BackgroundPreeclampsia is a complex pregnancy disorder characterized by the new onset of hypertension and organ dysfunction, often leading to significant maternal and fetal morbidity and mortality. Placental dysfunction is a hallmark feature of preeclampsia, which is often caused by inappropriate trophoblast cell function in association with oxidative stress, inflammation and/or pathological hypoxia. This study explores the role of oxidative stress in trophoblast cell-based models mimicking the preeclamptic placenta and evaluates potential therapeutic strategies targeting these mechanisms.MethodsUric acid (UA) and malondialdehyde (MDA) concentrations were measured in human plasma from women with preeclampsia (n = 24) or normotensive controls (n = 14) using colorimetric assays. Custom-made first trimester trophoblast cell line, ACH-3P, was exposed to various preeclampsia-like stimuli including hypoxia mimetic (dimethyloxalylglycine or DMOG, 1 mM), inflammation (tumour necrosis factor or TNF-α, 10 ng/mL) or mitochondria dysfunction agent, (Rhodamine-6G or Rho-6G, 1 μg/mL), ± aspirin (0.5 mM), metformin (0.5 mM), AD-01 (100 nM) or resveratrol (15 µM), for 48 h. Following treatments, UA/MDA, proliferation (MTT), wound scratch and cytometric bead, assays, were performed.ResultsOverall, MDA plasma concentration was increased in the preeclampsia group compared to healthy controls (p < 0.001) whereas UA showed a trend towards an increase (p = 0.06); when adjusted for differences in gestational age at blood sampling, MDA remained (p < 0.001) whereas UA became (p = 0.03) significantly correlated with preeclampsia. Our 2D first trimester trophoblast cell-based in vitro model of placental stress as observed in preeclampsia, mimicked the increase in UA concentration following treatment with DMOG (p < 0.0001), TNF-α (p < 0.05) or Rho-6G (p < 0.001) whereas MDA cell concentration increased only in the presence of DMOG (p < 0.0001) or Rho-6G (p < 0.001). Metformin was able to abrogate DMOG- (p < 0.01), Rho-6G- (p < 0.0001) or TNF-α- (p < 0.01) induced increase in UA, or DMOG- (p < 0.0001) or TNF-α- (p < 0.05)induced increase in MDA. AD-01 abrogated UA or MDA increase in the presence of TNF-α (p < 0.001) or Rho-6G (p < 0.001)/DMOG (p < 0.0001), respectively. The preeclampsia-like stimuli also mimicked adverse impact on trophoblast cell proliferation, migration and inflammation, most of which were restored with either aspirin, metformin, resveratrol, or AD-01 (p < 0.05).ConclusionOur 2D in vitro models recapitulate the response of the first trimester trophoblast cells to preeclampsia-like stresses, modelling inappropriate placental development, and demonstrate therapeutic potential of repurposed treatments.

Background and Objectives: Autologous platelet-rich plasma (PRP) transfusions are a relatively new treatment method used in different fields of medicine, including the field of reproductive medicine. One of the applications of these concentrated platelet infusions is the treatment of endometrial receptivity, which is a key factor for embryo implantation. There are implications that PRP infusions can lead to increased endometrial thickness, endometrial receptivity, and significantly elevated clinical pregnancy rates. Our objective is to briefly understand what PRP is and to, through a narrative review, summarize the findings from studies focused on evaluating the benefits of PRP infusions to treat thin endometrium with the goal of achieving better endometrial receptivity. Materials and Methods: Reference data was searched using Medline, PubMed, and EMBASE to identify reports from 2015 to 2024. The combination of search words used was “PRP” and “platelet-rich plasma” with “thin endometrium”, “endometrial receptivity”, “endometrial thickness”, and “endometrial implantation”. Obtained articles were screened, and suited studies (randomized controlled trials, case reports, case series, pilot studies, and reviews) were included in the present review. Reports not available in the English language were eliminated from the current review. Results: The results from most of the reviewed studies showed a positive effect of autologous PRP infusions on increasing endometrial thickness, enhancing endometrial receptivity, and elevating clinical pregnancy rates. The majority of the evaluated findings revealed endometrial thickness > 7 mm (increased endometrial thickness was observed in each evaluated study) following the PRP treatment. More than 50% of the evaluated studies resulted in enhanced endometrial thickness, increased endometrial receptivity, and an elevated pregnancy rate after the PRP application. Conclusions: Autologous PRP infusions for treating endometrium are a relatively new method that has shown promising results. Its major strengths are availability and proper application, which eliminates possible immunological reactions or disease transmission. The main drawbacks are not enough data on safety (i.e., its effect on endometriosis) and the lack of uniformity in the PRP preparation, which would provide optimal standardized quality and quantity of the PRP product and, thus, optimal treatment results.

