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PurposeTo determine the utility of the endometrial receptivity analysis (ERA) in women with prior failed embryo transfers (ET).MethodsThis was a retrospective study of patients who underwent an ERA test with a subsequent frozen ET. Women were classified based on their indication for an ERA test: (1) ≥ 1 prior failed ET (cases), or (2) as a prophylactic measure (controls). A subset analysis of women with ≥ 3 prior failed transfers was performed. Pregnancy outcomes of the subsequent cycle were examined, including conception, clinical pregnancy, and ongoing pregnancy/live birth.ResultsA total of 222 women were included, 131 (59%) women with ≥ 1 prior failed ET and 91 (41%) controls. Among the 131 women with ≥ 1 prior failed ET, 20 women (9%) had ≥ 3 prior failed ETs. The proportion of non-receptive ERA tests in the three groups were the following: 45% (≥ 1 prior failed ET), 40% (≥ 3 prior failed ETs), and 52% (controls). The results did not differ between cases and controls. The pregnancy outcomes did not differ between women with ≥ 1 prior failed ET and controls. In women with ≥ 3 prior failed ETs, there was a lower ongoing pregnancy/live birth rate (28% vs 54%, P = 0.046).ConclusionWomen with ≥ 1 prior failed ET and ≥ 3 prior failed ETs had a similar prevalence of non-receptive endometrium compared to controls. Women with ≥ 3 prior failed ETs had a lower ongoing pregnancy/live birth rate despite a personalized FET, suggesting that there are additional factors in implantation failure beyond an adjustment in progesterone exposure.

Abstract Context Ongoing research is needed to determine geo-epidemiologic differences of polycystic ovary syndrome (PCOS). Objective Determine hormonal and metabolic parameters of women with PCOS in 2 environments. Methods Prospective cohort study. Setting Tertiary-care based specialty clinics in Alabama and California. Patients or Other Participants A total of 1610 women with PCOS by National Institutes of Health Criteria from 1987 to 2010. Interventions Interview, physical examination, laboratory studies. Main Outcomes Measures Demographic data, menstrual cycle history, and hormonal and metabolic parameters were collected. Hirsutism was defined as modified Ferriman-Gallwey scores ≥4. Androgen values greater than laboratory reference ranges or >95th percentile of all values were considered elevated (hyperandrogenemia). Metabolic parameters included body mass index (BMI), waist-hip-ratio (WHR), glucose tolerance test, and homeostatic model assessment for insulin resistance (HOMA-IR) scores. Results Alabama women with PCOS were younger with a higher BMI. After adjustment for age and BMI, Alabama women with PCOS were more likely hirsute (adjusted odds ratio [aOR], 1.8; 95% CI, 1.4-2.4; P < 0.001), with elevated HOMA-IR scores (adjusted beta coefficient 3.6; 95% CI, 1.61-5.5; P < 0.001). California women with PCOS were more likely to have hyperandrogenemia (free testosterone aOR, 0.14; 95% CI, 0.11-0.18; P < 0.001; total testosterone aOR, 0.41; 95% CI, 0.33-0.51). Results were similar when stratified by White race. In Black women with PCOS, BMI and WHR did not differ between locations, yet differences in androgen profiles and metabolic dysfunction remained. Conclusion Alabama women with PCOS, regardless of Black or White race, were more likely hirsute with metabolic dysfunction, whereas California women with PCOS were more likely to demonstrate hyperandrogenemia, highlighting potential environmental impacts on PCOS.

The placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal–fetal health. The normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes (SEGs) not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background. Placenta expresses 14,979 polyadenylated genes above sequencing noise (transcripts per million > 0.66), with 10.7% SEGs across gestation. Differentially expressed genes (DEGs) account for 86.7% of genes in the full cohort [false discovery rate (FDR) < 0.05]. Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR < 0.001, fold change > 1.5), there remains 50.1% DEGs (3353 upregulated in first and 4155 upregulated in third trimester). This is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and SEGs may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers for maternal–fetal health. Summary Sentence Comparison of first versus third trimester human placenta mRNA finds a subset of SEGs as well as significant changes in 86.7% of transcripts, highlighting the dynamic nature of placental function across gestation. Graphical Abstract

