Reprod. Med., Volume 3, Issue 2 (June 2022) – 9 articles

Human endometrial stromal cells (ESCs) differentiate into decidual cells for embryo implantation during the mid-secretory phase of the menstrual cycle. Decidualization is characterized by enhanced production of insulin-like growth factor-binding protein 1 (IGFBP1) and prolactin (PRL) by ESCs and their morphological transformation into polygonal cells. Progesterone (P4) receptor membrane component 1 (PGRMC1) is a member of a P4-binding complex implicated in function in female reproduction. In this study, we explored the mechanisms that regulate PGRMC1 during decidualization of human ESCs. Immunohistochemical analysis of endometrial samples showed that PGRMC1 was expressed in endometrial glandular and luminal epithelial cells and stromal cells throughout the menstrual cycle; however, the protein level in stroma was reduced in the secretory phase. Incubation of ESCs with dibutyryl (db)-cAMP and P4 in vitro, which induces decidualization, decreased the PGRMC1 protein abundance. Further, treatment with a PGRMC1-targeting siRNA or PGRMC1 inhibitor (AG-205) promoted mRNA expression of the db-cAMP/P4- and db-cAMP-induced decidual markers IGFBP1 and PRL. Moreover, the microRNA miR-98, a potential repressor of PGRMC1, was upregulated during decidualization, and transfection of ESCs with a miR-98 mimic decreased the PGRMC1 protein level. These findings suggest that miR-98-mediated downregulation of endometrial PGRMC1 may promote decidualization for the establishment of pregnancy. Full article

Copy number variations (CNVs) have been implicated in various conditions of differences of sexual development (DSD). Generally, larger genomic aberrations are more often considered disease-causing or clinically relevant, but over time, smaller CNVs have been associated with various forms of DSD. The main objective of this study is to identify small CNVs and the smallest regions of overlap (SROs) in patients with atypical female genitalia (AFG) and build a CNV map of AFG. We queried the DECIPHER database for recurrent duplications and/or deletions detected across the genome of AFG individuals. From these data, we constructed a chromosome map consisting of SROs and investigated such regions for genes that may be associated with the development of atypical female genitalia. Our study identified 180 unique SROs (7.95 kb to 45.34 Mb) distributed among 22 chromosomes. The most SROs were found in chromosomes X, 17, 11, and 22. None were found in chromosome 3. From these SROs, we identified 22 genes as potential candidates. Although none of these genes are currently associated with AFG, a literature review indicated that almost half were potentially involved in the development and/or function of the reproductive system, and only one gene was associated with a disorder that reported an individual patient with ambiguous genitalia. Our data regarding novel SROs requires further functional investigation to determine the role of the identified candidate genes in the development of atypical female genitalia, and this paper should serve as a catalyst for downstream molecular studies that may eventually affect the genetic counseling, diagnosis, and management of these DSD patients. Full article

Our objective is to define a standard protocol for post-partum salpingectomy and provide a prospective assessment of safety and feasibility of such a procedure. Thus, a protocol for performing post-partum salpingectomy in limited-resource environments was created based on contemporary practices for tubal ligation. Gravidae presenting for post-partum tubal ligation following vaginal delivery or at time of cesarean were prospectively approached and, if consent was obtained, enrolled. Outcomes were compared to a historical cohort of gravidae who underwent standard post-partum tubal ligation following vaginal birth or at the time of cesarean as per institutional standard of care. The primary outcome was operative time. One hundred and fifty-seven subjects underwent post-partum salpingectomy following cesarean or vaginal delivery (on post-partum days 0–2). Post-partum salpingectomy performed after vaginal delivery (n = 97) resulted in slightly longer operative times (39.1 ± 11.8 vs. 34.3 ± 13.1 min, p = 0.003) and slightly greater blood loss (21.0 ± 22.0 vs. 13.4 ± 17.3 mL, p = 0.001) than modified Pomeroy tubal ligation (n = 200). Post-partum salpingectomy at cesarean resulted in no difference in estimated blood loss, but slightly longer operative times compared to Parkland tubal ligations (99.5 ± 47.3 vs. 86.5 ± 33.9 min, p = 0.048). Surgical complications for post-partum salpingectomy were similar to controls, regardless of when the procedure was performed. In conclusion, a standardized protocol created for post-partum salpingectomy using suture ligation is feasible and safe. Full article

