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International Journal of Molecular... Feb 2024Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of...
Miscarriages affect 50-70% of all conceptions and 15-20% of clinically recognized pregnancies. Recurrent pregnancy loss (RPL, ≥2 miscarriages) affects 1-5% of recognized pregnancies. Nevertheless, our knowledge about the etiologies and pathophysiology of RPL is incomplete, and thus, reliable diagnostic/preventive tools are not yet available. Here, we aimed to define the diagnostic value of three placental proteins for RPL: human chorionic gonadotropin free beta-subunit (free-β-hCG), pregnancy-associated plasma protein-A (PAPP-A), and placental growth factor (PlGF). Blood samples were collected from women with RPL ( = 14) and controls undergoing elective termination of pregnancy ( = 30) at the time of surgery. Maternal serum protein concentrations were measured by BRAHMS KRYPTOR Analyzer. Daily multiple of median (dMoM) values were calculated for gestational age-specific normalization. To obtain classifiers, logistic regression analysis was performed, and ROC curves were calculated. There were differences in changes of maternal serum protein concentrations with advancing healthy gestation. Between 6 and 13 weeks, women with RPL had lower concentrations and dMoMs of free β-hCG, PAPP-A, and PlGF than controls. PAPP-A dMoM had the best discriminative properties (AUC = 0.880). Between 9 and 13 weeks, discriminative properties of all protein dMoMs were excellent (free β-hCG: AUC = 0.975; PAPP-A: AUC = 0.998; PlGF: AUC = 0.924). In conclusion, free-β-hCG and PAPP-A are valuable biomarkers for RPL, especially between 9 and 13 weeks. Their decreased concentrations indicate the deterioration of placental functions, while lower PlGF levels indicate problems with placental angiogenesis after 9 weeks.
Topics: Pregnancy; Female; Humans; Pregnancy-Associated Plasma Protein-A; Placenta Growth Factor; Pregnancy Trimester, First; Placenta; Pregnancy Proteins; Chorionic Gonadotropin, beta Subunit, Human; Biomarkers; Abortion, Habitual; Blood Proteins
PubMed: 38339143
DOI: 10.3390/ijms25031865 -
Biochimica Et Biophysica Acta.... Feb 2024In intrahepatic cholestasis of pregnancy (ICP), there are elevated maternal serum levels of total bile acids, progesterone, and some sulfated metabolites, such as...
BACKGROUND
In intrahepatic cholestasis of pregnancy (ICP), there are elevated maternal serum levels of total bile acids, progesterone, and some sulfated metabolites, such as allopregnanolone sulfate, which inhibits canalicular function.
AIM
To investigate the relationship between cholestasis and the expression of crucial enzymes involved in progesterone metabolism in the liver and placenta.
METHODS
Obstructive cholestasis was induced by bile duct ligation (BDL). RT-qPCR (mRNA) and western blot (protein) were used to determine expression levels. Srd5a1 and Akr1c2 enzymatic activities were assayed by substrate disappearance (progesterone and 5α-dihydroprogesterone, respectively), measured by HPLC-MS/MS.
RESULTS
BDL induced decreased Srd5a1 and Akr1c2 expression and activity in rat liver, whereas both enzymes were up-regulated in rat placenta. Regarding sulfotransferases, Sult2b1 was also moderately up-regulated in the liver. In placenta from ICP patients, SRD5A1 and AKR1C2 expression was elevated, whereas both genes were down-regulated in liver biopsies collected from patients with several liver diseases accompanied by cholestasis. SRD5A1 and AKR1C2 expression was not affected by incubating human hepatoma HepG2 cells with FXR agonists (chenodeoxycholic acid and GW4064). Knocking-out Fxr in mice did not reduce Srd5a1 and Akr1c14 expression, which was similarly down-regulated by BDL.
CONCLUSION
SRD5A1 and AKR1C2 expression was markedly altered by cholestasis. This was enhanced in the placenta but decreased in the liver, which is not mediated by FXR. These results suggest that the excess of progesterone metabolites in the serum of ICP patients can involve both enhanced placental production and decreased hepatic clearance. The latter may also occur in other cholestatic conditions.
