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Journal of Immunology (Baltimore, Md. :... Oct 2021Infiltration of maternal peripheral leukocytes into the uterine tissues is a critical event occurring before, during, and after term labor (TL). In this article, we...
Infiltration of maternal peripheral leukocytes into the uterine tissues is a critical event occurring before, during, and after term labor (TL). In this article, we investigate the contribution of uterine smooth muscle (myometrium) and pregnant endometrium (decidua) to the inflammatory process during human TL. We hypothesize that labor-related physiological inflammation is orchestrated by uterine-secreted cytokines, which dually activate the uterine vascular endothelium and maternal leukocytes to promote their adhesion and infiltration into the uterus. Using Luminex and ELISA assays, we examine a full range of cytokines (45 proteins) in media conditioned by primary decidual and myometrial cells from TL and term not in labor (TNL) women. The effect of conditioned media on the activation of human uterine microvascular endothelial cells was measured by qPCR and on peripheral leukocytes by flow cytometry. Transendothelial migration of calcein-labeled primary leukocytes toward media was assessed by fluorometry. Stromal decidual cells secrete significantly higher levels of multiple cytokines compared with myometrial cells ( < 0.05) and significantly more cytokines during TL than TNL. These cytokines activate uterine microvascular endothelial cells through the upregulation of cell adhesion molecule VCAM-1 and peripheral leukocytes by upregulation of CD11b. Furthermore, multiple cytokines secreted from the TL decidua and myometrium significantly increase migration of granulocytes, monocytes, and lymphocytes compared with TNL ( < 0.05), which was blocked by a broad-spectrum chemokine inhibitor (FX125L). These data reveal the critical role for decidual- and myometrial-secreted cytokines in the activation of inflammatory pathways leading to labor. We suggest that these pathways represent targets for therapeutic intervention during preterm labor.
Topics: Chemokines; Endothelial Cells; Female; Humans; Inflammation; Labor, Obstetric; Myometrium; Obstetric Labor, Premature; Pregnancy
PubMed: 34526377
DOI: 10.4049/jimmunol.2100493 -
International Journal of Molecular... Feb 2022Recurrent implantation failure (RIF) is a multifactorial condition affecting 10-15% of in vitro fertilization (IVF) couples. Data suggest that functional dysregulation... (Review)
Review
Recurrent implantation failure (RIF) is a multifactorial condition affecting 10-15% of in vitro fertilization (IVF) couples. Data suggest that functional dysregulation of the endometrial immune system constitutes one of the main pathophysiological mechanisms leading to RIF. The aim of this article is to provide a thorough presentation and evaluation of the role of interleukins (ILs) in the pathogenesis of RIF. A comprehensive literature screening was performed summarizing current evidence. During implantation, several classes of ILs are secreted by epithelial and stromal endometrial cells, including IL-6, IL-10, IL-12, IL-15, IL-18, and the leukemia inhibitory factor. These ILs create a perplexing network that orchestrates both proliferation and maturation of uterine natural killer cells, controls the function of regulatory T and B cells inhibiting the secretion of antifetal antibodies, and supports trophoblast invasion and decidua formation. The existing data indicate associations between ILs and RIF. The extensive analysis performed herein concludes that the dysregulation of the ILs network indeed jeopardizes implantation leading to RIF. This review further proposes a mapping of future research on how to move forward from mere associations to robust molecular data that will allow an accurate profiling of ILs in turn enabling evidence-based consultancy and decision making when addressing RIF patients.
Topics: Embryo Implantation; Endometrium; Female; Fertilization in Vitro; Humans; Infertility, Female; Interleukins; Uterus
PubMed: 35216313
DOI: 10.3390/ijms23042198 -
Journal of Molecular Medicine (Berlin,... Oct 2021In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and...
