Endometrial biopsy-induced gene modulation: first evidence for the expression of bladder-transmembranal uroplakin Ib in human endometrium
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Abstract This summary of the findings of investigations of the changing transcriptional profile of human endometrium during the menstrual cycle shows that it is possible to classify the menstrual cycle based on the global gene expression profile, and identifies groups of known and novel genes that may be associated with different biological processes that occur in the endometrium such as implantation and menstruation.
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Summary Paired endometrial biopsy samples were taken from 530 subfertile mares, before and after treatment (where indicated) and a period of sexual rest. Prognoses were made after each biopsy (Categories 1A‐4A before treatment and Categories 1B‐4B after treatment), using histopathological criteria similar to those described by Kenney and Doig (1986). Eighty‐seven per cent of the mares were assigned to first biopsy prognosis Category 3A. The second biopsy prognosis produced a more even population distribution (10, 47, 40 and 3 per cent respectively for Category 1B, 2B, 3B and 4B mares). First biopsy Category 3A and 4A mares produced mean foaling rates of 51 and 40 per cent respectively. None of the 14 second biopsy Category 4B mares delivered a live foal (12 were barren, one aborted and one suffered early foetal death). This study supports the hypothesis that a breeding prognosis assigned on the basis of two endometrial biopsy samples, taken before and after specific uterine treatment, where indicated, which takes into consideration the mare's ability to respond to treatment, is likely to be more accurate than one assigned after a single biopsy sample.
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Abstract Study question Are dysregulated levels of immunomodulators (CXCL14, IL-15, and TIMP3) associated with aberrant decidual responses in the human endometrium? Summary answer Low transcript levels of CXCL14, IL-15, and TIMP-3 were associated with uterine natural killer (uNK) cell deficiency and pro-senescent response in the endometrium. What is known already In the mid-luteal phase, the endometrium becomes receptive to embryo implantation, while simultaneously poised for menstruation. Both events require decidualization, the differentiation of endometrial stromal cells into two cell subpopulations: progesterone-dependent decidual cells (DC) and progesterone-independent senescent decidual cells (snDC). Homeostatic balance between DC and snDC dictates endometrial fate. In non-conception cycles, snDC predominate as progesterone levels fall leading to menstruation. In conception cycles, endometrial transformation requires recruitment and activation of uNK cells, orchestrated by DC release of potent immunomodulators, CXCL14, IL-15, and TIMP3. This activation enables uNK cells to eliminate snDC, transforming the endometrium into the decidua of pregnancy. Study design, size, duration Endometrial biopsies (n = 730) were obtained from women attending the Implantation clinic at University Hospitals Coventry and Warwickshire (UHCW) NHS Trust. Collection was timed across the peri-implantation window based on the pre-ovulatory LH surge (LH + 6-11 days). Each biopsy was appropriately processed for immunohistochemistry and RT-qPCR analysis. Participants/materials, setting, methods Transcript levels of immunomodulators (CXCL14, IL-15, and TIMP3) were quantified in whole tissue by RT-qPCR, and uNK cells by immunohistochemical staining of CD56+. Due to changing expression levels across the luteal phase, results were normalized to the day of cycle using percentile charts. Expression levels of immunomodulators and uNK cells were compared to the expression of biomarkers of DC and snDC populations (SCARA5 and DIO2 respectively). Main results and the role of chance To understand the relationship between immunomodulators and decidual cell homeostasis, patient samples were separated into distinct categories of putative endometrial defects on the basis of DC and snDC biomarker expression. These included those with pro-decidual response (n = 61), pro-senescent response (n = 100), uNK cell deficiency (n = 42), and opposingly, uNK cell excess (n = 54). Expression of all tested immunomodulators (CXCL14, IL-15, and TIMP3) was significantly reduced in samples with a pro-senescent response (high DIO2, low SCARA5), compared to those displaying a pro-decidual response (high SCARA5, low DIO2; P < 0.0001; Kruskal-Wallis