Topics: Pregnancy; Humans; Female; Mice; Rats; Animals; Placenta; Progesterone; Tandem Mass Spectrometry; Liver; Cholestasis
PubMed: 37956602
DOI: 10.1016/j.bbadis.2023.166926 -
ESMO Open Aug 2023Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for...
BACKGROUND
Oocytes/embryo cryopreservation and ovarian function suppression with gonadotropin-releasing hormone (GnRH) agonists (GnRHas) are two established strategies for preserving fertility in patients with cancer, frequently both being offered to the same woman. As the first injection of GnRHa should be administered before chemotherapy, it is usually performed in the luteal phase of the urgent controlled ovarian stimulation (COS) cycle. The GnRHa flare-up effect on recently stimulated ovaries may cause ovarian hyperstimulation syndrome (OHSS) and this risk may discourage some oncologists to offer an ovarian function preservation method with proven efficacy. We suggest the long-acting GnRHa as an option to trigger ovulation for egg retrieval in oncological patients, whenever ovarian suppression during chemotherapy is planned.
PATIENTS AND METHODS
We retrospectively analyzed prospectively collected data from all consecutive ovarian stimulation cases in oncological patients for oocyte cryopreservation from 2016 to 2021 in a single academic referral center. The COS was performed according to good clinical practice standards. Since 2020 long-acting GnRHa trigger was offered to all patients for whom ovarian suppression after cryopreservation was planned. All other patients served as controls, stratified for the triggering method used: highly purified chorionic gonadotrophin 10 000 UI or short-acting GnRHa 0.2 mg.
RESULTS
Mature oocytes were collected, with the expected maturation rate, in all the 22 cycles triggered with GnRHa. The mean number of cryopreserved oocytes was 11.1 ± 4, with a maturation rate of 80% (57%-100%), versus 8.8 ± 5.8, 74% (33%-100%) with highly purified chorionic gonadotrophin and 14 ± 8.4, 80% (44%-100%) with short-acting GnRHa. No case of OHSS was observed after long-acting GnRHa triggering and by 5 days after egg retrieval most patients had reached luteinizing hormone levels showing suppression.
CONCLUSIONS
Our preliminary data show that long-acting GnRHa is efficacious in inducing the final oocytes' maturation, reducing OHSS risk and suppressing ovarian function by the start of chemotherapy.
Topics: Female; Humans; Fertility Preservation; Retrospective Studies; Ovarian Hyperstimulation Syndrome; Ovulation Induction; Chorionic Gonadotropin; Gonadotropin-Releasing Hormone
PubMed: 37421801
DOI: 10.1016/j.esmoop.2023.101597 -
Pregnancy Hypertension Dec 2023Human chorionic gonadotropin (hCG), a glycoprotein produced in the placenta, is crucial for a healthy pregnancy. We investigated the relationship between hCG levels and... (Meta-Analysis)
Meta-Analysis Review
Human chorionic gonadotropin (hCG), a glycoprotein produced in the placenta, is crucial for a healthy pregnancy. We investigated the relationship between hCG levels and adverse pregnancy outcomes. We conducted a systematic review including studies measuring hCG blood levels in the first or second trimester, reporting on any of the 12 predefined adverse pregnancy outcomes with logistic regression-adjusted association estimates. The primary outcomes were placenta-associated complications, such as miscarriage, preeclampsia, intrauterine growth restriction, and preterm delivery. We searched PubMed, Embase and CINAHL Complete. The hCG levels were analysed as multiple of the median (MoM). Odds ratio (OR) and 95% confidence interval (CI) were used. Risk of bias and the certainty of evidence were assessed using ROBINS-I and GRADE, respectively. Meta-analysis also showed that hCG levels, reported as MoM ≥2/2.31/2.5, might be associated with an increased risk of preeclampsia (OR 2.08, 95% CI 1.26 to 3.44) and preterm delivery (OR 1.29, 95% CI 1.12 to 1.47), but the evidence is very uncertain. High second trimester hCG levels may be associated with preeclampsia and preterm delivery but confidence in evidence is low.
