异常在位子宫内膜是内异症的病因吗？-在位内膜在内异症发病中的作用

Haiyuan Liu, Liu H, Jing He Lang, Lang JH
Medical science monitor : international medical journal of experimental and clinical research · 2011 · vol. 17(4) , pp. RA92–RA99 · doi:10.12659/msm.881707 · PMID:21455119 · PMC3539524 · W1482698202
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This paper examines how abnormal eutopic endometrium, with enhanced proliferation and implantation capabilities, contributes to endometriosis pathogenesis and infertility through backward flow and subsequent pelvic cavity colonization.

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This paper is a 2011 review examining whether abnormal eutopic endometrium can cause endometriosis, synthesizing evidence that the eutopic endometrium in affected women has enhanced proliferation, implantation, angiogenesis, and the ability to evade hostile conditions in the peritoneal cavity. It proposes a retrograde menstruation–based pathogenesis in which surviving endometrial cells undergo an “3A” sequence of attachment, aggression, and angiogenesis, with immune evasion mechanisms (e.g., reduced NK/T cell cytotoxicity, soluble ICAM-1, FasL-mediated apoptosis, and altered Tregs) and reduced apoptosis linked to altered Bcl-2/Bax expression, plus increased integrin-mediated adhesion. The authors acknowledge that natural disease sequencing is not precisely known and that multiple existing theories are debated, especially for explaining why reflux is common but disease prevalence is lower. This paper is centrally about endometriosis — specifically, it reviews the role of abnormal eutopic endometrium in the development and associated infertility of endometriosis.

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Abstract

Endometriosis (EM) is one of the most common diseases which severely affect the health and reproductive function of women of childbearing age. There are fundamental abnormal changes within the eutopic endometrium of women with endometriosis compared to normal endometrium of women without endometriosis. Eutopic endometrium shows enhanced ability of proliferation, implantation and angiogenesis, and greater probability of escaping the unfavorable conditions of the ectopic environment. Therefore, the character of eutopic endometrium determines the fate of the backward-flowing endometrial tissue - to live or to die. The abnormal endometrial tissue in EM patients flows backward to the pelvic cavity, completing a 3-step procedure of pathogenesis (attachment-aggression-angiogenesis), and ultimately develops into EM. Abnormal eutopic endometrium may also play important roles in endometriosis-associated infertility. This recognition regarding the pathogenesis of endometriosis ultimately will help to discover new methods for diagnosis and treatment. Endometrial markers for micro-invasive diagnosis and direct treatment of eutopic endometrium as the origin of the disease should be further investigated.
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How

The shed endometrial fragments lodged on peritoneum require the establishment of a new blood supply for the survival of implants after local invasion of the basement membrane. There is much evidence indicating that the human endometrium itself is highly angiogenic, which might contribute to the initiation of endometriosis [ 46 ]. Among the identified angiogenic factors, vascular endothelial growth factor (VEGF) is the most potent and studied factor in endometriosis. Donnez et al reported that eutopic epithelium of women with endometriosis, as compared to endometrium from healthy women, exhibited significantly increased VEGF levels, particularly during the late secretory phase of the menstrual cycle [ 47 ]. The biological activity of VEGF depends mainly on its binding to VEGF receptors (VEGFR), such as VEGFR-1, VEGFR-2, and neuropillin-1 and -2. Some studies have indicated that eutopic endometrium from women with endometriosis had significantly higher expression of VEGF-A (a member of the VEGF family) in glandular epithelium and VEGFR-2 in endometrial blood vessels than that from disease-free controls [ 48 , 49 ]. Epidermal growth factor (EGF) plays fundamental roles in diverse processes such as embryogenesis, development, proliferation, and differentiation. Recently research indicates that it also has an angiogenic activity. The EGF system consists of 4 receptors – human epidermal growth factor receptor (HER) 1–4. It has been shown that EGF and its receptor HER-1 are expressed in normal endometrium [ 50 ]. A recently published study using real-time PCR and immunochemistry demonstrated that HER1, HER2, and HER3 were higher in eutopic endometrium from patients with endometriosis compared with endometrium from healthy women, and that HER2 showed a pattern of distribution that differed between eutopic and healthy endometrium. The differences between normal and endometric endometrium were most prominent around the time of menstruation, with a significantly higher expression of HER1 and HER2 in the late secretory phase and HER3 in the proliferative phase, and a significant decrease in expression of HER2 and HER3 from late secretory to proliferative phase in eutopic endometrium [ 51 ]. The authors proposed that a high and specific pattern of expression of EGF receptors in menstrual endometrial fragments could aid ectopic implantation and angiogenesis [ 51 ].