Intravaginal drug administration offers a notable alternative to traditional oral delivery methods, allowing for precise targeting of effects both locally and systemically. In response to this, there has been a notable increase in the development of advanced in silico techniques for predicting drug permeability. These methods prove to be advantageous by bypassing the lengthy and resource-intensive processes typically associated with in vitro and in vivo experiments. This particular study delved into the creation of in silico models specifically tailored for predicting vaginal permeability. The models were meticulously constructed using SMILES descriptors and local molecular graph invariants, ensuring a conformation-independent QSAR model. Leveraging a Monte Carlo optimization strategy, the models were iteratively refined across three distinct molecular splits for training and testing purposes. For the best developed QSAR model following statistical parameters were obtained for training set r2 = 0.7152, CCC = 0.8340, IIC = 0.7572, q2 = 0.7011, RMSE = 0.0055, MAE = 0.0044 and F = 196; and for test set r2 = 0.8657, CCC = 0.8902, IIC = 0.6180, q2 = 0.8412, Rm2 = 0.6722, RMSE = 0.0040, MAE = 0.0030 and F = 168. These results underscored the exceptional predictive capabilities and robustness of the QSAR models developed in this study. Furthermore, the analysis pinpointed key molecular fragments derived from SMILES descriptors that significantly influence placental permeability. Given the prevalence of SMILES notation in most molecular databases, these well-constructed QSAR models can effectively serve as a rapid and precise screening tool for evaluating vaginal permeability.

This study explores the impact of metformin dosage and hyperprolactinemia on galectin-3 levels in women with Polycystic Ovary Syndrome (PCOS), providing novel insights into their roles in the metabolic and hormonal management of the condition. A cohort of 53 women, diagnosed using the Rotterdam criteria and undergoing in vitro fertilization (IVF) preparation, was analyzed to determine how these factors influence galectin-3, a biomarker in PCOS. Using high-performance liquid chromatography to measure metformin concentrations and ELISA for galectin-3, our results revealed that both metformin dosage and hyperprolactinemia significantly statistically associated with galectin-3 levels, while body mass index (BMI) showed no significant association. These findings challenge prior assumptions and suggest that galectin-3 may be regulated via pathways independent of metformin pharmacokinetics. Notably, the correlation between galectin-3 levels and metformin concentration was either absent or weak after adjusting for the daily dose, indicating that treatment duration and dosage, rather than absolute drug levels, may more critically influence galectin-3. This study offers deeper insights into the role of personalized metformin dosing in managing PCOS, enhancing the understanding of metabolic and hormonal regulation in this condition, and laying the groundwork for future targeted therapies.

Endometriosis and hyperprolactinaemia are conditions that might lead to infertility as a consequence. The aim of this article was to present the current knowledge about possible relationships between prolactin/hyperprolactinaemia and endometriosis-related infertility. Experimental studies on local prolactin acting as cytokine and relationship of prolactin and endometriotic tissue, as well as clinical studies on hyperprolactinaemia and endometriosis-related infertility suggest the possible role of prolactin in endometriosis-related infertility, but final proof is still missing and the exact pathogenesis of infertility in such cases is still under investigation. Novel strategies in the treatment of endometriosis-related infertility, based on its connection with prolactin such as the use of prolactin receptor antibodies and prolactin receptor antagonists, are under investigation, but adequate clinical studies have yet to be undertaken.

