydney Area Health Service and the University of Sydney.
Tissue collection
Samples of human endometrium collected by curettage from 76 women of reproductive age, with and without endometriosis as confirmed by laparoscopy, were identified from the Royal Prince Alfred Hospital, Anatomical Pathology Archives. There were 41 proliferative samples (21 and 20 women with and without endometriosis, respectively) and 35 menstrual samples (21 and 14 women with and without endometriosis, respectively). The mean age for women with and without endometriosis was 33 years (range 16–50 years) and 38 years (range 24–54 years), respectively. Samples had all been fixed in 10% neutral-buffered formalin for approximately 18–24 h, processed and embedded in paraffin using standard techniques.
Sound clinical data were available for all subjects. Out of endometriosis-positive subjects, 61% had peritoneal endometriosis and 39% had ovarian endometriosis with and without endometriosis at other sites. All women with endometriosis were experiencing pain symptoms; however, none had received medical or surgical therapy for endometriosis in the 3 months prior to endometrial sampling.
All samples were staged as accurately as possible by an experienced histopathologist (P.R) according to histological appearance of endometrium (Noyes et al., 1950; Robboy et al., 2002) as early Days 6–8; (n = 10), mid Days 9–11; (n = 20) or late Days 12–14; (n = 11) proliferative and early Days 1–2; (n = 13), mid Days 3–4; (n = 14) or late Day 5; (n = 8) menstrual phase of the cycle.
Immunohistochemistry
The paraffin-embedded tissue blocks were cooled on a cold plate (Leica EG1150C), following which a microtome (Leica RM 2135) was used to cut sections at 5 µm.
The sections were placed onto a 42°C tissue flotation water bath (TF35, Medizintechnik, Germany) and were mounted onto glass slides (SuperFrost Ultra Plus, Menzel Glaser, 100 Deckglaser 22 x 50 mm).
Prior to immunostaining, the tissue was deparaffinized and rehydrated. Antigen retrieval techniques were applied. The slides were placed in preheated antigen retrieval solution (1:10 dilution of Target Retrieval-pH 9, Dako Cytomation, Australia) and were incubated at 95–99° for 20 min. Sections were immunostained using CD68-PGM (phosphoglucomutase 1) (1:400 dilution), monoclonal mouse, anti-human antibody (Dako M0876, Dako Cytomation) for 30 min, following which they were washed in Tris buffer and incubated with Envision Dual Link (Dako Cytomation) for 30 min to reduce non-specific staining due to endogenous avidin–biotin activity. Application of Dako REAL Detection System, Alkaline Phosphatase/Red for 10 min, led to the formation of a permanent red end-product deposit at the site of the target antigen.
All immunostaining was performed using Dako Cytomation Autostainer, Universal Staining System (S3400, Dako Cytomation Inc., Carpinteria, CA, USA). A sample of tonsil tissue was used as positive control, due to known abundance of macrophages in this tissue. An additional endometrial tissue specimen was classed as negative control, and was only subjected to the immunoglobulin G3 isotope control (matched to the concentration of CD68-PGM1 antibody).
The slides were counterstained using Mayer's haematoxylin solution. Dried slides were immersed in Xylene solution and cover-slipped using ultramount.
Quantification
Slide analysis was performed using the Olympus BX51 microscope (Olympus, Tokyo) under x400 magnification. The macrophages were characterized by Fast Red chromogen spots on the blue background of endometrial tissue (Fig. 1). Slide analysis under the microscope ensured that adequate number of fields of view were available for each slide. The slides that showed at least five fields of view of the tissue were included for further analysis and quantification.
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The macrophages were identified according to their morphology and diameter range between 20 and 30 µ (Freitas, 2003
). Fast Red-positive spots, which showed a diameter in this range, were counted as macrophage-positive events. The fields of view were captured using Olympus DP70 digital camera (Olympus, Tokyo) and Image Pro Plus Discovery Software, Media Cybernetics (Olympus, Tokyo). The counting was performed on random fields on these images, and the investigator was blinded to presence or absence of endometriosis. The counting was also done blind with respect to the stage of menstrual cycle. Five to nine fields of view were quantified for each slide after which the results were tabulated. All fields of view were quantified by two separate blinded investigators, with good correlation (Pearson correlation coefficient = 0.952, P < 0.001).
Exclusion of specimens
Three initial endometriosis-positive, menstrual samples were excluded from analysis due to poor tissue quality, evidence of blood clot, mucous and high tissue fragmentation, which did not permit adequate number of fields for analysis. These were replaced with three good quality specimens.