In this study, we show that during normal rat pregnancy, there is a gestational stage-dependent decrease in androgen receptor (AR) abundance in the gravid uterus and that this is correlated with the differential expression of endometrial receptivity and decidualization genes during early and mid-gestation. In contrast, exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) or DHT alone significantly increased AR protein levels in the uterus in association with the aberrant expression of endometrial receptivity and decidualization genes, as well as disrupted implantation. Next, we assessed the functional relevance of the androgen-AR axis in the uterus for reproductive outcomes by treating normal pregnant rats and pregnant rats exposed to DHT and INS with the anti-androgen flutamide. We found that AR blockage using flutamide largely attenuated the DHT and INS-induced maternal endocrine, metabolic, and fertility impairments in pregnant rats in association with suppressed induction of uterine AR protein abundance and androgen-regulated response protein and normalized expression of several endometrial receptivity and decidualization genes. Further, blockade of AR normalized the expression of the mitochondrial biogenesis marker Nrf1 and the mitochondrial functional proteins Complexes I and II, VDAC, and PHB1. However, flutamide treatment did not rescue the compromised mitochondrial structure resulting from co-exposure to DHT and INS. These results demonstrate that functional AR protein is an important factor for gravid uterine function. Impairments in the uterine androgen-AR axis are accompanied by decreased endometrial receptivity, decidualization, and mitochondrial dysfunction, which might contribute to abnormal implantation in pregnant PCOS patients with compromised pregnancy outcomes and subfertility. KEY MESSAGES: The proper regulation of uterine androgen receptor (AR) contributes to a normal pregnancy process, whereas the aberrant regulation of uterine AR might be linked to polycystic ovary syndrome (PCOS)-induced pregnancy-related complications. In the current study, we found that during normal rat pregnancy there is a stage-dependent decrease in AR abundance in the gravid uterus and that this is correlated with the differential expression of the endometrial receptivity and decidualization genes Spp1, Prl, Igfbp1, and Hbegf. Pregnant rats exposed to 5α-dihydrotestosterone (DHT) and insulin (INS) or to DHT alone show elevated uterine AR protein abundance and implantation failure related to the aberrant expression of genes involved in endometrial receptivity and decidualization in early to mid-gestation. Treatment with the anti-androgen flutamide, starting from pre-implantation, effectively prevents DHT + INS-induced defects in endometrial receptivity and decidualization gene expression, restores uterine mitochondrial homeostasis, and increases the pregnancy rate and the numbers of viable fetuses. This study adds to our understanding of the mechanisms underlying poor pregnancy outcomes in PCOS patients and the possible therapeutic use of anti-androgens, including flutamide, after spontaneous conception.
Topics: Androgens; Animals; Decidua; Dihydrotestosterone; Embryo Implantation; Endometrium; Female; Hyperandrogenism; Insulin; Insulin Resistance; Male; Mitochondria; Polycystic Ovary Syndrome; Pregnancy; Rats; Rats, Sprague-Dawley; Receptors, Androgen; Uterus
PubMed: 34180022
DOI: 10.1007/s00109-021-02104-z -
Reproduction & Fertility Nov 2023Approximately 50% of human pregnancies humans fail, most before or during implantation. One factor contributing to pregnancy loss is abnormal glucose metabolism in the...
Approximately 50% of human pregnancies humans fail, most before or during implantation. One factor contributing to pregnancy loss is abnormal glucose metabolism in the endometrium. Glucose contributes to preimplantation embryo development, uterine receptivity, and attachment of the embryo. Across multiple species, the epithelium stores glucose as the macromolecule glycogen at estrus. This reserve is mobilized during the preimplantation period. Glucose from circulation or glycogenolysis can be secreted into the uterine lumen for use by the embryo or metabolized via glycolysis, producing ATP for the cell. The resulting pyruvate could be converted to lactate, another important nutrient for the embryo. Fructose is an important nutrient for early embryos, and the epithelium and placenta can convert glucose to fructose via the polyol pathway. The epithelium also uses glucose to glycosylate proteins, which regulates embryo attachment. In some species, decidualization of the stroma is critical to successful implantation. Formation of the decidua requires increased glucose metabolism via the pentose phosphate pathway and glycolysis. After decidualization, the cells switch to aerobic glycolysis to produce ATP. Paradoxically, the decidua also stores large amounts of glucose as glycogen. Too little glucose or an inability to take up glucose impairs embryo development and decidualization. Conversely, too much glucose inhibits these same processes. This likely contributes to the reduced pregnancy rates associated with conditions like obesity and diabetes. Collectively, precise control of glucose metabolism is important for several endometrial processes required to establish a successful pregnancy. The factors regulating these metabolic processes remain poorly understood.
PubMed: 37934727
DOI: 10.1530/RAF-23-0016 -
F&S Science Aug 2022To present the framework of Stanford Fertility and Reproductive Health's comprehensive reproductive biobanking initiatives and the results of the first year of...
OBJECTIVE
To present the framework of Stanford Fertility and Reproductive Health's comprehensive reproductive biobanking initiatives and the results of the first year of recruitment.
DESIGN
Technical description article.
SETTING
Academic fertility center.
PATIENT(S)
Fertility patients >18 years of age.
INTERVENTION(S)
Enroll the patients interested in research in biobanking protocols.
MAIN OUTCOME MEASURE(S)
Patient recruitment and sample inventory from September 2020 to September 2021.
RESULT(S)
A total of 253 patients have enrolled in the Stanford Fertility and Reproductive Health biobanking initiatives since September 2020. The current inventory consists of 1,176 samples, including serums, plasmas, buffy coats, endometria, maternal deciduae, miscarriage chorionic villi, and human embryos (zygote, cleavage, and blastocyst stages).