Aim To investigate the factors affecting metformin concentrations after chronic administration in patients with polycystic ovary syndrome (PCOS), focusing on the pharmacokinetic variability and its implications for personalized therapy. Methods This study enrolled 53 PCOS patients undergoing long-term metformin treatment at the Clinic for Gynecology and Obstetrics in Ni & scaron;, Serbia, from February to December 2019. Pharmacokinetic parameters were measured from blood samples, and metformin concentrations were determined with validated analytical techniques. Results There was a significant variability in metformin concentrations among PCOS patients, with body mass index (BMI) identified as a major influencing factor. Higher BMI was associated with lower plasma metformin levels, a finding suggesting an altered pharmacokinetic profile in obese patients. Conclusions This study highlights the critical role of BMI in influencing metformin pharmacokinetics in PCOS patients and underscores the need for personalized treatment strategies in patients with PCOS.

Background: Uterine torsion represents a rare condition that may occur during pregnancy or in non-gravid women. This condition is difficult to diagnose, since there are no specific signs besides abdominal pain. Thus, most of the cases are not diagnosed correctly before a surgical procedure and may result in complications and poor outcomes. Methods: We present the first case of uterine torsion of 1080 degrees counterclockwise, with asymptomatic cervical amputation. Results: The intraoperative finding was a uterus that was twisted 1080 degrees around its longitudinal axis, a large fibroid > 15 cm, a large ovarian tumor > 15 cm, and a missing cervix. Upon further inspection, the cervix was found, completely separated from the body of the uterus. After the surgery, the patient remained stable, and her postoperative course was uneventful. She was discharged on the eighth postoperative day. No complications were detected 2 months after the surgery. Conclusions: This specific case is extremely unique, being the only one in searched literature with a 1080° torsion and an amputated cervix. Uterine torsion, especially in postmenopausal women, is a highly rare condition and is difficult to diagnose, with potentially serious outcomes. Any doubts should be assessed as quickly as possible and be dealt with appropriately. If possible, MRI and CT scans could be of great help in differential diagnosis.

Background Preeclampsia is a complex pregnancy disorder characterized by the new onset of hypertension and organ dysfunction, often leading to significant maternal and fetal morbidity and mortality. Oxidative stress has been implicated as a critical factor in preeclampsia pathogenesis, particularly through its detrimental effects on trophoblast cells. This study explores the role of oxidative stress in trophoblast cell-based preeclampsia models and evaluates potential therapeutic strategies that can target these mechanisms. Methods Uric acid (UA) and malondialdehyde (MDA) concentrations were measured in human plasma from women with preeclampsia (n = 24) or normotensive controls (n = 14) using colorimetric assays. Custom-made first trimester trophoblast cell line, ACH-3P, was exposed to various preeclampsia-like stimuli including hypoxia (dimethyloxalylglycine or DMOG, 1mM), inflammation (TNF-α, 10ng/ml) or mitochondria dysfunction agent, Rhodamne-6G (Rho-6G, 1 µg/ml), ± aspirin (0.5mM), metformin (0.5mM), AD-01 (100nM) or resveratrol (15 µM), for 48 h. Following treatments, proliferation assay (MTT), wound scratch assay, cytometric bead assay to measure inflammation and Western blotting to determine FKBPL expression, were performed. UA and MDA concentrations were also measured in cell lysates. Results UA and MDA plasma concentrations were increased in preeclampsia compared to healthy controls using patient samples (UA: p = 0.06; MDA: p < 0.001); when adjusted for differences in gestational age for sample collection, MDA remained (P < 0.001) whereas UA became (p = 0.03) significantly correlated with preeclampsia. Our 2D first trimester trophoblast cell-based in vitro model, mimic the increase in UA concentration following treatment with DMOG (p < 0.0001), TNF-α (p < 0.05) or Rho-6G (p < 0.001) whereas the increase in MDA concentration was only present with DMOG (P < 0.0001) and Rho-6G (p < 0.001). Metformin was able to abrogate Rho-6G- (p < 0.0001) or TNF-α- (p < 0.01) induced increase in UA, or DMOG-induced increase in MDA (p < 0.0001). AD-01 abrogated UA increase with TNF-α (p < 0.001), and MDA increase with Rho-6G (p < 0.001). The preeclampsia-like stimuli also mimicked adverse impact on trophoblast cell proliferation, migration and inflammation, most of which were restored with either aspirin, metformin, resveratrol, or AD-01. Conclusions Our 2D in vitro models of preeclampsia recapitulate aspects of inappropriate placental development in preeclampsia and demonstrate therapeutic potential of repurposed treatments.

