Period Of Uterine Receptivity Research Articles

The Endometrial Immune Profiling May Positively Affect the Management of Recurrent Pregnancy Loss.

IntroductionThe endometrial immune profiling is an innovative approach based on the analysis of the local immune reaction occurring in the endometrium at the time of the embryo implantation. By documenting the local immune activation during the period of uterine receptivity, we aim to detect and correct potential imbalances before and at the very beginning of placentation. The main objective of the study was to analyze in women with a history of repeated pregnancy loss (RPL) the association of personalized strategies based on immune dysregulations with live birth rates. The secondary objective was to highlight the main prognostic factors for live births.MethodsThis is an observational retrospective analysis of 104 patients with RPL, included between January 2012 and December 2019. Inclusion criteria included a spontaneous fertility with at least three miscarriages, an assessment including a three-dimension ultrasound scan, an endometrial biopsy for uterine immune profiling and a follow-up over at least 6 months with personalized care if indicated after the complete assessment. We defined as a success if the patients had a live birth after the suggested plan, as a failure if the patient either did not get pregnant or experienced a new miscarriage after the targeted therapies.ResultsUterine immune profiling was the only exploration to be significantly associated with a higher live birth rate (LBR) if a dysregulation was identified and treated accordingly (55% vs 45%, p=0.01). On the contrary, an absence of local dysregulation (resulting in an apparently balanced immune environment) was associated with a higher risk of a new miscarriage, suggesting that the cause inducing RPL still needed to be identified. Independently of age and AMH level, dysregulated immune profile is significatively associated with 3 times higher LBR than a non-deregulated profile (OR=3.4 CI 95%1.27-9.84) or five times in case of an overactive profile treated by immunotherapy (OR=5 CI 95% 1.65-16.5). The usage of ART was significantly associated with lower LBR regardless of the presence of a subfertility factor (p=0.012). Personalization of medical care using natural cycle or simple hormonal stimulation is associated with a significantly higher LBR than personalization including ART treatments regardless of maternal age and AMH level (OR= 2.9 CI 95% 1.03-8.88).ConclusionOur study suggests that some endometrial immune profiles with targeted management of RPL are associated with a higher rate of LBR. ART may be negatively associated with LBR.

Testosterone Reduces Tight Junction Complexity and Down-regulates Expression of Claudin-4 and Occludin in the Endometrium in Ovariectomized, Sex-steroid Replacement Rats.

It was hypothesized that endometrial tight junction morphology and expression of tight junction proteins i.e., claudin-4 and occludin in the uterus, are affected by testosterone. Therefore, the effects of testosterone on these parameters in the uterus during receptivity period were investigated. Ovariectomized adult female rats were given testosterone (1 mg/kg/day) alone or in combination with flutamide or finasteride between days 6 to 8 of sex-steroid replacement treatment, which was considered the period of uterine receptivity. Ultramorphology of tight junctions was visualized by transmission electron microscopy while distribution and expression of claudin-4 and occludin were examined by immunofluorescence and real-time polymerase chain reaction respectively. Administration of testosterone caused loss of tight junction complexity and down-regulated expression of claudin-4 and occludin in the uterus. Decreased endometrial tight junction complexity and expression of claudin-4 and occludin in the uterus during receptivity period by testosterone may interfere with embryo attachment and subsequent implantation.

Activation of the transcription factor, nuclear factor kappa-B, during the estrous cycle and early pregnancy in the pig

Establishment and maintenance of pregnancy in the pig involves intricate communication between the developing conceptuses and the maternal endometrium. This process occurs during trophoblast elongation which is spaciotemporally associated with conceptus synthesis and release of IL1B concomitant with pregnancy-specific endometrial up-regulation of IL-1 receptors, providing the potential for activation of the transcription factor, NFKB. The objective of the current investigation was to determine changes in expression and cellular localization of NFKB and associated factors during the estrous cycle and early pregnancy in the pig. In situ hybridization was used to localize changes in PGR, ESR1, and TNFRSF11A during the peri-implantation period. Quantitative RT-PCR was utilized to demonstrate gene expression changes for NFKB1, RELA, TNFRSF11A, TLR4, NFKBIA and NFKBIB. Transcription factor ELISA demonstrated an overall increase in RELA during the peri-implantation period in both cyclic and pregnant gilts. While the presence of TNFSF11A and TLR4 were both detected, TLR4 expression changes were temporally associated with NFKB expression and activation. Collectively, these data demonstrate that NFKB activation may occur during the period of uterine receptivity in both the cyclic and pregnant endometrium.