test). Additionally, patients with high numbers of uNK cells had a ∼2-fold-increase in CXCL14 (P = 0.0023), and IL-15 (P = 0.0052), and a 3-fold increase in TIMP3 (P < 0.0001) expression, compared to those with uNK cell deficiency. The data suggests that abnormal levels of these immunomodulators may dysregulate uNK cell activity and disrupt endometrial homeostasis, ultimately leading to miscarriage. Limitations, reasons for caution In this study, we showed the relationship between immunomodulators and decidual subpopulations. At present, it is not clear whether dysregulated levels of immunomodulators cause endometrial dyshomeostasis or are a result of the impaired decidual response. Further investigation is required to explore the “chicken-or-egg” dilemma. Wider implications of the findings Analysing these immunomodulators in a large number of samples provides a deeper understanding of the homeostatic relationship between uNK cells, DC, and snDC during the implantation window. This may be an invaluable diagnostic tool to identify women at risk of miscarriage, and in monitoring the effectiveness of pre-pregnancy interventions. Trial registration number N/A
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Sampling the endometrium. The anatomy and histology of the endometrium. The normal endometrium as seen in biopsy material. Functional disorders of the endometrium. The effect of therapeutic and contraceptive hormones on the endometrium. Endometrial changes associated with intrauterine contraceptive devices. Inflammation of the endometrium. Miscellaneous benign conditions of the endometrium. Endometrial hyperplasias and intra-endometrial adenocarcinoma. Carcinoma of the endometrium (endometrial Mullerian epithelial tumours). Non-epithelial and mixed endometrial tumours of Mullerian origin. Non-Mullerian endometrial neoplasms. The endometrium in normal and abnormal pregnancy. Gestational trophoblastic disease. Endometrial biopsy in specific circumstances.
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To determine whether serum levels of placental protein 14, a major product of the progesterone-induced secretory endometrium, accurately reflect histologic maturation of the endometrium.Daily serum levels of placental protein 14 were compared in 50 normally cycling women with normal or delayed endometrial maturation, as assessed by histologic dating of an endometrial biopsy in the midluteal phase of the same cycle. Ten of these subjects had placental protein 14 measurements but no biopsy in an additional cycle to examine the potential effects of the biopsy on secretion of this protein.Serum placental protein 14 concentrations started to increase 8 days after the LH surge and peaked at similar levels on the first day of the next menses in biopsy and non-biopsy cycles. The biopsy cycles had a shorter luteal phase but a slightly faster increase in placental protein 14 concentrations. Both the integrated secretion of this protein and single measurements on the day of the biopsy or at the onset of the next menses overlapped substantially in women with different degrees of endometrial development, even when differentiation of the endometrium was severely delayed.Serum measurements of placental protein 14 do not accurately predict, and thus should not replace, histologic evaluation of the endometrium at nidation.
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We previously demonstrated that the human endometrium synthesizes and secretes a specific protein designated “Progestagen-associated Endometrial Protein” or PEP. This work was undertaken to determine luteal phase levels of PEP in serum of cycling women with histologic evidence ofadequate endometrium (endometrium in phase) or inadequate endometrium (endometrium out of phase by 3-4 days). The results provide a normative curve with 95% confidence limits for serum PEP concentrations vs normalized cycle day in women with adequate endometrium (judged by histologic endometrial dating), and indicate that the PEP concentration increases exponentially after day 22, with a mean doubling time of 2.9511.60 (mean±SD) days (based on serial data from 13 women). More importantly, the proportion of serum PEP values falling outside of the 95% confidence limits was significantly greater (p<0.001) in women with inadequate endometrium (83%) than in women with adequate endometrium (16%). Therefore, determination of PEP in serum, rather than the more invasive endometrial biopsy examination, may serve as a method of choice for evaluating endometrial adequacy in infertile women.
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