Fertility preservation is an important concern for young cancer patients. Oocyte or embryo cryopreservation prior to chemotherapy administration is desirable but often difficult for patients with hematopoietic and lymphoid tissue tumors. In this study, we examined the results of fertility preservation therapy in patients with hematopoietic and lymphoid tissue tumors. We retrospectively examined hematopoietic and lymphoid tissue tumors of five patients who underwent oocyte cryopreservation as a fertility preservation therapy after chemotherapy, at Showa University Hospital from February 2017 to September 2020. Eleven treatment cycles were administered (one of which was cancelled). The mean age of the patients was 28.6 years. The mean controlled ovarian stimulation duration for 10 cycles was 15.9 days, the mean total gonadotropin dose was 3705 IU, and the mean peak E2 was 502.8 (pg/mL). The mean number of eggs retrieved was 3.2, the mean number of mature oocytes was 2.1, and the mean maturation rate (mature oocytes/returned oocytes) was 70.7%. Fertility preservation procedures in the early period after chemotherapy may be viable because they allow for the acquisition of mature oocytes, even though the procedures may take longer and yield fewer oocytes. Full article

Despite advances in surgical techniques and chemotherapy, ovarian cancer is still a leading cause of death among gynecological cancers. In addition to the late detection of the disease, the main reason for poor prognosis is resistance to pharmacotherapy, mostly platinum compounds. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time, eventually, 80% of other patients develop chemoresistance, which makes the recurrence of disease incurable. In this review, we describe a difficult clinical hurdle faced in ovarian cancer therapy as a result of platinum resistance, as well as resistance to newer targeted therapy with PARP inhibitors and bevacizumab. We, furthermore, give attention also to the role of the tumor microenvironment as it is less well understood than the tumor cell-intrinsic mechanism. Because a central goal in ovarian cancer research is the development of novel strategies to overcome chemoresistance, treatment for cancer is moving toward personalized therapy. Full article

Poor placentation is closely related with the etiology of preeclampsia and may impact fetal growth restriction. For placental developmental growth, we have demonstrated that dysregulation of autophagy, a key mechanism to maintain cellular homeostasis, in trophoblasts contributes to the pathophysiology of preeclampsia, a severe pregnancy complication, associated with poor placentation. It remains, however, unknown whether autophagy inhibition affects trophoblast syncytialization. This study evaluated the effect of autophagy in an in vitro syncytialization method using BeWo cells and primary human trophoblasts (PHT). In this study, we observed that autophagic activity decreased in PHT and BeWo cells during syncytialization. This decreased activity was accompanied by downregulation of the transcription factor, TFEB. Next, bafilomycin A1, an inhibitor of autophagy via suppressing V-ATPase in lysosomes, inhibited hCG production, CYP11A1 expression (a marker of differentiation), p21 expression (a senescence marker), and cell fusion in BeWo cells and PHT cells. Finally, LLOMe, an agent inducing lysosomal damage, also inhibited syncytialization and led to TFEB downregulation. Taken together, the autophagy-lysosomal machinery plays an important role in cytotrophoblast fusion, resulting in syncytiotrophoblasts. As autophagy inhibition contributed to the failure of differentiation in cytotrophoblasts, this may result in the poor placentation observed in preeclampsia. Full article

Inflammatory mechanisms have a critical role in parturition, which results from a gathering of different stimuli that collectively initiate labour. In fact, a sophisticated interaction occurs between contractile and immuno-inflammatory pathways, whereby proinflammatory amplification is intensified by collaborative connections between cells, ligands, and tissues. Preterm birth (PTB) is one of the major challenges of modern obstetrics and still lacks an efficient treatment. Therefore, the scientific research of modern therapies is warranted. This systematic review aims to provide an overview of recent research into inflammation and PTB. The main inclusion criterion was articles concerning birth and inflammation, and searches were performed in the electronic databases MEDLINE, Embase, Scopus, Web of Science and Cochrane Library, from 2017 to 2021. A literature search from all databases yielded 1989 results which, applying the specified eligibility criteria, resulted in the 16 articles included in this review. Delivery is the consequence of an inequity between maternal inflammation and hormonal-driven uterine quiescence. Studies show that the distinction between term and preterm labour could consist of a pre-existing disproportion of decidual inflammatory signalling, or an unusual stimulus eliciting inflammatory pathways, comparable to both. Thus, controlling inflammation could be hopeful for detaining PTB. Full article

