When the Embryo Meets the Endometrium: Identifying the Features Required for Successful Embryo Implantation.

Evaluation of the optimal number of embryos, their quality, and the precise timing for transfer are critical determinants in reproductive success, although still remaining one of the main challenges in assisted reproduction technologies (ART). Indeed, the success of in vitro fertilization (IVF) treatments relies on a multitude of events and factors involving both the endometrium and the embryo. Despite concerted efforts on both fronts, the overall success rates of IVF techniques continue to range between 25% and 30%. The role of the endometrium in implantation has been recently recognized, leading to the hypothesis that both the "soil" and the "seed" play a central role in a successful pregnancy. In this respect, identification of the molecular signature of endometrial receptivity together with the selection of the best embryo for transfer become crucial in ART. Currently, efforts have been made to develop accurate, predictive, and personalized tests to identify the window of implantation and the best quality embryo. However, the value of these tests is still debated, as conflicting results are reported in the literature. The purpose of this review is to summarize and critically report the available criteria to optimize the success of embryo transfer and to better understand current limitations and potential areas for improvement.

High mobility group box 1 in women with unexplained recurrent pregnancy loss.

OBJECTIVES: To investigate whether high mobility group box 1 (HMGB1) is involved in unexplained recurrent pregnancy loss (uRPL). METHODS: Plasma levels of HMGB1 were measured by ELISA in non-pregnant women with (n=44) and without (n=53 controls) uRPL. Their platelets and plasma-derived microvesicles (MVs) were also assayed for HMGB1. Endometrial biopsies were taken in selected uRPL (n=5) and control women (n=5) and the tissue expression of HMGB1 was determined by western blot and immunohistochemistry (IHC). RESULTS: plasma levels of HMGB1 were significantly higher in women with uRPL than in control women. HMGB1 content in platelets and MVs obtained from women with uRPL was significantly higher than that obtained from control women. HMGB1 expression in endometrium was higher in tissues obtained from women with uRPL than in tissues obtained from control women. IHC analysis revealed that HMGB1 is expressed in endometrium with different patterns between uRPL and control women. CONCLUSIONS: HMGB1 could be involved in uRPL.

Diagnostic factors for recurrent pregnancy loss: an expanded workup.

PURPOSE: There is limited information on the risk factors for recurrent pregnancy loss (RPL). METHODS: In this study, a patient-based approach was used to investigate the possible involvement and relative relevance of a large number of diagnostic factors in 843 women with RPL who underwent an extensive diagnostic workup including 44 diagnostic factors divided into 7 major categories. RESULTS: The rates of abnormalities found were: (1) genital infections: 11.74%; (2) uterine anatomic defects: 23.72%; (3) endocrine disorders: 29.42%; (4) thrombophilias: 62%; (5) autoimmune abnormalities: 39.2%; (6) parental karyotype abnormalities 2.25%; (7) clinical factors: 87.78%. Six hundred and fifty-nine out of eight hundred and forty-three women (78.17%) had more than one abnormality. The mean number of pregnancy losses increased by increasing the number of the abnormalities found (r = 0.86949, P < 0.02). The factors associated with the highest mean number of pregnancy losses were cervical isthmic incompetence, anti-beta-2-glycoprotein-1 antibodies, unicornuate uterus, anti-prothrombin A antibodies, protein C deficiency, and lupus anticoagulant. The majority of the considered abnormalities had similar, non-significant prevalence between women with 2 versus ≥ 3 pregnancy losses with the exception of age ≥ 35 years and MTHFR A1298C heterozygote mutation. No difference was found between women with primary and secondary RPL stratified according to the number of abnormalities detected (Chi-square: 8.55, P = 0.07). In these women, the only factors found to be present with statistically different rates were age ≥ 35 years, cigarette smoking, and genital infection by Ureaplasma. CONCLUSION: A patient-based diagnostic approach in women with RPL could be clinically useful and could represent a basis for future research.

HLA-G and Recurrent Pregnancy Loss.

Placentation is an immunological compromise where maternal immune system cells and trophoblastic cells interact to reach an equilibrium condition. Although the cross talk between the two systems is complex and not completely understood, Human Leukocyte Antigen G (HLA-G), expressed on trophoblastic cell surfaces, seems to be one of the main molecules involved in the modulation of both local and systemic maternal immune response. The prevalence of recurrent pregnancy loss (RPL), probably underestimated, is 5% of all women who achieve pregnancy, and about 40-60% percent of RPL cases are unexplained. There is an immunological analogy between allograft rejection and miscarriage, and the purpose of this review is to describe how the HLA-G pathway alterations are involved in disrupting the immunologic balance and in increasing the risk of recurrent pregnancy loss.