Topics: Pregnancy; Infant, Newborn; Female; Humans; Premature Birth; Pre-Eclampsia; Pregnancy Outcome; Chorionic Gonadotropin; Abortion, Spontaneous; Pregnancy Trimester, Second
PubMed: 37951184
DOI: 10.1016/j.preghy.2023.11.003 -
International Journal of Medical... 2024Prokineticin 1 (PROK1) is a secreted protein involved in a range of physiological activities such as cell proliferation, migration, angiogenesis, and neuronal cell... (Review)
Review
Prokineticin 1 (PROK1) is a secreted protein involved in a range of physiological activities such as cell proliferation, migration, angiogenesis, and neuronal cell proliferation. Emerging evidences show that PROK1/PROK receptors (PROKRs) are expressed by trophoblasts, and decidual stroma cells at the maternal-fetal interface. PROK1 plays a critical role in successful pregnancy establishment by regulating the decidualization, implantation and placental development. Dysregulation of prokineticin signaling has been described in certain pathological states associated with pregnancy, including pre-eclampsia, recurrent miscarriage and fetal growth restriction. In this review, the expression and pleiotropic roles of PROK1 under physiological and pathological pregnancy conditions are discussed.
Topics: Pregnancy; Female; Humans; Placenta; Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; Signal Transduction; Trophoblasts; Pre-Eclampsia; Gastrointestinal Hormones
PubMed: 38164347
DOI: 10.7150/ijms.76817 -
Journal of Assisted Reproduction and... Mar 2024Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies... (Review)
Review
Since the world's first in vitro fertilization baby was born in 1978, there have been more than 8 million children conceived through assisted reproductive technologies (ART) worldwide, and a significant proportion of them have reached puberty or young adulthood. Many studies have found that ART increases the risk of adverse perinatal outcomes, including preterm birth, low birth weight, small size for gestational age, perinatal mortality, and congenital anomalies. However, data regarding the long-term outcomes of ART offspring are limited. According to the developmental origins of health and disease theory, adverse environments during early life stages may induce adaptive changes and subsequently result in an increased risk of diseases in later life. Increasing evidence also suggests that ART offspring are predisposed to an increased risk of non-communicable diseases, such as malignancies, asthma, obesity, metabolic syndrome, diabetes, cardiovascular diseases, and neurodevelopmental and psychiatric disorders. In this review, we summarize the risks for long-term health in ART offspring, discuss the underlying mechanisms, including underlying parental infertility, epigenetic alterations, non-physiological hormone levels, and placental dysfunction, and propose potential strategies to optimize the management of ART and health care of parents and children to eliminate the associated risks. Further ongoing follow-up and research are warranted to determine the effects of ART on the long-term health of ART offspring in later life.
Topics: Child; Pregnancy; Infant, Newborn; Female; Humans; Middle Aged; Young Adult; Adult; Pregnancy Outcome; Premature Birth; Pregnancy, Multiple; Placenta; Reproductive Techniques, Assisted
PubMed: 38146031
DOI: 10.1007/s10815-023-02988-5 -
American Journal of Obstetrics and... May 2024Gestational diabetes mellitus affects up to 10% of pregnancies and is classified into subtypes gestational diabetes subtype A1 (GDMA1) (managed by lifestyle...
BACKGROUND
Gestational diabetes mellitus affects up to 10% of pregnancies and is classified into subtypes gestational diabetes subtype A1 (GDMA1) (managed by lifestyle modifications) and gestational diabetes subtype A2 (GDMA2) (requiring medication). However, whether these subtypes are distinct clinical entities or more reflective of an extended spectrum of normal pregnancy endocrine physiology remains unclear.
OBJECTIVE
Integrated bulk RNA-sequencing (RNA-seq), single-cell RNA-sequencing (scRNA-seq), and spatial transcriptomics harbors the potential to reveal disease gene signatures in subsets of cells and tissue microenvironments. We aimed to combine these high-resolution technologies with rigorous classification of diabetes subtypes in pregnancy. We hypothesized that differences between preexisting type 2 and gestational diabetes subtypes would be associated with altered gene expression profiles in specific placental cell populations.