PURPOSE:In order to ensure that drug administration is safe during pregnancy, it is crucial to have the possibility to predict the placental permeability of drugs in humans. The experimental method which is most widely used for the said purpose is in vitro human placental perfusion, though the approach is highly expensive and time consuming. Quantitative structure-activity relationship (QSAR) modeling represents a powerful tool for the assessment of the drug placental transfer, and can be successfully employed to be an alternative in in vitro experiments.METHODS:The conformation-independent QSAR models covered in the present study were developed through the use of the SMILES notation descriptors and local molecular graph invariants. What is more, the Monte Carlo optimization method, was used in the test sets and the training sets as the model developer with three independent molecular splits.RESULTS:A range of different statistical parameters was used to validate the developed QSAR model, including the standard error of estimation, mean absolute error, root-mean-square error (RMSE), correlation coefficient, cross-validated correlation coefficient, Fisher ratio, MAE-based metrics and the correlation ideality index. Once the mentioned statistical methods were employed, an excellent predictive potential and robustness of the developed QSAR model was demonstrated. In addition, the molecular fragments, which are derived from the SMILES notation descriptors accounting for the decrease or increase in the investigated activity, were revealed.CONCLUSION:The presented QSAR modeling can be an invaluable tool for the high-throughput screening of the placental permeability of drugs.

Preeclampsia is a pregnancy-specific cardiovascular disorder, involving significant maternal endothelial dysfunction. Although inappropriate placentation due to aberrant angiogenesis, inflammation and shallow trophoblast invasion are the root causes of preeclampsia, pathogenic mechanisms are poorly understood, particularly in early pregnancy. Here, we first confirm the abnormal expression of important vascular and inflammatory proteins, FK506-binding protein-like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissues from women with preeclampsia and normotensive controls. We then employ a three-dimensional microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signaling in inflammatory conditions. In human samples, both circulating ( n = 17 controls; n = 30 preeclampsia) and placental ( n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel endothelial vascular networks. Inflammatory cytokine tumour necrosis factor-α (10 ng/mL) modulates both FKBPL and Gal-3 signaling in conjunction with trophoblast migration and impairs vascular network formation ( p < 0.005). Our placenta-on-a-chip recapitulates aspects of inappropriate placental development and vascular dysfunction in preeclampsia.

The association of cervical pregnancy and gestational trophoblastic disease is extreme rare, but it is obvious that such combination is associated with devastating effects on future fertility. We present a case of the patient with cervical molar pregnancy, who was admitted due to hemorrhagic shock caused by profuse metrorrhagia at 7 th gestational week. Slightly enlarged uterine corpus, with bulky cervix and normal adnexa were found on laparotomy. Total abdominal hysterectomy with the conservation of one ovary was performed. Pathohistological examination confirmed cervical molar pregnancy. In the case of an ectopic, molar or ectopic molar pregnancy, the early visit to gynecologist would give the opportunity to plan the treatment and to preserve the uterus for further pregnancies.