Clinical significance of endometrial abnormalities: an observational study on 1020 women undergoing hysteroscopic surgery.

BACKGROUND: The overall clinical significance of the finding of endometrial abnormalities in predicting premalignant/malignant endometrial lesions is still incompletely determined. For this reason the management, surgical or expectant, of women in which an endometrial abnormality has been detected is debated. METHODS: This retrospective study was carried out on 1020 consecutive women, 403 premenopausal and 617 postmenopausal, who underwent operative hysteroscopy in a University Hospital for suspected endometrial abnormalities, which were detected by transvaginal ultrasound (TVS) and/or office hysteroscopy. In these women, the clinical characteristics and findings at TVS and hysteroscopy were evaluated in relation to the presence/absence of premalignant/malignant endometrial lesions at pathology report. RESULTS: The clinical characteristics considered were significantly different when the study women were compared according to their menopausal status. Premalignant/malignant lesions were found in 34/1020 (3.33%) women. Complex hyperplasia with atypia and endometrial cancer were detected in 22 (2.15%) and 12 (1.17%) cases, respectively. The postmenopausal women had a significantly higher risk of premalignant/malignant lesions than premenopausal women (O.R. = 5.098 [95% C.I.: 1.782-14.582], P < 0.005). This risk was even higher when abnormal uterine bleeding (AUB) was present (O.R. = 5.20 [95% C.I.: 2.38-11.35], P < 0.0001). The most significant associations with premalignant/malignant endometrial lesions were BMI, AUB in postmenopause, overall polyp size, atypical aspect of endometrial polyps at hysteroscopy, postmenopausal status, diabetes mellitus and patient age. CONCLUSIONS: The results of the present study suggest that the proper, aggressive or expectant, management of endometrial abnormalities should take into account both ultrasonographic and hysteroscopic findings together with the specific clinical characteristics of the patients.

Uterine and placental blood flow indexes and antinuclear autoantibodies in unexplained recurrent pregnancy loss: should they be investigated in pregnancy as correlated potential factors? A retrospective study.

BACKGROUND: The potential role of antinuclear antibodies (ANA) in recurrent pregnancy loss (RPL) pathogenesis is still debated, although some evidences suggest that they could affect pregnancy outcome, leading to a higher miscarriage rate in these patients. A hypothesized mechanism is through changes in uterine flow in pre-conceptional stage, by modifying endometrial receptivity in RPL. However, scant data are available, in pregnancy, about their role in RPL placental perfusion, also in relation to its potential treatments, such as low molecular weight heparin (LMWH). The aim of this study is to retrospectively further investigate the correlation between two-dimensional (2D) and three-dimensional (3D) uterine and placental flow indexes and the presence or the absence of ANA in women with unexplained RPL (uRPL), treated or not treated with LMWH. METHODS: 2D Doppler measurement of pulsatility index (PI) of the uterine arteries and 3D ultrasonography determination of vascularization index (VI), flow index (FI) and vascularization flow index (VFI) was carried out with the aid of the virtual organ computer-aided analysis (VOCAL) technique in LMWH treated (n 24) and not treated-uRPL patients (n 20) and in the relative control group (n 27), each group divided in ANA+ and ANA- subgroups. Serum assay for the presence of ANA was performed in all women. RESULTS: No differences were found in PI, VFI and VI values, by comparing the different groups. A difference in VI values was found for ANA- patients between RPL women not treated with LMWH and the treated ones (p = 0,01), which have lower VI values and similar to controls. By considering only ANA- treated and not treated RPL patients, the ROC curve shows an area of 0,80 and at the VI cut-off of 11,08 a sensitivity of 85% and a specificity of 67%. CONCLUSIONS: LMWH could exert a potential beneficial effect in restoring the physiological blood flow supply in terms of VI in uRPL ANA- status, suggesting to include ANA and VI investigations in the RPL diagnostic algorithm in a research context, since further studies are needed to clarify this challenging hypothesis in order to try to ameliorate ANA and abnormal placental vascularization negative influence on RPL pregnancy outcome .

Longitudinal Changes of Subpubic Arch Angle throughout Pregnancy.

