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Maternal and fetal pregnancy outcomes related to placental function vary based on fetal sex, which may be due to sexually dimorphic epigenetic regulation of RNA expression. We identified sexually dimorphic miRNA expression throughout gestation in human placentae. Next-generation sequencing identified miRNA expression profiles in first and third trimester uncomplicated pregnancies using tissue obtained at chorionic villous sampling (n = 113) and parturition (n = 47). Sequencing analysis identified 986 expressed mature miRNAs from female and male placentae at first and third trimester (baseMean>10). Of these, 11 sexually dimorphic (FDR < 0.05) miRNAs were identified in the first and 4 in the third trimester, all upregulated in females, including miR-361-5p, significant in both trimesters. Sex-specific analyses across gestation identified 677 differentially expressed (DE) miRNAs at FDR < 0.05 and baseMean>10, with 508 DE miRNAs in common between female-specific and male-specific analysis (269 upregulated in first trimester, 239 upregulated in third trimester). Of those, miR-4483 had the highest fold changes across gestation. There were 62.5% more female exclusive differences with fold change>2 across gestation than male exclusive (52 miRNAs vs 32 miRNAs), indicating miRNA expression across human gestation is sexually dimorphic. Pathway enrichment analysis identified significant pathways that were differentially regulated in first and third trimester as well as across gestation. This work provides the normative sex dimorphic miRNA atlas in first and third trimester, as well as the sex-independent and sex-specific placenta miRNA atlas across gestation, which may be used to identify biomarkers of placental function and direct functional studies investigating placental sex differences. Summary sentence Sex dimorphism in miRNA expression is more pronounced in first compared to third trimester placenta, and there are 62.5% more female exclusive gestational differences, indicating miRNA abundance across human gestation is also sexually dimorphic.

Abstract Context Infertility affects 10% of the reproductive-age population. Even the most successful treatments such as assisted reproductive technologies still result in failed implantation. In addition, adverse pregnancy outcomes associated with infertility have been attributed to these fertility treatments owing to the presumed epigenetic modifications of in vitro fertilization and in vitro embryo development. However, the diagnosis of infertility has been associated with adverse outcomes, and the etiologies leading to infertility have been associated with adverse pregnancy and long-term outcomes. Evidence Acquisition We have comprehensively summarized the data available through observational, experimental, cohort, and randomized studies to better define the effect of the underlying infertility diagnosis vs the epigenetics of infertility treatments on treatment success and overall outcomes. Evidence Synthesis Most female infertility results from polycystic ovary syndrome, endometriosis, and unexplained infertility, with some cases resulting from a polycystic ovary syndrome phenotype or underlying endometriosis. In addition to failed implantation, defective implantation can lead to problems with placentation that leads to adverse pregnancy outcomes, affecting both mother and fetus. Conclusion Current research, although limited, has suggested that genetics and epigenetics of infertility diagnosis affects disease and overall outcomes. In addition, other fertility treatments, which also lead to adverse outcomes, are aiding in the identification of factors, including the supraphysiologic hormonal environment, that might affect the overall success and healthy outcomes for mother and child. Further studies, including genome-wide association studies, epigenomics studies, and experimental studies, are needed to better identify the factors leading to these outcomes. Genetics and epigenetics of infertility etiologies and epigenetics of fertility treatment affect implantation and placentation, which affect short- and long-term maternal and fetal/childhood outcomes.

Abstract Context Epidemiologic studies of polycystic ovary syndrome (PCOS) are limited, especially in populations where diagnostic resources are less available. In these settings, an accurate, low-cost screening tool would be invaluable. Objective To test the use of a simple questionnaire to identify women at increased risk for PCOS and androgen excess (AE) disorders. Study Design Prospective cohort study from 2006–2010. Setting Community-based. Participants Women aged 14 to 45 years. Intervention A screening telephone questionnaire consisting of 3 questions was tested, where participants were asked to self-assess the presence/absence of male-like hair and menstrual irregularity. Participants were then invited to undergo a direct examination, including completing a medical history and undergoing a modified Ferriman-Gallwey (mFG) hirsutism score, ovarian ultrasound, and measurement of circulating total and free testosterone, DHEAS, TSH, prolactin and 17-hydroxyprogesterone levels. Main Outcome Measure Accuracy of questionnaire in predicting PCOS, AE, and irregular menses. Results Participants with self-assessed irregular menses and/or excess hair were labeled “Possible Androgen Excess (Poss-AE)” and those self-assessed with regular menses and no excess hair were labeled “Probable Non-Androgen Excess (Non-AE).” The study was completed in 206/298 (69%) of the Poss-AE and in 139/192 (73%) of the Non-AE. Of Poss-AE and Non-AE subjects, 82.5% and 15.8%, respextively, presented with PCOS. The calculated sensitivity, specificity, positive predictive value, and negative predictive value of the 3-question telephone survey to predict PCOS was 89%, 78%, 85%, and 83%, respectively. Conclusions A simple telephone questionnaire, based on self-assessment of body hair and menstrual status, can be used with a high predictive value to identify women at risk for AE disorders, including PCOS, and to detect healthy controls. This approach could be an important tool for needed epidemiologic studies.