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences 16.0 Statistical Analysis Software. Correlation between two blind investigators was conducted using Pearson correlation. CD68-PGM1 + cell counts were analysed with respect to presence and absence of peritoneal or other endometriosis throughout proliferative and menstrual phases and were analysed separately according to early, mid or late sub-groups. Due to the variation in the number of fields of view between subjects, the data analysis was based on the fields of view. Square-root transformation was applied to rectify macrophage count skewing.
The phases and sub-groups were analysed using the descriptive statistics, which showed the minimum, maximum, mean and SD values (Table I). Student t-test was applied to analyse differences in macrophage density between women with and without endometriosis with respect to the phase (proliferative/menstrual) and sub-group (early/mid/late) and the statistical power of significant tests was reported. The differences between the comparison groups were considered to be statistically significant at P < 0.01.
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The count of CD68-PGM1 clone-positive cells (x400) in the eutopic endometrium of women with and without endometriosis was expressed as the mean number (±SD) of CD68+ cells per mm2 throughout proliferative and menstrual phases (Table I). Fig. 1 shows eutopic endometrium (x400 magnification) for endometriosis positive subjects during proliferative (A) and menstrual (B) stages of the cycle.
Proliferative group macrophages
During the proliferative phase, an overall significant increase in macrophage density was observed in women with endometriosis compared with those in women without the disease (t = –11.622, df = 339, P < 0.001; 100% power). In women with endometriosis mean macrophage densities ranged between 44.1 and 404.4 (mean ± SD = 182.7 ± 72.9/mm2), while in women without the disease the macrophage densities ranged between 7.4 and 264.7 (mean ± SD = 101.6 ± 53.4), with little overlap between the groups (Fig. 2A).
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A significant increase in proliferative phase macrophage density in women with endometriosis compared with controls was also evident throughout all sub-groups; early (t = –5.977, df = 85, P < 0.001; 100% power), mid (t = –9.465, df = 159, P < 0.001; 100% power) and late (t = –4.542, df = 91, P < 0.001; 99.4% power). The histogram (Fig. 3A) shows macrophage (CD68-PGM1+ cell) densities per mm2 within the functional layer of eutopic endometrium in women with and without endometriosis during the early, mid and late proliferative phase of the menstrual cycle.
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Menstrual group macrophages
Significant differences in endometrial macrophage infiltration were not demonstrated between the two comparison groups in the menstrual phase (t = 1.468, df = 270, P = 0.143). However, there was a great variation in macrophage densities in both groups in this cycle phase (14.7–463.2; mean 152.6 ± 106.3 SD in women with endometriosis; and 7.4–691.2; mean 181.3 ± 138.9 SD in women without endometriosis). SDs were much greater for the groups in the menstrual compared with proliferative phase (Fig. 2B).
In the analysis of sub-groups, a significantly higher density of macrophages was evident in the mid-menstrual phase (Days 3–4) in normal controls compared with women with endometriosis (t = 2.99, df = 99, P = 0.004; 84% power); however, differences were not demonstrated within the early and late menstrual sub-groups (t = –0.502, df = 106, P = 0.617; t = –0.588, df = 61, P = 0.579) (Fig. 3B).
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Discussion |
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Changes in the response of certain immune cells within the peritoneal cavity of women with endometriosis have been demonstrated by many studies (Oosterlynck et al., 1993
; Jones et al., 1998; Gazvani et al., 2002; Lebovic et al., 2002); however, recent studies are beginning to show that changes inherent within the eutopic endometrium may precede development of well-documented changes at the peritoneal and other ectopic sites (Mettler et al., 1996; Ota et al., 1996; Bulmer et al., 1998; Akoum et al., 2006).
To our knowledge, only two studies have directly investigated the macrophage cell populations of the eutopic endometrium in women with and without endometriosis and have obtained controversial results. One study showed reduction in macrophage cell populations during early proliferative phase with no further differences during later stages of the cycle (Braun et al., 2002), where the phase of the menstrual cycle for women participating in the study was defined by histological appearance of endometrium using hematoxylin–eosin stain. Another study showed increase in macrophage cell populations during both the proliferative and secretory stages of the cycle in women with endometriosis (Khan et al., 2004) compared with controls. Our study demonstrated a significant increase in macrophage cell populations across all proliferative phase sub-groups (early, mid and late) in women with endometriosis compared with the normal controls (P < 0.001). We have also demonstrated a significant increase in macrophage density in women without endometriosis compared with those with the disease during the mid-menstrual phase (P < 0.01). This rise in macrophage density was not evident in women with endometriosis. On the contrary, the endometrial macrophage density in women with endometriosis showed a gradual decline throughout the menstrual phase. Significant differences could be observed during the early and late stages of the menstrual phase between the two groups.