Polycystic ovary syndrome (PCOS), an endocrine disorder that affects 10% of women worldwide. In 1990, the NIH established the first consensus on diagnostic criteria for PCOS which included chronic anovulation with clinical and/or biochemical hyperandrogenism, after the exclusion of related disorders. Traditionally the assessment of hyperandrogenism included serum studies of total testosterone (TT), free testosterone (FT), and dehydroepiandrosterone sulfate (DHEA-S), and physical exam assessing hirsutism using the modified Ferriman-Gallwey (mFG) score. The most recent 2018 International Guidelines suggest the measurement of DHEA-S can be considered if TT or FT are not elevated, but probably provide limited diagnostic value. We evaluated the diagnostic utility of TT, FT, DHEA-S and hirsutism in a large prospective cohort of PCOS women. Subjects presented to tertiary-care specialty clinics with symptoms of androgen excess in Birmingham, Alabama and Los Angeles, California from 1987-2010. Clinical hyperandrogenism was assessed using the mFG score, and hirsutism was defined as mFG >4. Participants underwent serum studies to assess for hyperandrogenemia and exclude other causes of hyperandrogenism. Fasting blood samples were obtained on cycle days 3 through 8 of a spontaneous or progesterone-induced vaginal bleed for measurement of TT, FT and DHEA-S. Elevated serum androgens were defined as values exceeding the laboratory reference range or greater than the 95th percentile of reported values. Subjects were considered to have oligomenorrhea if they reported >35 day cycles, <10 bleeds per year or reported being eumenorrheic but were confirmed non-ovulatory with a luteal phase progesterone <4 ng/mL. One thousand six hundred and ten women and adolescents (n=1610), aged > 14 years, were diagnosed with PCOS by NIH Criteria and included. Of these 1610 subjects, 39.3% (n=643) were diagnosed with PCOS based upon an elevated TT and FT with oligomenorrhea; 23.9% (n=384) based upon an elevated TT, normal FT and oligomenorrhea; 11.3% (n=182) based upon an elevated FT, normal TT and oligomenorrhea; 1.1% (n=17) based upon oligomenorrhea with normal TT, normal FT and elevated DHEA-S; and 23.9% (n=384) based upon normal serum androgens, oligomenorrhea, and hirsutism (mFG>4). Results suggest that the diagnosis of PCOS is rarely made based upon elevated DHEA-S in the setting of normal TT and FT. Most women had elevated TT and/or FT values, but still a significant proportion (23.9%) of women were diagnosed with PCOS based upon hirsutism in the context of normal serum androgens. Thus, an assessment of hirsutism, which is both timely and inexpensive, is a strong predictor and valuable tool in diagnosing PCOS, reserving DHEAS when better measures of hyperandrogenism are not diagnostic. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

The placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal- fetal health.BackgroundThe placenta, composed of chorionic villi, changes dramatically across gestation. Understanding differences in ongoing pregnancies are essential to identify the role of chorionic villi at specific times in gestation and develop biomarkers and prognostic indicators of maternal- fetal health.The normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background.MethodsThe normative mRNA profile is established using next-generation sequencing of 124 first trimester and 43 third trimester human placentas from ongoing healthy pregnancies. Stably expressed genes not different between trimesters and with low variability are identified. Differential expression analysis of first versus third trimester adjusted for fetal sex is performed, followed by a subanalysis with 23 matched pregnancies to control for subject variability using the same genetic and environmental background.Placenta expresses 14,979 mRNAs above sequencing noise (TPM>0.66), with 1,545 stably expressed genes across gestation. Differentially expressed genes account for 86.7% of genes in the full cohort (FDR<0.05). Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR<0.001, fold change>1.5), there are 6,941 differentially expressed protein coding genes (3,206 upregulated in first and 3,735 upregulated in third trimester).ResultsPlacenta expresses 14,979 mRNAs above sequencing noise (TPM>0.66), with 1,545 stably expressed genes across gestation. Differentially expressed genes account for 86.7% of genes in the full cohort (FDR<0.05). Fold changes highly correlate between the full cohort and subanalysis (Pearson = 0.98). At stricter thresholds (FDR<0.001, fold change>1.5), there are 6,941 differentially expressed protein coding genes (3,206 upregulated in first and 3,735 upregulated in third trimester).This is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and stably expressed genes may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers in maternal-fetal disease.ConclusionThis is the largest mRNA atlas of healthy human placenta across gestation, controlling for genetic and environmental factors, demonstrating substantial changes from first to third trimester in chorionic villi. Specific differences and stably expressed genes may be used to understand the specific role of the chorionic villi throughout gestation and develop first trimester biomarkers of placental health that transpire across gestation, which can be used for future development of biomarkers in maternal-fetal disease.