Impaired bone morphogenetic protein (BMP) signaling pathways disrupt decidualization in endometriosis.

Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor ß (TGFß) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFß signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFß family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals.

Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis.

Endometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that 2 RTKs, macrophage-colony stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration. Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3, and AKT signaling pathways, which control key proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis.

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis.

It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in individuals with endometriosis. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from individuals with or without endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified differences in key pathways between the two groups, including defective bone morphogenetic protein (BMP)/SMAD4 signaling (ID2, ID3, FST), oxidate stress response (NFE2L2, ALOX15, SLC40A1), and retinoic acid signaling pathways (RARRES, RARB, ALDH1B1). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 and H3K27Ac in the decidualized stromal cells from individuals without endometriosis relative to those with endometriosis, with target genes enriched in pathways related to signaling by transforming growth factor ß (TGFß), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation in endometriosis patient-derived assembloids elevated the expression of decidualization markers. In summary, transcriptomic and genome-wide binding analyses of patient-derived endometrial cells and assembloids identified that a functional BMP/SMAD1/5/4 signaling program is crucial for engaging decidualization.

Spontaneous preterm birth as a function of normal cervical length in low-risk women.

OBJECTIVES: To identify if there is an increased risk for spontaneous preterm birth (sPTB) across the continuum of measured, normal cervical lengths (CL) in low-risk women. METHODS: Retrospective cohort study of women with singleton pregnancies and no history of prior sPTB. Women were included if they underwent mid-trimester transvaginal CL measurement between February 2016 and August 2018 and had a measured, normal CL ≥25mm. Women were excluded for progesterone exposure, fetal anomalies, or an unmeasurable CL due to a poorly developed lower uterine segment. The primary study outcome was sPTB <37 weeks. Secondary outcomes included: sPTB <35 weeks, birth gestational age (GA), and the number of hospital evaluations for suspected preterm labor (PTL). Cervical length was considered in interval groups 25-29mm, 30-34mm, 35-39mm, 40-44mm, and ≥45mm. Outcomes were analyzed with χ2 test of trend and as a continuum (linear models, logistic regression and ROC curve), where appropriate. RESULTS: 985 women were included. The incidence of sPTB <37 weeks was 3.7%, with a mean birth GA of 38.7 ± 2.4 weeks. The odds of sPTB <37 weeks decreased with increasing cervical length, considered in 5 mm intervals (odds ratio = 0.67; 95% confidence interval 0.49-0.90) and an increasing birth GA of 1 additional day for each CL increase of 3mm (p = .0002). Conversely, sPTB <35 weeks (p = .49) and mean hospital evaluations for PTL (p = .26) were similar across groups. The ROC curve area-under-the-curve for sPTB <37 weeks of 0.64 showed poor predictive value. CONCLUSIONS: Among women without a history of sPTB, there was an association of decreased risk of sPTB <37 weeks and advanced delivery GA with increasing, but normal-range CL measurements. However, the association was poor and was not associated with spontaneous preterm birth <35 weeks, or the number of hospital evaluations for PTL.

Mid-Trimester Cervical Length Screening: Effect of Poorly Developed Lower Uterine Segment on Pregnancy Outcome.

OBJECTIVES: To identify whether a poorly developed lower uterine segment (PDLUS) observed during cervical length (CL) screening affects the duration of gestation in women with no prior spontaneous preterm birth (sPTB). MATERIALS AND METHODS: A retrospective cohort study of women with a singleton gestation and no prior sPTB, who underwent transvaginal CL screening at our institution. We excluded women with progesterone exposure, major anomalies, and women delivering elsewhere. Women with PDLUS were compared to those with a measured (normal) CL ≥25 mm. PRIMARY OUTCOME: birth gestational age (GA). SECONDARY OUTCOMES: sPTB <35 and 37 weeks, hospital evaluation for preterm labor without delivery, delivery indication, and mode. A Cox proportional-hazards survival model considered time from CL scan to delivery. We powered the study to detect a one-half week difference in birth GA. RESULTS: We included 270 women with PDLUS and 985 women with normal CL. Mean birth GA was 38.9 ± 2.0 weeks with PDLUS versus 38.7 ± 2.4 weeks with normal CL (p = .10). Women with PDLUS were less likely to experience sPTB <37 weeks (1.1% vs 3.6%; p = 0.04). There was no difference in sPTB <35 weeks (0.8% vs 1.7%; p = .25). Hospital evaluation for preterm labor (17% vs 19%; p = .54), delivery indication, and mode were not different. The hazard ratio for earlier birth in women with PDLUS was 0.67 (95% CI 0.46, 0.98; p = .04). CONCLUSIONS: We observed no difference in mean GA at birth; however, PDLUS was protective against sPTB <37 weeks and was associated with a lower hazard ratio for earlier birth.

Vasa previa: a multicenter retrospective cohort study.

OBJECTIVE: The objective of the study was to describe the characteristics and outcomes of patients with antenatal diagnosis of vasa previa and evaluate the predictive factors of resolution in a contemporary large, multicenter data set. STUDY DESIGN: This was a retrospective multicenter cohort study of all antenatally diagnosed cases of vasa previa, identified via ultrasound and electronic medical record, between January 2011 and July 2018 in 5 US centers. Records were abstracted to obtain variables at diagnosis, throughout pregnancy, and outcomes, including maternal and neonatal variables. Data were reported as median [range] or n (percentage). Descriptive statistics, receiver-operating characteristics, and logistic regression analysis were used as appropriate. RESULTS: One hundred thirty-six cases of vasa previa were identified in 5 centers during the study period, 19 (14%) of which resolved spontaneously at median estimated gestational age of 27 weeks [19-34]. All subjects with unresolved vasa previa underwent cesarean delivery at a median estimated gestational age of 34 weeks [27-39] with the median estimated blood loss of 800 mL [250-2000]. Rates for vaginal bleeding, preterm labor, premature rupture of membrane, and need for blood product transfusion were not different between the resolved and unresolved group (P = NS). The odds ratio for resolution in those with the estimated gestational age of less than 24 weeks at the time of diagnosis was 7.9 (95% confidence interval, 2.1-29.4) after adjustment for confounding variables. CONCLUSION: Our data suggest that outcomes in antenatally diagnosed cases of vasa previa are excellent. Furthermore, our data report a higher chance of resolution when the condition is diagnosed before 24 weeks of gestation.

Successful yolk-sac tumor treatment with fertility-sparing partial oophorectomy.

Yolk-sac tumors account for about 20% of ovarian germ cell tumors and occur predominantly in women below 35 years of age. Modern evidence-based treatment strategies have ensured long term post-treatment survival, but with increased survival, attention has been turned to an urgent need for developing fertility sparing treatment strategies. In this report we describe the successful treatment of a young woman who was able to conceive and deliver two children, in spite of the loss of one ovary two years prior to being diagnosed with an ovarian yolk-sac tumor on the remaining ovary.