OBJECTIVE: The objective of this study is to assess whether the subpubic arch angle (SPA) changes throughout pregnancy. MATERIALS AND METHODS: We recruited a group of nulliparous women in the first trimester of pregnancy. Each woman was assessed 3 times throughout pregnancy, once per each trimester, by measuring SPA using a recently described highly reproducible three-dimensional transperineal ultrasound (linear reconstruction with contrast enhancement technique; OmniView-volume contrast imaging). Repeated measures analysis of variance was used to study SPA changes during pregnancy. RESULTS: Overall, 97 women were included in the final analysis. SPA increased progressively and significantly (F = 27.824, p < 0.001) from the first to the second trimester (121.8 ± 8.7 vs. 123.5 ± 8.4°, p = 0.01) and from the second to the third trimester (123.5 ± 8.4 vs. 125.3 ± 8.1°, p = 0.01). CONCLUSION: SPA width increases progressively but slightly during pregnancy. Although this finding is interesting, the extremely small difference detected is unlikely to be clinically significant.

Amniotic fluid antiphospholipid antibodies: potential role in antiphospholipid syndrome-independent aberrant implantation process.

BACKGROUND: The direct role of antiphospholipid antibodies (aPL) at maternal-fetal interface has not been fully investigated, especially whether they are involved in physiological and pathological implantation conditions, in an antiphospholipid syndrome (APS)-independent manner. In fact, trophoblast cells and placental endothelial cells at the implantation site express potential aPL targeted-phospholipid antigens (PL Ags); thus, the local production and presence of their specific antibodies, not related to APS (characterized by aPL presence in the peripheral blood), could be a potential marker of aberrant invasion, implantation and fetal-maternal immune tolerance processes. METHODS: Anti-Beta2glycoprotein I (anti-ß2GPI) and anticardiolipin (aCL Ab) antibodies (the most clinically relevant aPL) were detected by immunoenzymatic assay (ELISA), in the amniotic fluid (AF) of 167 women with physiological and complicated common pregnancy conditions, sharing an aberrant implantation process, such as recurrent pregnancy loss (RPL), autoimmune hypothyroidism (ahT) and smoking. All women included in the study were negative to peripheral blood aPL. RESULTS: aCL and anti-ß2GPI antibodies were detectable in all the AF samples. RPL, ahT and smoking patients had higher level of anti-ß2GPI Abs (IgM) compared to women with physiological pregnancies (p < 0.0001). Since IgM cannot cross the placenta, their local production in response to maternal-fetal interface stimuli, could be hypothesized. CONCLUSIONS: The presence of aPL in the AF (not related to APS) could reveal a potential clinical significance at maternal-fetal interface in selected pregnancy complications, in which an aberrant implantation process, and in turn an impaired fetal-maternal immune tolerance cross-talk, could occur.

RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss.

Unexplained recurrent pregnancy loss (uRPL) is associated with repeated embryo loss and endometrial repair with elevated endometrial expression of inflammatory cytokines, including IFN-γ. Notch signaling through its transcription factor recombination signal binding protein Jκ (RBPJ) regulates mechanisms including the immune response and repair after tissue injury. Initially, null mutation of RBPJ in the mouse uterus ( Pgrcre/+Rbpjf/f; Rbpj c-KO) results in subfertility, but we have found that these mice become infertile after pregnancy as a result of dysfunctional postpartum uterine repair, including delayed endometrial epithelial and myometrial regeneration. RNA sequencing of postpartum uterine repair sites revealed global up-regulation of inflammatory pathways, including IFN signaling. Consistent with elevated IFN-γ, macrophages were recruited and polarized toward an M1-cytotoxic phenotype, which is associated with preventing repair and promoting further tissue injury. Through embryo transfer experiments, we show that dysfunctional postpartum repair directly impairs future embryo implantation in Rbpj c-KO mice. Last, we clinically correlated our findings from the Rbpj c-KO mouse in women diagnosed with uRPL. Reduced RBPJ in women with uRPL was associated with increased levels of IFN-γ. The data, taken together, indicate that RBPJ regulates inflammation during endometrial repair, which is essential for future pregnancy potential, and its dysregulation may serve as an unidentified contributor to uRPL in women.-Strug, M. R., Su, R.-W., Kim, T. H., Mauriello, A., Ticconi, C., Lessey, B. A., Young, S. L., Lim, J. M., Jeong, J.-W., Fazleabas, A. T. RBPJ mediates uterine repair in the mouse and is reduced in women with recurrent pregnancy loss.