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.

Most recent guidelines classify a modified FerrimanGallwey score of 4 or greater as hirsute.3 Biochemical hyperandrogenism can be identified with elevated levels of serum-free or total testosterone or dehydroepiandrosterone sulfate.1 Ovulatory dysfunction often presents as amenorrhea, irregular (missed or delayed) menstrual cycles, or infertility.1,4,5 In a woman or adolescent more than 3 years from menarche, irregular menstrual cycles are defined as cycles lasting less than 21 days or greater than 35 days, less than 8 total cycles per year, or greater than 90 days for any 1 cycle.1 PCOM is defined as the presence of greater than or equal to 20 antral follicles per ovary (previously 12) or a volume greater than or equal to 10 mL p er ovary, according to the most recent international guidelines (Figure 2).1,3,5 Women with PCOS are also at risk for long-term health sequelae, including infertility, insulin resistance, obesity, cardiovascular disease, metabolic syndrome, obstructive sleep apnea, and mood disorders. A genetic basis for PCOS was initially suggested by twin studies.14 More recently, genome-wide association studies have identified 19 specific loci associated with PCOS, the majority of which are shared among women of different races.15 However, these 19 genetic loci account for less than 10% of PCOS hereditability, suggesting the role of environmental factors.15 The impact of the environment on PCOS in a genetically predisposed individual may begin as early as in utero and continues throughout an individual's lifetime, with environmental influences including geography, nutrition, socioeconomic status, and toxin exposures.16 Although there is not one specific \"PCOS diet\" for patients, research has shown that starch, whey, and dairy products have negative effects on metabolic function in women with PCOS and that fruits and beans (foods rich in inositol) have a positive effect.16 In addition, women with PCOS and a vitamin D deficiency are at increased risk of dysglycemia.17 The impact of socioeconomic status on PCOS was examined in one 2011 study, which found that women with a high education level whose parents had a low education level (defined as less than high school) were at the highest risk of developing PCOS, after adjustment for age, body mass index (BMI), and race (adjusted odds ratio, 2.5; 95% CI, 1.4-4.4).18 There is also a negative association between endocrine-disrupting chemicals and PCOS. Insulin resistance (IR) is one of the most notable risks associated with PCOS, with a recent meta-analysis finding an odds ratio of 3.26 (95% CI 2.17-4.90) compared with the general population.28 In women with PCOS, IR has been associated with a higher prevalence of earlieronset glucose intolerance (30%-40%) and type 2 diabetes (10%), and this risk is independent of, yet exacerbated by, the presence of obesity.29 Patients with PCOS should have IR screening at time of PCOS diagnosis and every 1 to 3 years thereafter.3,5,29 An oral glucose tolerance test (OGTT), fasting plasma glucose, or hemoglobin A can be used to assess glycemic status, but an OGTT is recommended in high-risk women (ie, BMI > 25 kg/m2 or > 23 kg/m2 in Asian women).3 In patients who desire pregnancy, the 75-g OGTT should be offered preconception, and if a woman is already pregnant, the test should be completed before 20 weeks' gestation due to the elevated risk of gestational diabetes.3 Obesity is highly associated with PCOS and intensifies features of PCOS, such as infertility and IR. OSA rates have been found to be 5- to 10-fold higher in patients who are obese and have PCOS.30 OSA increases the risk of a woman with PCOS developing cardiovascular disease (CVD).30 Dyslipidemia is another key adverse effect of PCOS, with prevalence of up to 70%.31 The Androgen Excess Society recommends that all patients with PCOS get a complete fasting lipid panel as a screening tool.32,33 PCOS, in women with obesity and without, is associated with elevated levels of total cholesterol and low-density lipoprotein, placing patients at risk for metabolic syndrome as well as CVD.32-35 The association between PCOS and CVD is inconclusive, but research has shown a correlation between exposure over time to worsening disease in this population.36,37 It has been demonstrated that increased coronary artery and aortic calcification exists in patients with PCOS that worsens with age,37 leading to premature atherosclerosis or subclinical vascular disease.38,39 Recommended screening guidelines for CVD in women with PCOS include a measurement of weight and BMI every 6 to 12 months and a measurement of blood pressure at least once per year.3 Women with PCOS should be considered at risk of CVD if they have any additional risk factors (obesity, use of tobacco, dyslipidemia, hypertension, impaired glucose tolerance, or lack of physical activity).3 Endometrial hyperplasia is another sequela of PCOS and a risk factor for the development of endometrial carcinoma.