CONCLUSION(S)
This biobanking initiative addresses a critical, unmet need in reproductive health research to make it possible for patients to donate excess embryos and gametes and preserves, for future research, valuable somatic and reproductive tissues that would otherwise be discarded. We present the framework of this biobanking initiative in order to support future efforts of establishing similar biorepositories.
Topics: Abortion, Spontaneous; Biological Specimen Banks; Blastocyst; Female; Fertility; Humans; Pregnancy; Zygote
PubMed: 35977803
DOI: 10.1016/j.xfss.2022.01.001 -
Acta Obstetricia Et Gynecologica... Oct 2022The increasing cesarean section rate has led to an increase in the number of subsequent pregnancies resulting in a cesarean scar pregnancy. There appears to be...
INTRODUCTION
The increasing cesarean section rate has led to an increase in the number of subsequent pregnancies resulting in a cesarean scar pregnancy. There appears to be preferential attachment of the blastocyst to the scar site, which may be associated with defective decidua in that region, resulting in abnormal implantation, which can in turn negatively affect the success of the pregnancy. The aim of the current study was to evaluate the extravillous trophoblast, decidua, and myometrium in scar and adjacent non-scar regions of the implantation site of a cesarean scar pregnancy.
MATERIAL AND METHODS
Samples containing a gestational mass were obtained by laparoscopic excision from patients with a cesarean scar pregnancy at 6-11 weeks of gestation as diagnosed by transvaginal or transabdominal ultrasound (n = 8 type II cesarean scar pregnancy). Cesarean scar pregnancy tissues were separated into scar and non-scar regions, and the scar regions were sub-separated into non-implantation and implantation sites. Serial sections were histologically examined after hematoxylin and eosin, Masson's trichrome and immunochemical staining, and changes in the myometrium, extravillous trophoblast, and decidua were evaluated.
RESULTS
In cesarean scar pregnancy, compared with scars not in the implantation site, scars in the implantation site displayed increased fibrosis, and had disrupted myometrium, which was related to varying patterns of E-cadherin expression as a response to extravillous trophoblast invasion. In addition, local decidua was found at the non-scar implantation sites, with multinucleated trophoblast giant cell accumulation and shallow invasion. These features were not evident in the scar implantation sites.
CONCLUSIONS
This study emphasizes that the decidua drives multinucleated trophoblast giant cell differentiation, limiting the degree of invasion. Better characterization of this differentiation process may be helpful for better management and avoidance of the consequences of cesarean scar pregnancy.
Topics: Cadherins; Cesarean Section; Cicatrix; Eosine Yellowish-(YS); Female; Hematoxylin; Humans; Placenta Accreta; Pregnancy; Pregnancy, Ectopic; Trophoblasts
PubMed: 35924378
DOI: 10.1111/aogs.14435 -
International Journal of Molecular... Jun 2023Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled...
Progestin-only long-acting reversible-contraceptive (pLARC)-exposed endometria displays decidualized human endometrial stromal cells (HESCs) and hyperdilated thin-walled fragile microvessels. The combination of fragile microvessels and enhanced tissue factor levels in decidualized HESCs generates excess thrombin, which contributes to abnormal uterine bleeding (AUB) by inducing inflammation, aberrant angiogenesis, and proteolysis. The- zinc finger and BTB domain containing 16 (ZBTB16) has been reported as an essential regulator of decidualization. Microarray studies have demonstrated that levels are induced by medroxyprogesterone acetate (MPA) and etonogestrel (ETO) in cultured HESCs. We hypothesized that pLARC-induced ZBTB16 expression contributes to HESC decidualization, whereas prolonged enhancement of ZBTB16 levels triggers an inflammatory milieu by inducing pro-inflammatory gene expression and tissue-factor-mediated thrombin generation in decidualized HESCs. Thus, ZBTB16 immunostaining was performed in paired endometria from pre- and post-depo-MPA (DMPA)-administrated women and oophorectomized guinea pigs exposed to the vehicle, estradiol (E), MPA, or E + MPA. The effect of progestins including MPA, ETO, and levonorgestrel (LNG) and estradiol + MPA + cyclic-AMP (E + MPA + cAMP) on levels were measured in HESC cultures by qPCR and immunoblotting. The regulation of levels by MPA was evaluated in glucocorticoid-receptor-silenced HESC cultures. was overexpressed in cultured HESCs for 72 h followed by a ± 1 IU/mL thrombin treatment for 6 h. DMPA administration in women and MPA treatment in guinea pigs enhanced ZBTB16 immunostaining in endometrial stromal and glandular epithelial cells. The findings indicated that: (1) ZBTB16 levels were significantly elevated by all progestin treatments; (2) MPA exerted the greatest effect on levels; (3) MPA-induced expression was inhibited in glucocorticoid-receptor-silenced HESCs. Moreover, overexpression in HESCs significantly enhanced prolactin (), insulin-like growth factor binding protein 1 (), and tissue factor () levels. Thrombin-induced interleukin 8 ( and prostaglandin-endoperoxide synthase 2 ( mRNA levels in control-vector-transfected HESCs were further increased by overexpression. In conclusion, these results supported that ZBTB16 is enhanced during decidualization, and long-term induction of ZBTB16 expression by pLARCs contributes to thrombin generation through enhancing tissue factor expression and inflammation by enhancing and levels in decidualized HESCs.