Role

The pathogenesis of endometriosis-related infertility is still unclear. Numerous mechanisms have been proposed to account for fertility impairment in these patients, including altered folliculogenesis, ovulatory dysfunction, poor oocyte quality, luteal phase defects, reduced fertilization, and abnormal embryogenesis. Studies have shown that patients with endometriosis have reduced receptivity due to compromised endometrium [ 69 , 70 ]. It was also found that dysregulation of select genes in eutopic endometrium of patients with endometriosis may lead to impaired embryonic attachment, embryotoxicity, immune dysfunction and apoptosis during the window of implantation [ 70 ]. Some researchers also found a reduced decidualization capacity in endometrium from women with endometriosis, and the milieu surrounding the uterine cavity may be involved in impaired eutopic endometrium decidualization [ 71 , 72 ]. The role of eutopic endometrium in endometriosis-related infertility is still unknown due to a lack of understanding about the normal physiologic mechanisms of embryo implantation.

Other

Aromatase is an important enzyme in estrogen synthesis in target tissues. Expression of aromatase has been detected in the eutopic endometrium of endometriosis patients but not in normal endometrium of disease-free patients [ 52 – 54 ]. The intense inflammatory reaction triggered by retrograde menstrual debris in the pelvic cavity could produce large amounts of prostaglandins and other inflammatory factors that could stimulate aromatase expression [ 55 ]. The over-expression of aromatase would in turn induce local production of estrogen, which further induces prostaglandin synthesis by activating the COX II (cyclooxygenase II) enzyme [ 56 , 57 ]. Thus, a feed-back cycle is created between inflammation and estrogen production, involving overexpression of aromatase and COX II, and continuous production of estradiol and prostaglandins [ 58 , 59 ]. Excessive local estrogen would inhibit the phagocytosis of macrophages and NK cells and facilitate the implantation of endometrial cells in the peritoneum [ 60 , 61 ]. Nerve fibres have been identified within the functional layer of endometrium and in increased concentration within the myometrium of women with endometriosis, which could not be observed in women without the disease [ 62 ]. Women with endometriosis and pain symptoms have significantly higher nerve fibre density in comparison with women with infertility but no pain. This finding indicates that the nerve fibres in endometriotic plaques may originate from nerve fibre progenitors in the functional layer of the endometrium, which probably provides a mechanism for lesion-specific pain in endometriosis.. We also speculate that primary abnormalities in eutopic endometrium of patients have a role not only in the genesis of endometriosis, but also in the genesis of symptoms. Dendritic cells (DCs) are antigen presenting cells that are highly involved in the initiation and modulation of the immune response. Recently, a study by Schulke et al. showed changes in endometrial DC populations in women with endometriosis, observing increased CD1a immature DC cell populations during the proliferative phase and decreased CD83 mature DC cell populations in the eutopic endometrium of women with endometriosis, compared to the normal controls across all stages of the menstrual cycle [ 63 ]. This finding indicates that primary defect in immune cell function in eutopic endometrium of women with endometriosis could predispose these women to develop endometriosis. Recently, extensive investigations have been performed on the characterization of possible stem cells in the eutopic endometrium. Leyendecker et al found the menstrual flow of women with this disease was composed of significantly more endometrial tissue shed from the basal layer, which is considered the residing site of endometrial stem cells [ 64 ]. Götte et al. found increased expression of the adult stem cell marker Musashi-1 in eutopic endometrium of patients with endometriosis, which favors the stem cell origin of endometriosis [ 65 ]. Furthermore, endometrial stem cells could regenerate not only endometrial and stromal cells, but also endothelial cells, and form mature blood vessels [ 66 ]. The predominant hypotheses proposes that ectopic endometriotic lesions might originate from eutopic endometrial stem cells, which probably abnormally shed from their location in the basal layer of eutopic endometrium from the women with endometriosis, but is not seen in women without this disease [ 67 , 68 ].