STUDY DESIGN
In a large case-cohort design, we compared validated cases of GDMA1, GDMA2, and type 2 diabetes mellitus (T2DM) to healthy controls by bulk RNA-seq (n=54). Quantitative analyses with reverse transcription and quantitative PCR of presumptive genes of significant interest were undertaken in an independent and nonoverlapping validation cohort of similarly well-characterized cases and controls (n=122). Additional integrated analyses of term placental single-cell, single-nuclei, and spatial transcriptomics data enabled us to determine the cellular subpopulations and niches that aligned with the GDMA1, GDMA2, and T2DM gene expression signatures at higher resolution and with greater confidence.
RESULTS
Dimensional reduction of the bulk RNA-seq data revealed that the most common source of placental gene expression variation was the diabetic disease subtype. Relative to controls, we found 2052 unique and significantly differentially expressed genes (-2
2 thresholds; q<0.05 Wald Test) among GDMA1 placental specimens, 267 among GDMA2, and 1520 among T2DM. Several candidate marker genes (chorionic somatomammotropin hormone 1 [CSH1], period circadian regulator 1 [PER1], phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [PIK3CB], forkhead box O1 [FOXO1], epidermal growth factor receptor [EGFR], interleukin 2 receptor subunit beta [IL2RB], superoxide dismutase 3 [SOD3], dedicator of cytokinesis 5 [DOCK5], suppressor of glucose, and autophagy associated 1 [SOGA1]) were validated in an independent and nonoverlapping validation cohort (q<0.05 Tukey). Functional enrichment revealed the pathways and genes most impacted for each diabetes subtype, and the degree of proximal similarity to other subclassifications. Surprisingly, GDMA1 and T2DM placental signatures were more alike by virtue of increased expression of chromatin remodeling and epigenetic regulation genes, while albumin was the top marker for GDMA2 with increased expression of placental genes in the wound healing pathway. Assessment of these gene signatures in single-cell, single-nuclei, and spatial transcriptomics data revealed high specificity and variability by placental cell and microarchitecture types. For example, at the cellular and spatial (eg, microarchitectural) levels, distinguishing features were observed in extravillous trophoblasts (GDMA1) and macrophages (GDMA2). Lastly, we utilized these data to train and evaluate 4 machine learning models to estimate our confidence in predicting the control or diabetes status of placental transcriptome specimens with no available clinical metadata. CONCLUSION
Consistent with the distinct association of perinatal outcome risk, placentae from GDMA1, GDMA2, and T2DM-affected pregnancies harbor unique gene signatures that can be further distinguished by altered placental cellular subtypes and microarchitectural niches.
PubMed: 38763341
DOI: 10.1016/j.ajog.2024.05.014 -
Veterinary Research Communications Sep 2023The adherens junctions (AJs) maintain the epithelial cell layers' structural integrity and barrier function. AJs also play a vital role in various biological and...
The adherens junctions (AJs) maintain the epithelial cell layers' structural integrity and barrier function. AJs also play a vital role in various biological and pathological processes. AJs perform these functions through the cadherin-catenin adhesion complex. This study investigated the presence, cell-specific localization, and temporal distribution of AJ components such as classical type I cadherins and beta-catenin in the cow cervix and vagina during the estrous cycle. Immunohistochemistry and Western blot analysis results demonstrated that beta-catenin and epithelial (E)-, neural (N)-, and placental (P)-cadherins are expressed in the cow cervix and vagina during the estrous cycle. These adhesion molecules were localized in the membrane and cytoplasm of the ciliated and non-ciliated cervical cells and the stratified vaginal epithelial cells. Positive immunostaining for P-, N-cadherin, and beta-catenin was also observed in the vascular endothelial cells of the cervical and vaginal stroma. Quantitative immunohistochemistry examinations revealed that in the cervical and vaginal epithelia, P-cadherin's optical density values (ODv) were the highest; in contrast, the N-cadherin ODv were the lowest. The ODv of P-cadherin and beta-catenin in the cervical epithelium and E-cadherin in the vagina were significantly higher in the luteal phase versus the follicular phase of the estrous cycle. Furthermore, the ODv of P-cadherin, N-cadherin, and beta-catenin in the cervix's central and peripheral epithelial regions were different during the estrous cycle. These findings indicate that classical cadherins and beta-catenin in the cervix and vagina exhibit cell- and tissue-specific expression patterns under the influence of estrogen and progesterone hormones during the estrous cycle.
