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), growthregulated oncogene-α (GRO-α), interleukin-15 (IL-15), and macrophage inflammatory protein 1B (MIP-1B), were detected in day-21 endome-trial 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.

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.

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.Reproduction (2012) 144 661-668

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. Keywords Dendritic cells; implantation; inflammation; pregnancy The uterus and implantationEmbryo implantation, which is an absolute requirement for reproduction, starts with blastocyst apposition to the uterine endometrium, followed by its attachment to the endometrial surface epithelium. Implantation can only take place in a receptive uterus. In humans the uterus becomes receptive during the mid-secretory phase (days 19-23) of the menstrual cycle, commonly known as the window of implantation (WOI). Rodents exhibit a relatively short (4 days) estrous cycle and develop a receptive uterus on day 4 after mating. 1 The uterine endometrium consists of two distinct cellular components, the stromal cells and the cells of the epithelium. The cellular changes during the WOI include the transformation of the fibroblast-like endometrial stromal cells into larger and rounded decidual cells (decidualization), 2 as well as the growth and development of secretory glandules and the emergence of large apical protrusions (pino-podes) and microvilli on the luminal epithelium. In parallel, modulations in the expression of different cytokines, chemokines growth factors, and adhesion molecules take place. 2,3 These changes are subjected to regulation by the ovarian steroid hormones, 17beta-estradiol and progesterone. 4,5 The modulated expression of the above-mentioned molecules at the WOI provides circumstantial evidence for their role in this process. However, the association of some of these specific endometrial genes with impaired fertility in humans has not been consistent. 5,6 Moreover, global microarray analysis employ...