Yulia Gnainsky

Local injury of the endometrium induces an inflammatory response that promotes successful implantation

OBJECTIVE To study whether an injury-induced inflammation might be the mechanism underlying the favorable effect of endometrial biopsy on the implantation rate in in vitro fertilization (IVF) patients. DESIGN Controlled clinical study. SETTING A medical center IVF unit and a research institute. PATIENT(S) Women undergoing IVF who had previous failed treatment cycles. INTERVENTION(S) Endometrial samples were collected from two groups of patients on day 21 of their spontaneous menstrual cycle. The experimental, but not the control group underwent prior biopsy treatment on days 8 or/and 11 to 13 of that same cycle. MAIN OUTCOME MEASURE(S) Abundance of immune cells, cytokines/chemokines level, correlation between these parameters and pregnancy outcome. RESULT(S) A statistically significantly higher amount of macrophages/dendritic cells (HLA-DR+ CD11c+ cells) and elevated proinflammatory cytokines, tumor necrosis factor-α (TNF-α), growth-regulated oncogene-α (GRO-α), interleukin-15 (IL-15), and macrophage inflammatory protein 1B (MIP-1B), were detected in day-21 endometrial samples of the experimental group. A direct stimulatory effect of TNF-α on MIP-1B, GRO-α, and IL-15 messenger RNA (mRNA) expression was demonstrated. A positive correlation was found between the levels of macrophages/dendritic cells, MIP-1B expression, and TNF-α expression and the pregnancy outcome. CONCLUSION(S) A biopsy-induced inflammatory response may facilitate the preparation of the endometrium for implantation. Increased MIP-1B expression could possibly serve for prediction of implantation competence.

Inflammation and Implantation

Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate‐limiting step for the success of the in vitro fertilization (IVF) treatments. It has been demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury‐derived inflammation in the biopsy‐treated patients generates a focus for uterine DCs accumulation that, in turn, enhances the endometrial expression of essential molecules, which facilitate the interaction between the embryo and the uterine epithelium.

Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium

OBJECTIVE To explore the possibility that endometrial injury modulates the expression of specific genes that may increase uterine receptivity. DESIGN Controlled clinical study. SETTING Clinical IVF unit and academic research center. PATIENT(S) IVF patients with 28- to 30-day menstrual cycles. INTERVENTION(S) Endometrial biopsies from two groups of patients were collected on days 20-21 of their spontaneous menstrual cycle. The experimental, but not the control, group underwent biopsies on days 11-13 and 21-24 of their preceding cycle. MAIN OUTCOME MEASURE(S) Global endometrial gene expression and specific analysis of uroplakin Ib (UPIb) mRNA level throughout the menstrual cycle. RESULT(S) Local injury modulated the expression of a wide variety of genes. One of the prominently up-regulated genes was the bladder transmembranal protein, UPIb, whose expression by the endometrium is shown here for the first time. Endometrial UPIb mRNA increases after biopsy in the same cycle wct 2with an additional elevation in the following cycle. Immunohistochemical analysis localized the UPIb protein to the glandular-epithelial cells. Genes encoding other membrane proteins such as adipose differentiation-related protein and mucin 1, transmembrane, were also up-regulated. CONCLUSION(S) The biopsy-induced increase in the expression of UPIb and other genes encoding membrane proteins supports the possible importance of the membrane structure and stability during implantation. The specific role of UPIb in uterine receptivity should be elucidated.

Endometrial inflammation and effect on implantation improvement and pregnancy outcome

Implantation failure, which is presently the major barrier in human fertility, is attributed, in many cases, to the failure of the uterus to acquire receptivity. The transition into a receptive uterus includes cellular changes in the endometrium and the modulated expression of different cytokines, growth factors, transcription factors, and prostaglandins. These molecules partake in the generation of an inflammatory response followed by the recruitment of immune cells. These cells have shown to be involved in the maternal immune tolerance toward the implanted embryo as well as in the maternal-fetus interaction during pregnancy. Most of the accumulated evidence indicates that embryo implantation is associated with an active Th1 inflammatory response while a Th2-humoral inflammation is required for pregnancy maintenance. Yet, recent findings suggest that a Th1 inflammatory response is also necessary for the acquisition of uterine receptivity. This notion was originally suggested by reports from our and other clinical centers worldwide that IVF patients with repeated implantation failure subjected to endometrial biopsy exhibit a substantial improvement in their chances to conceive. These findings, followed by the demonstration of an elevated pro-inflammatory cytokine/chemokine expression, as well as an increased abundance of immune cells, in the endometrium of these patients, raised the idea that acquisition of uterine receptivity is closely associated with an inflammatory response. This review summarizes the molecular and biochemical evidence that confirm this notion and proposes a mechanism by which injury-induced inflammation improves uterine receptivity and the subsequent pregnancy outcome.