Preeclampsia is still the leading cause of morbidity and mortality in pregnancy without a cure. There are two phenotypes of preeclampsia, early-onset (EOPE) and late-onset (LOPE) with poorly defined pathogenic differences. This study aimed to facilitate better understanding of the mechanisms of pathophysiology of EOPE and LOPE, and identify specific biomarkers or therapeutic targets. In this study, we conducted an untargeted, label-free quantitative proteomic analyses of plasma samples from pregnant women with EOPE (n = 17) and LOPE (n = 11), and age, BMI-matched normotensive controls (n = 18). Targeted proteomics approach was also employed to validate a subset of proteins (n = 17). In total, there were 26 and 20 differentially abundant proteins between EOPE or LOPE, and normotensive controls, respectively. A series of angiogenic and inflammatory proteins, including insulin-like growth factor-binding protein 4 (IGFBP4; EOPE: FDR = 0.0030 and LOPE: FDR = 0.00396) and inter-alpha-trypsin inhibitor heavy chain H2-4 (ITIH2-4), were significantly altered in abundance in both phenotypes. Through validation we confirmed that ITIH2 was perturbed only in LOPE ( p = 0.005) whereas ITIH3 and ITIH4 were perturbed in both phenotypes ( p < 0.05). Overall, lipid metabolism/transport proteins associated with atherosclerosis were highly abundant in LOPE, however, ECM proteins had a more pronounced role in EOPE. The complement cascade and binding and uptake of ligands by scavenger receptors, pathways, were associated with both EOPE and LOPE.

Objectives: Urinary tract anomalies account for approximately one-quarter of all antenatally detected anomalies. The aim of this study was to identify factors associated with severe adverse neonatal outcomes of a prenatally diagnosed urinary tract anomaly. Material and methods: A retrospective-prospective study included 101 pregnant women with prenatally diagnosed fetal urinary tract anomalies presented to the Council for Fetal Anomalies. Prenatal diagnoses were compared with autopsy findings in cases of terminated pregnancy or with clinical and operative findings of the infants. Results: The mortality rate in the group of patients with fetal obstructive uropathy (60 patients) was 10% and in the group of patients with fetal multicystic dysplastic kidney (38 patients) 15.7%. Surgery was performed on 53.4% of the children, whereas more than half of the operations involved resolving associated urinary tract anomalies. Postoperative renal function deterioration occurred in 19% of the children. Conclusions: The prognosis of renal function in obstructive uropathies is excellent if oligoamnios does not develop prenatally and in case of timely provided surgical care is provided postnatally. The finding of the bilateral multicystic dysplastic kidney is associated with poor prognosis. The prognosis in fetal unilateral multicystic dysplastic kidney depends primarily on the condition of the contralateral kidney and the existence of associated anomalies.

Women with endometriosis often need some of the assisted reproductive techniques to conceive.Regarding literature, there is no consensus about the pregnancy outcome in patients with endometriosis who underwent in vitro fertilization.This study was undertaken to give the best direction for infertile patients with this problem regarding in vitro fertilization outcome.This study included 78 patients who underwent surgery for endometriosis.Forty patients were diagnosed with minimal and mild endometriosis (American Society for Reproductive Medicine stage I/II) and 38 patients with moderate and severe endometriosis (stage III/IV).IVF outcome was compared between 3 groups of patients.The first group included patients who had one surgery without endometriosis during IVF procedure, the second group included patients also with one surgery but with recurrent endometriosis during IVF and the third group included patients who had more than one surgery.Number of aspirated oocytes, pregnancy rates and live birth rates after IVF were compared between groups.IVF outcome in patients who had more than one surgery was significantly worse.Patents who had one surgery for endometriosis should be advised to go directly to IVF even if they have recurrent disease.

Hyperprolactinaemia is one of the most frequent causes of anovulation, resulting in infertility and hypoestrogenic state with consequences on overall women’s health. Recent investigations on biological actions of prolactin, especially prolactin of extrapituitary origin, expand our knowledge on prolactin role in the human organism and open new questions connected with female reproductive function and treatment of female infertility. This article represents the review of current knowledge on prolactin physiology, etiopathogenesis, clinical features, assessment , differential diagnosis ,and teatment of hyperprolactinaemia in the female patient.