Endometrial Immune Dysfunction in Recurrent Pregnancy Loss.

Recurrent pregnancy loss (RPL) represents an unresolved problem for contemporary gynecology and obstetrics. In fact, it is not only a relevant complication of pregnancy, but is also a significant reproductive disorder affecting around 5% of couples desiring a child. The current knowledge on RPL is largely incomplete, since nearly 50% of RPL cases are still classified as unexplained. Emerging evidence indicates that the endometrium is a key tissue involved in the correct immunologic dialogue between the mother and the conceptus, which is a condition essential for the proper establishment and maintenance of a successful pregnancy. The immunologic events occurring at the maternal-fetal interface within the endometrium in early pregnancy are extremely complex and involve a large array of immune cells and molecules with immunoregulatory properties. A growing body of experimental studies suggests that endometrial immune dysregulation could be responsible for several, if not many, cases of RPL of unknown origin. The present article reviews the major immunologic pathways, cells, and molecular determinants involved in the endometrial dysfunction observed with specific application to RPL.

Molecular Signaling Regulating Endometrium-Blastocyst Crosstalk.

Implantation of the embryo into the uterine endometrium is one of the most finely-regulated processes that leads to the establishment of a successful pregnancy. A plethora of factors are released in a time-specific fashion to synchronize the differentiation program of both the embryo and the endometrium. Indeed, blastocyst implantation in the uterus occurs in a limited time frame called the "window of implantation" (WOI), during which the maternal endometrium undergoes dramatic changes, collectively called "decidualization". Decidualization is guided not just by maternal factors (e.g., estrogen, progesterone, thyroid hormone), but also by molecules secreted by the embryo, such as chorionic gonadotropin (CG) and interleukin-1ß (IL-1 ß), just to cite few. Once reached the uterine cavity, the embryo orients correctly toward the uterine epithelium, interacts with specialized structures, called pinopodes, and begins the process of adhesion and invasion. All these events are guided by factors secreted by both the endometrium and the embryo, such as leukemia inhibitory factor (LIF), integrins and their ligands, adhesion molecules, Notch family members, and metalloproteinases and their inhibitors. The aim of this review is to give an overview of the factors and mechanisms regulating implantation, with a focus on those involved in the complex crosstalk between the blastocyst and the endometrium.

Ectopic pregnancy in women with recurrent miscarriage.

AIM: The aim of this study was to investigate the possible association between recurrent miscarriage (RM) and ectopic pregnancy (EP). METHODS: In this case-control retrospective study, the clinical cards of women followed as outpatients in the RM and low-risk pregnancy offices of the Obstetrics and Gynecology Unit at the Policlinico Tor Vergata University Hospital were carefully reviewed for the occurrence of EP. RESULTS: Overall, 598 women with RM and 2043 normal women without RM (controls) were included in the study. Among these women, 4974 pregnancies were analyzed, in which 2028 miscarriages occurred. The EP rate (3.51%) was significantly higher in RM than in control women (1.51%) [odds ratio = 2.31 (95% confidence interval: 2.3-2.4)]; it was particularly high in women with primary RM (5.11%). However, when EP rates were calculated not by women but by overall pregnancies, no differences could be found between RM and control women. In control women, the absence of a miscarriage in the reproductive history was associated with a lower rate of EP. CONCLUSIONS: Women with RM, particularly primary RM, are at increased risk of EP. This increased risk seems to be dependent on the high number of pregnancies occurring in women with RM rather than to specific characteristics of these women.

hCG and Its Disruption by Environmental Contaminants during Human Pregnancy.

Human chorionic gonadotropin (hCG) is a hormone of considerable importance in the establishment, promotion and maintenance of human pregnancy. It has been clearly demonstrated that hCG exerts multiple endocrine, paracrine and autocrine actions on a variety of gestational and non-gestational cells and tissues. These actions are directed to promote trophoblast invasiveness and differentiation, placental growth, angiogenesis in uterine vasculature, hormone production, modulation of the immune system at the maternal-fetal interface, inhibition of myometrial contractility as well as fetal growth and differentiation. In recent years, considerable interest has been raised towards the biological effects of environmental contaminants, particularly endocrine disrupting chemicals (EDCs). Emerging evidence suggests that prenatal exposure to selected EDCs can have a deleterious impact on the fetus and long-lasting consequences also in adult life. The results of the in vitro effects of commonly found EDCs, particularly Bisphenol A (BPA) and para-Nonylphenol (p-NP), indicate that these substances can alter hCG production and through this action could exert their fetal damage, suggesting that hCG could represent and become a potentially useful clinical biomarker of an inappropriate prenatal exposure to these substances.