Clinical

There is a general consensus that laparoscopy is the gold standard for the diagnosis of endometriosis. It allows direct visualization of the lesions and histological confirmation. Unfortunately, laparoscopy is a costly invasive procedure requiring general anaesthesia, and it is inevitably associated with potentially severe complications. There is a wide spectrum of symptom severity, and the stage of endometriosis on laparoscopy correlates poorly with the extent and severity of pain. Some patients with minimal disease have severe pain, whereas other women with severe stage III to IV disease are asymptomatic. There is no good noninvasive test for endometriosis even though the evolving genomic and proteomic technologies have been used in the discovery of potential biomarkers of this complex disease [ 73 ]. Therefore, there is often a significant delay in diagnosis of endometriosis. In relation to treatment, it is difficult for surgical procedures to succeed in removing the entire implant, and hormonal therapy does not cure endometriosis. The symptoms of the disease are likely to recur once treatment is discontinued. The high recurrence rates may be caused by the basic differences between the eutopic endometrium of women with endometriosis and disease-free controls, which is not targeted by both medical and surgical treatment. Therefore, the successful diagnosis and treatment of endometriosis may lie in the dysfunctional eutopic endometrium itself. Endometrial biomarkers for diagnosis and treatment of eutopic endometrium as the origin of the disease are promising approaches. Kitawaki et al. reported that detection of aromatase P450 protein in endometrial biopsy samples strongly correlated with the presence of endometriosis or adenomyosis [ 74 ], and suggested that this approach could be used as an outpatient screening test for endometriosis, with sensitivity and a specificity of 91% and 100%, respectively. Another marker being explored for the diagnosis of endometriosis is endometrial biopsy with detection of nerve fibres, which are primarily small unmyelinated sensory C fibers in the functional layer of endometrium. Results from a double blind study yielded a specificity and sensitivity of 83% and 98%, respectively, a positive predictive value of 91% and a negative predictive value of 96%, which is close to the accuracy of laparoscopic assessment by experienced gynecological laparoscopists [ 62 ]. Danazol is very effective in controlling endometriosis-associated pain; however, its androgenic side effects such as oily skin, hirsutism, deepening voice, acne and weight gain may affect patient compliance with treatment. These side effects may be diminished by the vaginal route of administration of danazol because the systemic levels of danazol will be lower and the concentration of the drug reaching the uterus may be higher than that achieved by the oral route. A clinical study has indicated that a low dose of vaginal danazol (200 mg/d) for 12 months could result in even greater efficacy in the control of endometriosis-related pain, with far fewer side effects [ 75 ]. More importantly, because ovulation is not blocked, over half the patients become pregnant while using the vaginal danazol ring with no harmful effects [ 76 ]. The mechanism of these beneficial effects on both fertility and pain of endometriosis may be the result of a direct inhibitory effect of danazol on aromatase expression in eutopic endometrium. The presence of aromatase in eutopic endometrium of patients with endometriosis was reported to be related with pain and decreased endometrial receptivity to implantation [ 77 , 78 ]. In this aspect, inhibition of aromatase expression in eutopic endometrium would explain the pain relief and fertility enhancing effects of vaginal danazol treatment in endometriosis. Dysmenorrhea is the most frequent symptom in women with endometriosis, and this symptom is decreased in most women using the levonorgestrel intrauterine system (LNG-IUS). Therefore, LNG-IUS has recently been studied as an alternative treatment for endometriosis-associated pain. A recent multicentre randomized, controlled clinical trial to compare the efficacy of LNG-IUS and GnRH-analogue in the control of endometriosis-related pain over a period of 6 months shows that the LNG-IUS and the GnRH-analogue are equally effective in the control of endometriosis-associated chronic pelvic pain [ 79 ].Another randomized controlled trial comparing LNG-IUS to depot medroxyprogesterone acetate (MPA) for patients with endometriosis following conservative surgery in symptom control and recurrence prevention shows that LNG-IUS is as effective as MPA in symptom control and prevention of recurrence, and LNG-IUS users show better compliance [ 80 ]. In addition to its effectiveness, LNG-IUS shows fewer side effects associated with hypoestrogenism. More importantly, a recent study also shows that it may increase bone mineral density after use for 3 years, and some cardiovascular risk markers on the lipid profile could be positively impacted [ 80 , 81 ]. All these findings justify long-term treatment of endometriosis-associated pain using LNG-IUS. The mechanism of LNG-IUS in treatment of endometriosis may be a direct effect on eutopic endometrium as the origin of the disease. Our own study indicates that after treatment with LNG-IUS, eutopic endometrium of patients with endometriosis showed increased apoptosis in both endometrial and stromal cells [ 82 ]. Another study demonstrated that 6 months of LNG-IUS treatment reduces the expression of the cell proliferation markers estrogen receptor-a (ER-a) and progesterone receptor-a (PRA), and increases the expression of apoptosis markers Fas in eutopic endometrium of patients with endometriosis [ 83 ]. These findings explain the mechanism of the clinical improvement observed in endometriosis patients using the LNG-IUS.