Expression of oestrogen receptors α and β during the period of uterine receptivity in rat: effect of ormeloxifene, a selective oestrogen receptor modulator

In the present study, we investigated expression, distribution and regulation of oestrogen receptors (ERs) alpha and beta and their modulation by ormeloxifene (Orm) during the period of uterine receptivity in rat uterus in order to determine their role in endometrial sensitization. Uterine tissues of control and Orm-treated (1.25 mg kg(-1), orally) rats were collected on days 3, 4, 5 morning and day 5 evening post-coitum referring to non-receptive, pre-receptive and receptive phases respectively. mRNA and protein expression levels were determined by RT-PCR and Western blot respectively. Immunohistochemical technique was used to localize the receptors. RT-PCR analysis revealed that ERalpha mRNA reached a peak level on day 5 morning whereas ERbeta mRNA expression was found to be very low. In Orm-treated rats, the ERalpha mRNA was suppressed at day 5. The protein expression of ERalpha increased after day 3 and that of ERbeta remained very low throughout the pre-implantation period; Orm caused a decrease in ERalpha on day 5 morning. In endometrium, ERalpha expression was regulated differentially in luminal epithelium, glandular epithelium and stroma. Orm caused a decrease in the percentage of ERalpha-positive nuclei in all the three endometrial compartments on days 4 and 5, and the magnitude of reduction varied spatio-temporally. In case of ERbeta, immunostaining was not detectable in Orm-treated and control groups. It appears that the complex uterine response to implantation is governed by differential cell-specific ERalpha expression. The study suggested the inhibitory activity of Orm on ERalpha during the period of uterine receptivity.

Proteomic Analysis Identifies Immunophilin FK506 Binding Protein 4 (FKBP52) as a Downstream Target of Hoxa10 in the Periimplantation Mouse Uterus

The process of implantation absolutely requires synchronized development of the blastocyst to implantation competency, differentiation of the uterus to the receptive state, and a reciprocal dialogue between the blastocyst and uterine luminal epithelium. Genetic and molecular approaches have identified several signaling pathways that are critical to this process. The transcription factor Hoxa10 is one such critical player in implantation. Hoxa10-/- female mice have implantation and decidualization failure due specifically to reduced uterine responsiveness to progesterone and defective stromal cell proliferation during uterine receptivity and implantation. However, the downstream signaling pathways of Hoxa10 in these events remain largely unknown. Using the proteomics approach of difference gel electrophoresis, we have identified an immunophilin FKBP52 (FK506 binding protein 4) as one of the Hoxa10-mediated signaling molecules in the uterus. We found that FKBP52, a cochaperone protein known to influence steroid hormone receptor functions, is down-regulated in stromal cells of Hoxa10-/- mice. More importantly, FKBP52 shows differential uterine cell-specific expression during the periimplantation period. Whereas it is primarily expressed in the uterine epithelium on d 1 of pregnancy, the expression expands to the stroma on d 4 during the period of uterine receptivity and becomes localized to decidualizing stromal cells surrounding the implantation site on d 5. This suggests that FKBP52 is important for the attainment of uterine receptivity and implantation. Furthermore, FKBP52 shows differential cell-specific expression in the uterus in response to progesterone and/or estrogen consistent with its expression patterns during the periimplantation period. Collectively, these results and the female infertility phenotype of FKBP52 suggest that a Hoxa10-FKBP52 signaling axis is critical to uterine receptivity and implantation.

Multiple roles for heparin-binding epidermal growth factor-like growth factor are suggested by its cell-specific expression during the human endometrial cycle and early placentation.