(Background) The transition from in utero to ex utero life is associated with rapid changes in the brain that are both protective and required for newborn functional activities, allowing adaption to the changing environment. The current study aimed to reveal new insights into adaptations required for normal ongoing brain development and function after birth. (Methods) Time-mated dams were randomly allocated to fetal collection at gestational age 68 or spontaneous term delivery followed by neonatal collection within 24 h of birth. Immunohistochemistry was performed to examine mature myelin formation and neuronal nuclei coverage. RT-PCR was used to quantify the mRNA expression of key markers of the oligodendrocyte lineage, neuronal development, and GABAergic/glutamatergic pathway maturation. (Results) Mature myelin was reduced in the subcortical white matter of the neonate, whilst neuronal nuclei coverage was increased in both the hippocampus and the overlying cortical region. Increased mRNA expression in neonates was observed for oligodendrocyte and neuronal markers. There were also widespread mRNA changes across the inhibitory GABAergic and excitatory glutamatergic pathways in neonates. (Conclusions) This study has identified important adaptations in the expression of key neurodevelopmental structures, including oligodendrocytes and neurons, that may be essential for appropriate transition in neurodevelopment to the postnatal period. Full article

Objectives—To conduct a secondary analysis of prediction accuracy of biophysical markers for suspected Preeclampsia (PE), Fetal Growth Restriction (FGR) and the two combined near delivery in a Slovenian cohort. Methods—This was a secondary analysis of a database of a total 125 Slovenian pregnant women attending a high-risk pregnancy clinic due to suspected PE (n = 31), FGR (n = 16) and PE + FGR (n = 42) from 28–39 weeks gestation and their corresponding term (n = 21) and preterm (PTD, n = 15) controls. Data for Mean Arterial blood Pressure (MAP) and Uterine artery pulsatility index (UtA PI) estimated by Doppler sonography were extracted from the database of patients who were tested at admission to the high-risk clinic with the suspected complications. The reactive hyperemia index (RHI), and the Augmentation Index (AIX%) were extracted from the patient database using measured values obtained with the assistance of the Endo PAT, a device set to measure the signal of the peripheral arterial tone (PAT) from the blood vessels endothelium. Linear regression coefficients, Box and Whisker plots, Area under the Curve (AUC) of receiver Operation Characteristic (ROC) curves, and multiple regression were used to assess the marker accuracy using detection rate (DR) and false-positive rate (FPR) and previously reported cut-offs for estimating the positive and negative predictive value (NPV and PPV). The SPSS non-parametric statistics (Kruskal Wallis and Mann–Whitney) and Spearman’s regression coefficient were used to assess marker accuracy; p < 0.05 was considered significant. Results—MAP values reached diagnostic accuracy (AUC = 1.00, DR = 100%) for early PE cases delivered < 34, whereas UtA Doppler PI values yielded such results for early FGR < 34 weeks and the two combined reached such accuracy for PE + FGR. To reach diagnostic accuracy for all cases of the complications, the Endo PAT markers with values for MAP and UtA Doppler PI were required for cases near delivery. Multiple regression analyses showed added value for advanced maternal age and gestational week in risk assessment for all cases of PE, FGR, and PE + FGR. Spearman’s regression coefficient yielded r > 0.6 for UtA Doppler PI over GA for PE and FGR, whereas for RHI over BMI, the regression coefficient was r > 0.5 (p < 0.001 for each). Very high correlations were also found between UtA Doppler PI and sFlt-1/PlGF or PlGF (r = −0.495, p < 0.001), especially in cases of FGR. Conclusion—The classical biophysical markers MAP and UtA Doppler PI provided diagnostic accuracy for PE and FGR < 34 wks gestation. A multiple biophysical marker analysis was required to reach diagnostic accuracy for all cases of these complications. The UtA Doppler PI and maternal serum sFlt-1/PlGF or PlGF were equally accurate for early cases to enable the choice of the markers for the clinical use according to the more accessible method. Full article