Three-hour analysis of non-invasive foetal sex determination: application of Plexor chemistry.

BACKGROUND: The knowledge of the individual genetic "status" in the prenatal era is particularly relevant in the case of positive family history for genetic diseases, in advanced maternal age and in the general screening for foetal abnormalities. In this context, here, we report an innovative molecular assay which utilizes the cell-free foetal DNA (cffDNA) as a source for the early and fast detection of the foetal sex. The study involved 132 pregnant women in their first 3 months of pregnancy, who agreed to give a blood sample. All the collected samples were immediately subjected to the separation of the plasma, which was utilized for the extraction of the cffDNA. Successively, the extracted cffDNA was analysed by a quantitative PCR (qPCR) method based on Plexor-HY chemistry, which is able to simultaneously identify, quantify and discriminate the autosomal DNA from the sex-linked DNA. RESULTS: Overall, the Plexor-HY assay demonstrated to be sensitive and specific for the determination of low-template DNA, such as the cffDNA. In fact, the Plexor-HY assay has been successfully performed in all the samples, identifying 70 males and 62 females. As the foetal sex can be provided in 120 min just by utilizing a maternal blood sample as cffDNA source, the assay represents a very fast, safe and non-invasive prenatal method. CONCLUSIONS: The possibility of determining the foetal sex in the early prenatal life consents the application of our assay as a helpful screening test for subjects and families at risk of sex-linked disorders. Moreover, the early knowledge of the foetal sex may be of great help even for the specialist, who might promptly advise the patients concerning the foetal risk of inheriting sex-linked disorders and the clinical utility of performing an invasive prenatal diagnosis.

Gestational age of pregnancy loss in women with unexplained recurrent miscarriage.

AIM: The aim of this study was to investigate the gestational age (GA) of pregnancy loss in women with unexplained recurrent miscarriage (RM) and to determine whether the miscarriages occur at similar GA in RM women. MATERIAL AND METHODS: This retrospective study was carried out in a university hospital and included 288 women with unexplained RM. The GA at which each miscarriage occurred was carefully determined. Overall, 739 miscarriages were analyzed. RESULTS: RM women had miscarriages at a median GA of 7 weeks (range: 3-20). In RM women, 47.2% (n = 136) experienced miscarriages within a 1-week range of GA and 53.4% (n = 154) had miscarriages in the same period of fetal development (pre-embryonic, embryonic or fetal). CONCLUSION: Women with unexplained RM tend to have miscarriages at the same GA, which is characteristic for each patient.

Type and Location of Adenomyosis in Women with Recurrent Pregnancy Loss: A Transvaginal Ultrasonographic Assessment.

The current knowledge on adenomyosis as a risk factor for RPL is very scant. Overall 120 women were included in this retrospective observational study. They were divided in three groups each of which consisted of 40 subjects: Group 1: women with RPL who were diagnosed to have adenomyosis on transvaginal ultrasound (TVS); Group 2: patients with RPL without ultrasonographic findings of adenomyosis; Group 3: patients with ultrasound diagnosis of adenomyosis without RPL and at least one live birth pregnancy. The copresence of endometriosis was also investigated. Among women with RPL, patients with adenomyosis (Group 1) had higher number of pregnancy losses (p = 0.03) and lower age at first pregnancy loss (p = 0.03) than women without adenomyosis (Group 2). Moreover, they had more frequently primary RPL (p = 0.008). Adenomyosis of the inner myometrium was found more frequently (p = 0.04) in patients of Group 1 than in patients of Group 3 in which adenomyosis was mainly in the outer myometrium (p= 0.02). No differences were found in the severity of adenomyosis between these two groups of women. TVS findings for endometriosis were observed more frequently in women with adenomyosis without RPL (Group 3) than in the other two groups of patients. Adenomyosis can be a factor involved in RPL. Differences in adenomyosis localization are associated with different risks for RPL. Patients with RPL should be investigated for the presence of adenomyosis and also for the type and localization of the disease in the different myometrial layers.

Estrogen replacement therapy and asthma.

