O-86: Endometrial Inflammatory Factors And Embryonic Implantation



Chronic endometritis (CE) represents a chronic inflammation of the endometrial lining. In most of cases diagnosis is casual on histological specimen taken for different gynecological indications (AUB, infertility etc.). CE in most of cases is asymptomatic or accompanied by mild disturbances like spotting or bleeding (94% of cases), mild and undefined pelvic pain, mild leucorrhoea. Its prevalencerange from 0.5 to 15% in general population, while is 70% in women referring to centres for sexual transmitted diseases, often representing an hidden pathology. The gold standard for the clinical definition and diagnosis of CE is represented by histology. The diagnosis of chronic endometritis relies on identification of plasma cells in the endometrial stroma. Lymphocytes, neutrophils, histiocytes, and eosinophils, are generally not diagnostic for endometritis, because they are normal constituents of the stroma. Inflammatory cells may infiltrate the wall of glands and may concentrate around vessels. The inconvenient factor is that these aspects may normally be present at menstruation and so diagnosis at histology may be missed. As regards the pathophysiology, an abnormal uterine bleeding (AUB) can be observed from 70 to 90% of cases in which histology results positive for CE (Greenwood, 1995), accompanied by symptoms such as chronic pelvic pain, infertility and, less frequently, leucorrhoea and/or fever. In a recent Italian study it was reported that the indication at hysteroscopy in 438women diagnosed with CE and 100 controls was 42% and 22% for dysfunctional uterine bleeding, respectively for CE and controls; 10% and 38% for positive transvaginale ultrasonography for endometrial polyp; 36% and 8% for infertility; 6% and 23% for submucous myoma and only 4% and 19% for mullerian abnormalities. These results show the significative relation between CE and AUB, and between CE and infertility. According to the pathophysiology of the endometrial bleeding, in accord with the studies by Ferenczy, during a normal menstruation, in which the upper 2/3 of the endometrial mucosa detach, the endometrial cells and inflammatory cells produce proteolytic lysosomial enzymes causing a tissue breakdown whit consequent tissue necrosis, disruption of microvasculature, migration of leukocytes and platelet/fibrin thrombosis in microvessels. On the other hand, during AUB, only the superficial layer (subsurface) detaches, diffusely (withdrawal bleeding) or focally (breakthrough bleeding). In the presence of the second evenience, CE and/or microerosions or vascular fragility due to structural abnormalities of microvessels could be frequent. However endometritis and microerosions may occur in otherwise normal endometrium, polyps, submucosal leiomyomata, atrophy and cancer (organic causes). In that condition, Gram negative bacteria, mycoplasma and other infective agents may evoke a Th-1 response with endotoxin, macrophages, IL-1, and TNF-alfa local secretion, determining a pro-inflammatory response, responsible of damage of the conceptus, implantation failure, spontaneous abortion and preterm delivery, when acting at endometrial level, and hypercontractility and pain when acting at myometrial level. The clinical diagnosis of CE is quite difficult. Physical signs are represented by uterine tenderness, spontaneous and at mobilization, leucorrhoea, cervical cyanosis, easy intracervical bleeding, but in most of cases is totally asymptomatic. Ultrasounds not specific signs are usually represented by endometrium out of phase, increased endometrial thickness and presence of endometrial fluid. In consideration of that, the role of hysteroscopy appears not only important but necessary. At CO2 hysteroscopy CE is Abstract of the 8th Royan International Twin Congress, Tehran, Iran, 5-7 September 2007 50 Yakhteh Medical Journal, Vol 9, Sup 1, Summer 2007 0 5 10 15 20 25 30 35 E. coli Strept. Staphyl. Enter. Faec. Chlam. Ureapl. Yeast % characterised by areas of red endometrium, flushed, with a white central point, localized or scattered out the cavity with the typical "strawberry aspect“described by Cravello. More recently for that purpose, Cicinelli proposed the fluid diagnostic minihysteroscopy which characterizes for being painless and safe, performable also in case of bleeding (continuous-flow), easy to perform (learning curve shorter than with gas hysteroscopy), smooter distention of the uterine cavity (less pain), low costs and floating of ingrowths, with possible detection of subtle lesions. In detail, while saline solution allows floating of ingrowths while CO2 causes flattening of ingrowths against the endometrial surface and, therefore, the diagnostic images obtained at fluid hysteroscopy may do not correspond to those described at traditional CO2 hysteroscopy. Cervical signs of CE in course of fluid mini- Hysteroscopy may be represented by hyperemia, easy bleeding, cervical polyps, micropolyps, adhesions and leucorrhoea. On the other hand, endometrial signs are