Topics: Female; Humans; Animals; Guinea Pigs; Progestins; Interleukin-8; Thrombin; Contraceptive Agents; Thromboplastin; Glucocorticoids; Cyclooxygenase 2; Endometrium; Estradiol; Inflammation; Stromal Cells; Cells, Cultured; Decidua; Medroxyprogesterone Acetate
PubMed: 37445713
DOI: 10.3390/ijms241310532 -
The Journal of Obstetrics and... Jul 2020Fine-tuning of the endometrium during the evanescent 'window of implantation' relies upon an array of diverse and redundant signaling molecules, particularly the ovarian... (Review)
Review
Fine-tuning of the endometrium during the evanescent 'window of implantation' relies upon an array of diverse and redundant signaling molecules, particularly the ovarian steroids E2 and P4, but also growth factors, eicosanoids, and vitamins including the vitamin A compounds (retinoids). Pregnancy complications such as preeclampsia (PE) can result from aberrations in the production or function of these molecules that arise during this critical period of decidual development. Such aberrations may be reflected by incomplete decidualization, reduced spiral artery modification, and/or loss of immune tolerance to the developing fetus. Our understanding of the role of the active retinoid metabolite all-trans retinoic acid (RA) in maintaining immune balance in certain tissues, along with data describing its role in decidualization, present a compelling argument that aberrant RA signaling in the decidua can play a significant role in the etiology of PE. Recent findings that decidualization and expression of the anti-angiogenic gene product, 'soluble fms-like tyrosine kinase-1' (sFLT1) are negatively correlated and that sFLT1 expression is directly inhibited by RA, provide additional evidence of the critical role of this retinoid in regulating early vascular development in the decidua. This review provides insight into the production and function of RA in the decidua and how modifications in its metabolism and signaling might lead to certain pregnancy disorders such as PE.
Topics: Decidua; Female; Humans; Pre-Eclampsia; Pregnancy; Tretinoin; Vascular Endothelial Growth Factor Receptor-1
PubMed: 32343034
DOI: 10.1111/jog.14262 -
Biomolecules Jan 2022A high number of leucocytes reside in the human endometrium and are distributed differentially during the menstrual cycle and pregnancy. During early pregnancy, decidual... (Review)
Review
A high number of leucocytes reside in the human endometrium and are distributed differentially during the menstrual cycle and pregnancy. During early pregnancy, decidual natural killer (dNK) cells are the most common type of natural killer (NK) cells in the uterus. The increase in the number of uterine NK (uNK) cells during the mid-secretory phase of the menstrual cycle, followed by further increase of dNK cells in early pregnancy, has heightened interest in their involvement during pregnancy. Extensive research has revealed various roles of dNK cells during pregnancy including the formation of new blood vessels, migration of trophoblasts, and immunological tolerance. The present review article is focused on the significance of NK cells during pregnancy and their role in pregnancy-related diseases. The article will provide an in-depth review of cellular and molecular interactions during pregnancy and related disorders, with NK cells playing a pivotal role. Moreover, this study will help researchers to understand the physiology of normal pregnancy and related complications with respect to NK cells, so that future research work can be designed to alleviate the complications.
Topics: Decidua; Female; Humans; Immune Tolerance; Killer Cells, Natural; Pregnancy; Pregnancy Complications; Trophoblasts
PubMed: 35053216
DOI: 10.3390/biom12010068 -
Mitochondrial DNA. Part B, Resources Feb 2021L. and Forsk. belong to the Capparaceae family. The two species are important medicinal plants uses in treatment of various ailments. In this study, we present the...
L. and Forsk. belong to the Capparaceae family. The two species are important medicinal plants uses in treatment of various ailments. In this study, we present the complete chloroplast genomes of the two species. The complete plastome genomes of the two species have a circular structure and a length of 157,728 bp in and 157,573 bp in and GC content of 35.91, 35.96% respectively. The chloroplast genome of and is divided into four regions: LSC of 86,732 and 85,950 bp respectively, SSC from 18,322 to 18,621 bp and a pair of inverted repeats 26,337 and 26,501 bp each. Both of the chloroplast genomes contained 115 different genes, including 80 protein coding genes, 31 tRNA genes and four rRNA genes. A phylogenetic analysis demonstrated that . is sister to . The two species are sister to .
PubMed: 33681464
DOI: 10.1080/23802359.2020.1852902