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

Hand grip strength (GS) is a predictor of mortality in older adults and is moderately to highly heritable, but no genetic variants have been consistently identified. We aimed to identify single nucleotide polymorphisms (SNPs) associated with GS in middle-aged to older adults using a genome-wide association study (GWAS). GS was measured using handheld dynamometry in community-dwelling men and women aged 55–85 from the Hunter Community Study (HCS, N  = 2088) and the Sydney Memory and Ageing Study (Sydney MAS, N  = 541). Genotyping was undertaken using Affymetrix microarrays with imputation to HapMap2. Analyses were performed using linear regression. No genome-wide significant results were observed in HCS nor were any of the top signals replicated in Sydney MAS. Gene-based analyses in HCS identified two significant genes ( ZNF295 , C2CD2 ), but these results were not replicated in Sydney MAS. One out of eight SNPs previously associated with GS, rs550942, located near the CNTF gene, was significantly associated with GS ( p  = 0.005) in the HCS cohort only. Study differences may explain the lack of consistent results between the studies, including the smaller sample size of the Sydney MAS cohort. Our modest sample size also had limited power to identify variants of small effect. Our results suggest that similar to various other complex traits, many genetic variants of small effect size may influence GS. Future GWAS using larger samples and consistent measures may prove more fruitful at identifying genetic contributors for GS in middle-aged to older adults.

Expanded genetic testing of BRCA mutations has led to identification of more reproductive-aged women who test positive for the mutation which might impact attitudes and decisions about relationships, childbearing and the use of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND). A cross-sectional survey was administered to 1081 self-reported BRCA carriers to investigate how knowledge of BRCA status influences these issues. The mean age at BRCA test disclosure was 44 years and 36 % reported a personal history of cancer. Of 163 women who were unpartnered, 21.5 % felt more pressure to get married. Of 284 women whose families were not complete, 41 % reported that carrier status impacted their decision to have biological children. Women with a history of cancer were more likely to report that knowledge of BRCA+ status impacted their decision to have a child (OR 1.8, 95 % CI 1–3.2). Fifty-nine percent thought PGD should be offered to mutation carriers and 55.5 % thought PND should be offered. In conclusion, knowledge of BRCA status impacts attitudes regarding relationships and childbearing, and most carriers believe that PGD and PND should be offered to other carriers. This study suggests that BRCA carriers desire and would benefit from reproductive counseling after test disclosure.

Purpose Data have demonstrated an association between regret and lack of fertility counseling among patients undergoing treatment for non-gynecologic cancers. We sought to determine if fertility-related regret is reduced with pre-treatment counseling or fertility-sparing surgery (FSS) in patients with gynecologic cancers. Methods A cross-sectional survey was administered to 593 reproductive-age survivors (18–40 years old at diagnosis) of localized cervix, ovarian, or endometrial cancers that were eligible for FSS. A validated decision regret score was used to evaluate regret in patients. Results Four hundred seventy women completed the survey. Forty-six percent received pre-treatment counseling about treatment’s effects on fertility. Having received counseling (adjusted ß-coefficient of −1.24, 95 % CI = −2.29 to −0.18, p  = 0.02), satisfactory counseling (adjusted ß-coefficient of −2.71, 95 % CI = −3.86 to −1.57, p  < 0.001), and FSS (adjusted ß-coefficient of −1.26, 95 % CI = −2.39 to −0.14, p  = 0.03) were associated with lower regret post-treatment, after adjusting for age. Time since diagnosis, prior parity, socioeconomic status and cancer type were not associated with regret ( p  > 0.05). While 50 % of women reported desiring more children after diagnosis, desire for children after treatment was associated with increased regret (adjusted ß-coefficient of 3.97, 95 % CI = 2.92–5.02, p  < 0.001). Conclusions Though less than half of study participants received counseling about the effect of cancer treatment on future fertility, both fertility counseling and FSS were associated with decreased regret in reproductive-aged women with gynecologic cancers. The desire for more children after treatment was associated with increased regret. Implications for cancer survivors Inquiring about fertility desires and providing counseling regarding reproductive outcomes following cancer treatment should be implemented as part of the treatment process.

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.