endometrial edema in the follicular phase (out of phase endometrium), diffuse or focal hyperemia (periglandular), endometrial polyps, adhesions and micropolyps, often representing, however, subtle lesions of difficult identification. Endometrial micropolyps are described as an atypical aspect of endometrial surface characterized by the presence of very small (less that 1 mm of size) peduncolatous polyps showing a vascular axis. These subtle lesions may be sporadic or may cover most of the endometrial surface. According to Cicinelli, 93.7% cases of micropolyps showed CE at histology and endometrial micropolyps are detected in 53.6% of all cases of CE at histology. The presence of micropolyps shows a sensitivity of 54% and a specificity proxime to 99%, and the likelihood to have histological diagnosis of CE for women with micropolyps is very high (O.R. 124.2, C.I. 50.3 to 205.4). As regards the etiology, the prevalence as percentage of infectious agents detected at vaginal (blue bars), at endocervical (red bars) and at endometrial cultures (yellow bars) in women with signs of chronic endometritis at hysteroscopy, according to Cicinelli et al. is represented in the following figure. These studies have been prevalently oriented at the definition of CE in order to investigate its role in the blastocyst implantation process. The human reproduction represents, in fact, a classical paradox, according to which it is critical to the survival of the species but relatively inefficient. Maximal fecundity (the probability of conception during one menstrual cycle) is approximately only 30% (Zinaman et al., Fertil Steril 1996); only 50 to 60% of all conceptions advance beyond 20 weeks of gestation (Wilcox et al., N Engl J Med 1988); of the pregnancies that are lost, 75% represent a failure of implantation and are therefore not clinically recognized as pregnancies (Wilcox et al., N Engl J Med 1988); failed implantation is also a major limiting factor in assisted reproduction (Spandorfer & Rosenwaks, 1999); delivery rate per retrieval is 29.4%. The implantation process occurs 6-7 days after conception (fertilization) and, in primates, includes 3 stages: Apposition: initial adhesion of the blastocyst to the uterine wall. Microvilli on the apical surface of syncytiotrophoblasts interdigitate with microprotrusions from the apical surface of the uterine epithelium (pinopodes). Adhesion: characterized by increased physical interaction between the blastocyst and the uterine epithelium. Invasion: syncytiotrophoblasts penetrate the uterine epithelium. By then, the blastocyst is oriented with its embryonic pole toward the uterine epithelium. The uterine receptivity represents the state during the period of endometrial maturation when the blastocyst can become implanted and the optimal period for implantation ranges between days 20 to 24 of a regular 28-day menstrual cycle. Uterine receptivity features include: endometrial histologic changes, more vascular and edematous glands, enhanced secretory activity; pinopodes develop on the Abstract of the 8th Royan International Twin Congress, Tehran, Iran, 5-7 September 2007 Yakhteh Medical Journal, Vol 9, Sup 1, Summer 2007 51 luminal surface of the epithelium and myometrial activity changes. Successful implantation is the end result of complex molecular interactions between the hormonally primed uterus and a mature blastocyst and the failure to synchronize the component processes involved in these interactions may results in a failure of implantation. Implantation factors, apart from the hormonal influence by estradiol and progesterone, include peptide hormones, growth factors and cytokines acting with autocrine/paracrine activity, involved in the cross-talk between endometrium and blastocyst. According to these new acquisitions, leukemia inhibiting factor (LIF) could be considered as a new markers of endometrial receptivity. In detail its levels in both the luminal and glandular epithelium of the uterus rise dramatically in the midsecretory phase of the menstrual cycle and a diminished secretion of this factor is associated with recurrent pregnancy loss. Similarly, also adhesion molecules (integrins) and mucins are being considered valuable markers of endometrial receptivity. Mechanisms that enable the blastocyst to actively initiate implantation include: catecholestrogens, leukemia inhibiting factor, transforming growth factor, platelet-derived growth factor, insulin-like growth factor II, colony-stimulating factor 1, interleukin-1, interleukin-6, prostaglandin E2, plateletactivating factor and epidermal-growth-factor receptors and heparan sulfate proteoglycans able to interact with factor–like ligands. The finest understanding of the processes involved in inflammatory factors could be helpful to better manage the embryonic implantation failures in assisted reproduction and could pave the way to innovative diagnostic and therapeutic protocols which, in the next years, could be responsible of a pregnancy rate increase, in opposition to the “human reproduction paradox” quoted before.