In comparison to the previous studies, where the entire study population was selected from a group of patients following infertility evaluation (Braun et al., 2002) and where only those subjects with endometriosis were selected following infertility evaluation (Khan et al., 2004), our study comprised endometriosis-positive women who had undergone laparoscopic examination in response to symptoms of pain and who had no recorded history of infertility.
In addition to this, we have noted that some variation exists between the three studies in the choice of CD68 antibody clones. While Braun et al. (2002) and our study used PGM1, study by Khan et al. (2004) utilized KP1 clone. While the average proliferative group macrophage densities as obtained by our study in women without endometriosis showed positive correlation to those as detected by Braun et al. (2002), significant variation was observed in macrophage density between the two studies during the proliferative phase of women with endometriosis. On the other hand, while our total proliferative phase results are comparable to those of Khan et al. (2004), in terms of significant macrophage increase in endometriosis, variations were observed in magnitude of absolute macrophage density. These variations may be attributed to the use of different antibody clone between the two studies. Certainly, challenges exist in studying immune cells, especially in immunohistochemistry. Although CD68 is a pan-macrophage marker, evidence suggests that different macrophage subtypes arise in response to various polarization potentials (Mantovani et al., 2004), thus different antibody clones may not be directly comparable. In addition to this, it has been noted that variations in tissue fixation procedures may account for variations in the numbers of cells staining between individual laboratories (Salamonsen and Lathbury, 2000).
Furthermore, it is important to acknowledge that a great degree of heterogeneity appears to exist in macrophage content in specific microenvironments in the eutopic endometrium in women with and without endometriosis. Certainly, challenges exist in obtaining large enough numbers of specimens during certain sub-phases of the menstrual cycle for comparative analysis. A limitation of the current study, and indeed all studies to date in this area, is the lack of precision in terms of the actual day in the menstrual cycle. It is possible that differences in macrophage densities reported between women with and without endometriosis are purely reflections of differences in actual day of sample collection. Future studies would benefit from prospectively collecting information on precise day of the menstrual cycle perhaps with endocrine back up, although this is again complicated by variation in length of cycle between women.
Several studies provide indirect evidence as to why we may expect changes in macrophage cell populations in the eutopic endometrium of women with endometriosis. Increased levels of macrophage migration inhibitory factor (Akoum et al., 2006) during proliferative phase and increased MCP-1 (monocyte/macrophage activating chemoattractant protein) in both proliferative and secretory phases (Jolicoeur et al., 1998) have been reported within the eutopic endometrium of women with endometriosis compared with controls: these factors may, respectively, function to prevent random migration of macrophages and ensure macrophage recruitment into endometrium (Kibangou Bondza et al., 2006). Macrophage activation is characterized by their ability to synthesize and secrete a wide variety of mediators, such as cytokines and growth factors (King et al., 2003). These mediators can exert effects upon eutopic endometrial tissue and within the peritoneal cavity (Cao et al., 2005). Elevated expression of pro-inflammatory cytokines and growth factors; IL-1 (interleukin-1) (Cao et al., 2005), IL-6, IL-8, epidermal growth factor, HGF (Kibangou Bondza et al., 2006) have been observed in both the ectopic and eutopic endometrium of women with endometriosis. These data support the hypothesis that the eutopic endometrium of women with endometriosis may share changes similar to those observed in the peritoneal environment and in ectopic tissue, which are not seen in women without the disease (Harada et al., 2004).
In the analysis of menstrual phase, while Braun et al. (2002) analysed macrophage cell density in women with and without endometriosis during late secretory/menstrual stage combined (n = 7) for women with and without endometriosis, it is not known that what number of these women were menstruating at the time.