Embryonic expression of the epidermal growth factor (EGF) receptor as well as embryonic and steroid-dependent uterine secretion of its ligand, heparin-binding EGF-like growth factor (HB-EGF), are temporally associated with the period of blastocyst implantation. We examined the temporal cell type-specific expression of HB-EGF in human endometrium during the menstrual cycle by immunohistochemistry and in situ hybridization. Early first trimester implantation sites were also examined to determine HB-EGF protein levels in decidual and fetal tissues. In the endometrial stroma, HB-EGF protein expression increased markedly during the late proliferative phase and then decreased in the early secretory phase. By contrast, luminal and glandular epithelial cells as well as blood vessel endothelium accumulated the protein between midcycle and cycle day 20, with peak expression observed during the period of uterine receptivity for implantation. HB-EGF expression decreased dramatically at the end of the cycle, before menses. Spatiotemporal expression of HB-EGF messenger ribonucleic acid demonstrated a similar pattern. During early pregnancy, HB-EGF immunostaining was noted in the decidua and in both villous and extravillous trophoblast populations. These findings suggest that HB-EGF promotes implantation and trophoblast invasion through paracrine and autocrine signaling as cells penetrate the stroma and displace the arteriole endothelium.

Modulation of the baboon (Papio anubis) uterine endometrium by chorionic gonadotrophin during the period of uterine receptivity.

This study was undertaken to determine the modulation of uterine function by chorionic gonadotrophin (CG) in a nonhuman primate. Infusion of recombinant human CG (hCG) between days 6 and 10 post ovulation initiated the endoreplication of the uterine surface epithelium to form distinct epithelial plaques. These plaque cells stained intensely for cytokeratin and the proliferating cell nuclear antigen. The stromal fibroblasts below the epithelial plaques stained positively for alpha-smooth muscle actin (alphaSMA). Expression of alphaSMA is associated with the initiation of decidualization in the baboon endometrium. Synthesis of the glandular secretory protein glycodelin, as assessed by Western blot analysis, was markedly up-regulated by hCG, and this increase was confirmed by immunocytochemistry, Northern blot analysis, and reverse transcriptase-PCR. To determine whether hCG directly modulated these uterine responses, we treated ovariectomized baboons sequentially with estradiol and progesterone to mimic the hormonal profile of the normal menstrual cycle. Infusion of hCG into the oviduct of steroid-hormone-treated ovariectomized baboons induced the expression of alphaSMA in the stromal cells and glycodelin in the glandular epithelium. The epithelial plaque reaction, however, was not readily evident. These studies demonstrate a physiological effect of CG on the uterine endometrium in vivo and suggest that the primate blastocyst signal, like the blastocyst signals of other species, modulates the uterine environment prior to implantation.

The plasma membrane transformation does not last: microvilli return to the apical plasma membrane of uterine epithelial cells after the period of uterine receptivity.

Transmission electron microscopy was used to investigate morphological changes in surface ultrastructure of rat uterine luminal epithelial cells and to determine how quickly and to what extent microvilli return to the apical surface after the period of uterine receptivity for blastocyst attachment. Major, observable, differences in the surface morphology of uterine epithelial cells from six groups of pregnant rats were found. On the afternoon of day 6 of pregnancy, the apical surface is typically flattened and consists mostly of irregular projections, but by the morning of day 7, short, irregular microvilli are already evident among the remaining irregular projections giving the cell surface a 'taller' profile. By the afternoon of day 7, the microvilli have increased in height and frequency. This trend continues until by day 9 of pregnancy, the apical surface bears microvilli that are long, thin, and comparatively regularly distributed. These ultrastructural alterations demonstrate that the plasma membrane transformation of early pregnancy which is essential for uterine receptivity for blastocyst attachment, is transient and is followed by the return of regular microvilli.

Lectin - histochemical analysis of glycans defines the period of uterine receptivity in the baboon (Papio anubis).

Lectin - histochemical analysis of glycans defines the period of uterine receptivity in the baboon (Papio anubis).

Structure of the Plasma Membrane of Uterine Epithelial Cells in Blastocyst Attachment: a Review

Changes in the molecular organization of the plasma membrane of uterine epithelial cells during early pregnancy and, in particular, at the attachment period are reviewed. The review focuses on attachment in rodents but other species are also considered. Alterations in protein content and type, as determined with electrophoretic and freeze-fracture techniques, and an increase in tight junction complexity occur in several species. Ultrastructural histochemistry shows that glycocalyx carbohydrates of different species both increase and decrease depending on the type of carbohydrate. Changes in membrane cholesterol content also occur and recent studies showing major reorganization of the actin-containing membrane skeleton are reviewed to show the dynamism of this plasma membrane during the period of uterine receptivity for attachment of the blastocyst.