A growing body of clinical and experimental evidence indicates that female sex hormones, particularly estrogen, have significant effects on normal airway function as well as on respiratory disorders, such as asthma. These effects are very complex and are exerted at several levels, directly on airway reactivity or indirectly through regulation of the immune and inflammatory responses in the lung. They can have relevant clinical implications not only according to the phases of the reproductive life in women, but also in relation to the therapeutical administration of estrogen, as in the case of menopausal hormone therapy. Clinical evidence suggests that administration of estrogen to menopausal women is associated with increased rates of newly diagnosed asthma. Conversely, functional studies show that estrogen can improve objective indexes of respiratory functionality.

Antinuclear antibodies positivity in women in reproductive age: From infertility to adverse obstetrical outcomes - A meta-analysis.

This systematic review and meta-analysis were designed to identify possible correlations between isolated serum antinuclear antibody (ANA) and (i) infertility in the context of in-vitro fertilization (IVF), (ii) idiopathic recurrent pregnancy losses (RPL), and (iii) second/ third trimester pregnancy complications. We performed a systematic review and meta-analysis of the literature in PubMed Library database from inception to March 2022 following PRISMA guidelines. Our pooled results showed a lower pregnancy rate among ANA-positive women undergoing IVF/ICSI compared to ANA-negative women undergoing the same procedures (279/908 versus 1136/2347, random effect, odds ratio -OR- 0.50, 95% confidence interval -CI- 0.38-0.67, p 0.00001, I2 = 58%). We also reported a higher miscarriage rate among ANA-positive compared to ANA-negative women (48/223 versus 109/999, random effect, OR: 3.25 95% CI: 1.57-6.76, p = 0.002, I2 = 61%) and a lower implantation rate (320/1489 versus 1437/4205, random effect, OR: 0.51, 95% CI: 0.36-0.72, p = 0.0001, I2 = 78%). Regarding RPL, pooled results demonstrated a higher prevalence of ANA-positivity in RPL women compared to controls (698/2947 versus 240/3145, random effect, OR: 3.22, 95% CI: 2.12-4.88, p 0.00001, I2 77%), either using > 2 or > 3 pregnancy losses threshold for defining RPL. Heterogeneity of reporting outcome did not allow a quantitative analysis and led to no clear demonstration of an effect of serum ANA on the incidence of stillbirth, preeclampsia and hypertensive disorders. In conclusion, the unfavorable effect of serum ANA was observed in women following IVF. Similarly, ANA were associated with the risk of RPL, while data were unconclusive in terms of late pregnancy complications.

Beta-fibrinogen G-455A polymorphisms and recurrent miscarriage.

BACKGROUND/AIMS: The aim of this study was to investigate whether differences could be detected in genotype and allele frequencies of ß-fibrinogen G-455A in relation to recurrent miscarriage (RM). METHODS: ß-Fibrinogen G-455A polymorphism was investigated by sequencing analysis in 98 women with RM and 78 control women who had no history of miscarriage (controls). RESULTS: The frequency of the -455 A/A genotype of ß-fibrinogen was significantly different in women with RM compared with control women. The A/A genotype was found in 8 women of Group 1 (8.2%), but was not detected in any woman of the control group. In contrast, no differences were found in the allele frequencies between RM and control women. CONCLUSIONS: Women with the A/A genotype could have an increased risk of RM. However, the allele frequencies were similar between women with recurrent pregnancy loss and control women, suggesting that the effect of ß-fibrinogen polymorphisms on RM, if any, is actually very slight.

Clinical consequences of defective decidualization.

Decidualization is characterized by a series of genetic, metabolic, morphological, biochemical, vascular and immune changes occurring in the endometrial stroma in response to the implanting embryo or even before conception and involves the stromal cells of the endometrium. It is a fundamental reproductive event occurring in mammalian species with hemochorial placentation. A growing body of experimental and clinical evidence strongly suggests that defective or disrupted decidualization contributes to the establishment of an inappropriate maternal-fetal interface. This has relevant clinical consequences, ranging from recurrent implantation failure and recurrent pregnancy loss in early pregnancy to several significant complications of advanced gestation. Moreover, recent evidence indicates that selected diseases of the endometrium, such as chronic endometritis and endometriosis, can have a detrimental impact on the decidualization response in the endometrium and may help explain some aspects of the reduced reproductive outcome associated with these conditions. Further research efforts are needed to fully understand the biomolecular mechanisms ans events underlying an abnormal decidualization response. This will permit the development of new diagnostic and therapeutic strategies aimed to improve the likelihood of achieveing a successful pregnancy.