The menstrual phase results of our study suggest two things; first that the increase in macrophage cell population during mid-menstrual phase in normal controls may play roles in initiating apoptosis and removal of menstrual debris, as well as support endometrial repair and regeneration. In normal endometrium, during the time of menstruation, macrophages play substantial role in inflammatory endometrial destruction (Salamonsen and Lathbury, 2000); however, these processes may not be occurring efficiently in endometrium of women with endometriosis, where macrophage density steadily declines throughout the menstrual phase. Secondly, our study suggests that changes in macrophage density across the menstrual cycle (especially during menstruation) in women with and without endometriosis are likely to show a high degree of variability in macrophage and other immune cell expression between individual subjects. It is difficult to speculate that what changes are occurring in macrophages in endometriosis, in terms of their activation and function. It has been proposed that in endometriosis, macrophages encounter molecules, such as haptoglobin, which may alter their phagocytic function (Sharpe-Timms et al., 2005). Thus, instead of acting as scavenger cells which eradicate viable endometrial fragments under normal conditions, macrophages in endometriosis not only permit survival of shed endometrial cells, but secrete a wide variety of inflammatory mediators which further promote their ability to implant and proliferate at ectopic sites.
Changes in eutopic endometrium of women with endometriosis in terms of microscopic structure, immune components and cytokine production, angiogenesis, aromatase enzyme expression, and the presence of nerve fibres and adhesion molecules, as well as altered gene expression, have been widely reported (Ota et al., 1996; Vinatier et al., 1996; Vinatier et al., 2000; Sharpe-Timms, 2001; Giudice and Kao, 2004; Tokushige et al., 2006).
Nerve fibres have been identified within the functional layer of endometrium (Tokushige et al., 2006; Al-Jefout et al., 2007) and in increased concentration within the myometrium (Tokushige et al., 2006) of women with endometriosis, which could not be observed in women without the disease. It is known that macrophages play roles in supporting nerve fibre growth, development and repair (Faweett and Keynes, 1990). In turn, Nerve Growth Factor has been shown to play a role in enhancing macrophage function and inflammatory response (Gulati, 1998). Other immune cells, including dendritic cells (DCs), also show altered expression. Recently, a study by Schulke et al. (submitted for publication) showed changes in endometrial DC populations in women with endometriosis, observing increased CD1a immature DC cell populations during the proliferative phase and depressed CD83 mature DC cell populations in the eutopic endometrium of women with endometriosis, compared to the normal controls across all stages of the cycle. DCs and macrophages both arise from monocytes. These findings may suggest that monocyte differentiation is skewed towards particular cell lines in the presence of endometriosis, as it is with cell damage (Xu et al., 2006).
A large body of data points to specific intrauterine changes occurring in women with endometriosis. The eutopic endometrial glandular and stromal cells may be functioning differently in these women (Braun and Dmowski, 1998). In women without endometriosis during the process of menstruation, the sloughing endometrial cells undergo apoptosis, following which they are engulfed and phagocytosed by surrounding macrophages. The eutopic endometrial cells of women with endometriosis are less susceptible to apoptosis (Gebel et al., 1998; Liu et al., 2006), resulting in increase in viable cells, capable of implanting at ectopic sites (Matarese et al., 2003; Harada et al., 2004). The endometrial cells of women with endometriosis may therefore have intrinsic ability to escape immune surveillance (Kibangou Bondza et al., 2006), to implant, proliferate and respond differently to stimuli presented in their new environment (Jolicoeur et al., 1998). These cells may hold constituents, or acquired characteristics, that favour their survival outside the uterine cavity (Matarese et al., 2003). It is also likely that the cells of the eutopic endometrium of women with endometriosis are more invasive (Matarese et al., 2003) and adhesive and may be involved in triggering certain immune cell activation.
Endometriosis is a complex disease, whose aetiology is not completely understood; however, this study further supports an association between the immune changes in eutopic endometrium and presence of endometriosis. However, it remains uncertain if eutopic immune changes are primary or secondary occurrences: are these changes a cause of the disease or do they arise in response to other changes in the tissue? The variations between the studies in the literature regarding macrophage densities in eutopic endometrium of women with and without endometriosis, have led us to believe that these changes may be attributed to other external factors, the characteristics of the study population and the types of endometriotic lesions, rather than solely the presence or absence of endometriosis. In order to better understand the pathophysiology of endometriosis, it is important to characterize immune changes, not only according to the presence or absence of endometriosis within the endometrium, but also with respect to the study subject's characteristics, associated symptoms, history of pain/infertility and type of endometriosis, all of which may be significantly impacting on the immune environment of the eutopic endometrium.
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This study was financially supported by the Department of Obstetrics and Gynaecology, The University of Sydney.
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The authors wish to acknowledge Mr Lawrence Young (Dako, Australia) for his technical support and Dr Georgina Luscombe for statistical advice.
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Submitted on July 31, 2008; resubmitted on September 29, 2008; accepted on October 2, 2008.
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