Topics: Animals; Cattle; Female; Pregnancy; beta Catenin; Cadherins; Cervix Uteri; Endothelial Cells; Placenta; Vagina
PubMed: 36729278
DOI: 10.1007/s11259-023-10075-4 -
Cureus Sep 2023Cancer, the second leading cause of mortality worldwide, has been the subject of extensive and quickly changing scientific study and practice. Cancer remains a mystery... (Review)
Review
Cancer, the second leading cause of mortality worldwide, has been the subject of extensive and quickly changing scientific study and practice. Cancer remains a mystery despite the enormous effort put into understanding the genesis of cancerous cells, the development of malignant tissues, and the process by which they propagate and recur. Cells from humans that have been recruited by cancer and, to some extent, changed into pathogenic organisms or the foundation of tumors serve as agents of destruction. Understanding cancers leads to challenging philosophical issues since they undermine and use multicellular organization processes. Cancer metastasizing cells adopt new phenotypes while discarding previous behaviors. The absence of comprehensive knowledge of this has hampered the development of therapeutics for metastatic illness. For systems-level experimental and computational metastasis modeling, integrating these complex and interconnected features continues to be a problem because metastasis has typically been studied in separate physiological compartments. Lung, breast, and prostate cancers accounted for the bulk of the 18 million new cases of cancer that were diagnosed in 2018. The most frequent cancer in women is breast cancer. Animal experimentation plays a significant role in primary and translational breast cancer research. In theory, such breast cancer models should be comparable to breast cancer in humans in terms of tumor etiology, biological behavior, pathology, and treatment response.
PubMed: 37900385
DOI: 10.7759/cureus.45956 -
Biomolecules Nov 2023Pregnancy and lactation are critical periods for human well-being and are sensitive windows for pollutant exposure. Bisphenol A (BPA) is well demonstrated as a toxicant... (Review)
Review
Pregnancy and lactation are critical periods for human well-being and are sensitive windows for pollutant exposure. Bisphenol A (BPA) is well demonstrated as a toxicant and has been replaced in the plastic industry with other bisphenol analogs that share similarities in structure and characteristics, most commonly Bisphenol S (BPS) and Bisphenol F (BPF). Maternal exposure to BPS or BPF can result in their accumulation in the fetal compartment, leading to chronic exposure and potentially limiting normal fetal growth and development. This review summarizes considerable findings of epidemiological or experimental studies reporting associations between BPS or BPF and impaired fetal growth and development. Briefly, the available findings indicate that exposure to the two bisphenol analogs during pregnancy and lactation can result in multiple disturbances in the offspring, including fetal growth restrictions, neurological dysfunctions, and metabolic disorders with the potential to persist throughout childhood. The occurrence of premature births may also be attributed to exposure to the two bisphenols. The possible mechanisms of actions by which the two bisphenols can induce such effects can be attributed to a complex of interactions between the physiological mechanisms, including impaired placental functioning and development, dysregulation of gene expression, altered hormonal balance, and disturbances in immune responses as well as induced inflammations and oxidative stress. In conclusion, the available evidence suggests that BPS and BPF have a toxic potential in a compartment level to BPA. Future research is needed to provide more intensive information; long-term studies and epidemiological research, including a wide scale of populations with different settings, are recommended. Public awareness regarding the safety of BPA-free products should also be enhanced, with particular emphasis on educating individuals responsible for the well-being of children.
Topics: Child; Humans; Pregnancy; Female; Prenatal Exposure Delayed Effects; Placenta; Phenols; Benzhydryl Compounds; Vitamins
PubMed: 38002298
DOI: 10.3390/biom13111616