Background

Endometriosis affects 10–15% of women of reproductive age, appears to be increasing in prevalence, and is also considered as a “mystery disease of the modern age”. About 80% of women with endometriosis present with pelvic pain, and 50% co-exist with infertility. This disorder is one of the most common benign diseases which severely affect the health and quality of life of women of reproductive age. Endometriosis is a highly variable condition in terms of age at onset and mode of presentation, range of symptoms, anatomical sites and likelihood of recurrence. In the past few decades, endometriosis has been actively and widely investigated, yet it is still an enigmatic disease. It was first described by Von Rokitansky in 1885 [ 1 ]. Sampson proposed the leading theory of retrograde menstruation in 1921 [ 2 ]. Several other viable theses are development by metaplasia from Müllerian remnants [ 3 ] and distant implantation of menstrual debris [ 4 ]. These hypotheses are attractive since they can explain some clinical phenomenon; however, many points argue against them. Especially, Sampson’s reflux implantation theory, the most widely accepted hypothesis, faces many doubt and challenge. Why is retrograde menstruation a common event in women with patent fallopian tubes [ 5 ], but the morbidity of endometriosis is only 10–15%? The answer to this question may lie in the endometrium itself, since the eutopic endometrium of women with endometriosis shows fundamental differences compared with women without the disease [ 6 ]. These differences may contribute to the survival of regurgitated endometrial cells into the peritoneal cavity, and thus to the development of endometriosis. The explanation of this will lead to further understanding of the etiology of this disease and the high rate of recurrence after medical or surgical treatment. Although the natural process of disease development is not precisely known, endometriosis is established when retrograde endometrial cells engraft within the mesothelium and pelvic cavity. During this process, reflux menses possess the following necessary characteristics: (a) the endometrial debris, including both epithelial and stromal cells, must exist in the reflux menses reaching the pelvis through a patent tube; (b) two components of the endometrial gland and stromal cells must be viable; (c) these cells must have the potential ability to implant into the pelvic organs; (d) the observed anatomical distribution of peritoneal endometrial lesions must correspond to the dynamic mechanism of a tubal reflux. Before the progression into peritoneal endometriosis, the effluent viable endometrial cells must evade the immune attack within the pelvic cavity, attach to the peritoneum and other pelvic organs by the forefront step of adhesion, subsequently break through the extracellular matrix and basement membrane, and ultimately implant at an ectopic location and develop characterized by neo-vascular system formation. Variable and numerous studies indicate that the event sequencing during pathogenesis might be attachment, aggression, and angiogenesis, and we prefer to term it the “3A” model [ 7 ]. In this context, we review the published literature on the eutopic endometrium as the origin of endometriosis and its clinical application in diagnosis and treatment.

Conclusions

Even though the underlying mechanisms that lead to the development and maintenance of endometriosis are still an enigma, numerous data indicate that eutopic endometrial glandular and stromal cells may be functioning differently in women with endometriosis compared to normal endometrium in disease-free women. These cells have intrinsic characteristics that favor their survival outside the uterine cavity and precede development of well-documented changes at the peritoneum and other ectopic sites [ 84 ]. During menstruation, the sloughing endometrial cells in endometriosis patients could escape immune surveillance from the body and are less susceptible to apoptosis, resulting in an increase in viable cells. After overcoming a phase of immune tolerance, the next step in the development of early endometriosis is the adhesion of endometrial cells to mesothelium and invasion of the extracellular matrix, since the eutopic endometrium of women with endometriosis are more adhesive and invasive then normal endometrium. After the last step of angiogenesis, the endometrial cells establish a new blood supply for the survival of implants, continue to proliferate in ectopic sites, and finally result in endometriosis ( Figure 1 ). During this process of disease development, multiple factors in both the general and local environments have important roles in facilitating the development and maintenance of the disease. Many differences observed between eutopic endometrium and ectopic tissue of patients with endometriosis can be explained as the direct consequence of a different environment. However, this hypothesis may only apply to peritoneal endometriosis but not to endometrioma and deep endometriosis lesions, because the pathogeneses of endometriosis are different in different lesions [ 85 ]. The demonstration of the dysfunctional eutopic endometrium in women with endometriosis might provide the theoretical background for renewed progress in diagnosis and treatment. Endometrial marker for micro-invasive diagnosis and direct treatment of eutopic endometrium as the origin of the disease are promising and should be further investigated.

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Condition tags

endometriosisdie_deep_infiltratinginfertility

MeSH descriptors

Endometriosis Endometrium Cell Adhesion Endometriosis Endometriosis Endometriosis Endometriosis Endometrium Endometrium Endometrium Endometrium Epithelium Epithelium Female Humans Infertility, Female Infertility, Female Peritoneum Peritoneum

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