The role of inflammation for a successful implantation.

Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate‐limiting step for the success of the in vitro fertilization (IVF) treatments. We, as well as others, have demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies, and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury‐derived inflammation in the biopsy‐treated patients generates a focus for uterine DCs and Mac accumulation that, in turn, enhance the endometrial expression of essential molecules that facilitate the interaction between the embryo and the uterine epithelium.

Biopsy-induced inflammatory conditions improve endometrial receptivity: the mechanism of action

A decade ago, we first reported that endometrial biopsy significantly improves the success of pregnancy in IVF patients with recurrent implantation failure, an observation that was later confirmed by others. Recently, we have demonstrated that this treatment elevated the levels of endometrial pro-inflammatory cytokines and increased the abundance of macrophages (Mac) and dendritic cells (DCs). We therefore hypothesised that the biopsy-related successful pregnancy is secondary to an inflammatory response, and aimed at deciphering its mechanism of action. Supporting our hypothesis, we found that the pro-inflammatory TNFα stimulated primary endometrial stromal cells to express cytokines that attracted monocytes and induced their differentiation into DCs. These monocyte-derived DCs stimulated endometrial epithelial cells to express the adhesive molecule SPP1 (osteopontin (OPN)) and its receptors ITGB3 and CD44, whereas MUC16, which interferes with adhesion, was downregulated. Other implantation-associated genes, such as CHST2, CCL4 (MIP1B) and GROA, were upregulated by monocyte-derived Mac. These findings suggest that uterine receptivity is mediated by the expression of molecules associated with inflammation. Such an inflammatory milieu is not generated in some IVF patients with recurrent implantation failure in the absence of local injury provoked by the biopsy treatment.

An In Vitro Model for the Study of Human Implantation

Citation Holmberg JC, Haddad S, Wünsche V, Yang Y, Aldo PB, Gnainsky Y, Granot I, Dekel N, Mor G. An In vitro model for the study of human implantation. Am J Reprod Immunol 2012; 67: 169–178

REVIEW ARTICLE: Inflammation and Implantation

Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate‐limiting step for the success of the in vitro fertilization (IVF) treatments. It has been demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury‐derived inflammation in the biopsy‐treated patients generates a focus for uterine DCs accumulation that, in turn, enhances the endometrial expression of essential molecules, which facilitate the interaction between the embryo and the uterine epithelium.

Implantation: Mutual Activity of Sex Steroid Hormones and the Immune System Guarantee the Maternal-Embryo Interaction

Implantation is strictly dependent on the mutual interaction between a receptive endometrium and the blastocyst. Hence, synchronization between blastocyst development and the acquisition of endometrial receptivity is a prerequisite for the success of this process. This review depicts the cellular and molecular events that coordinate these complex activities. Specifically, the involvement of the sex steroid hormones, estrogen and progesterone, as well as components of the immune system, such as cytokines and specific blood cells, is elaborated.

REVIEW ARTICLE: Inflammation and Implantation: INFLAMMATION AND IMPLANTATION

Approximately half of all human embryo implantations result in failed pregnancy. Multiple factors may contribute to this failure, including genetic or metabolic abnormalities of the embryo. However, many of these spontaneous early abortion cases are attributed to poor uterine receptivity. Furthermore, although many fertility disorders have been overcome by a variety of assisted reproductive techniques, implantation remains the rate‐limiting step for the success of the in vitro fertilization (IVF) treatments. It has been demonstrated that endometrial biopsies performed either during the spontaneous, preceding cycle, or during the IVF cycle itself, significantly improve the rate of implantation, clinical pregnancies and live births. These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. In strong support of this idea, we recently found that dendritic cells (DCs), an important cellular component of the innate immune system, play a critical role in successful implantation in a mouse model. In this review, we discuss the hypothesis that the injury‐derived inflammation in the biopsy‐treated patients generates a focus for uterine DCs accumulation that, in turn, enhances the endometrial expression of essential molecules, which facilitate the interaction between the embryo and the uterine epithelium.