High-throughput mRNA sequencing of human placenta shows sex differences across gestation.

INTRODUCTION: Fetal sex affects fetal and maternal health outcomes in pregnancy, but this connection remains poorly understood. As the placenta is the route of fetomaternal communication and derives from the fetal genome, placental gene expression sex differences may explain these outcomes. OBJECTIVES: We utilized next generation sequencing to study the normal human placenta in both sexes in first and third trimester to generate a normative transcriptome based on sex and gestation. STUDY DESIGN: We analyzed 124 first trimester (T1, 59 female and 65 male) and 43 third trimester (T3, 18 female and 25 male) samples for sex differences within each trimester and sex-specific gestational differences. RESULTS: Placenta shows more significant sexual dimorphism in T1, with 94 T1 and 26 T3 differentially expressed genes (DEGs). The sex chromosomes contributed 60.6% of DEGs in T1 and 80.8% of DEGs in T3, excluding X/Y pseudoautosomal regions. There were 6 DEGs from the pseudoautosomal regions, only significant in T1 and all upregulated in males. The distribution of DEGs on the X chromosome suggests genes on Xp (the short arm) may be particularly important in placental sex differences. Dosage compensation analysis of X/Y homolog genes shows expression is primarily contributed by the X chromosome. In sex-specific analyses of first versus third trimester, there were 2815 DEGs common to both sexes upregulated in T1, and 3263 common DEGs upregulated in T3. There were 7 female-exclusive DEGs upregulated in T1, 15 female-exclusive DEGs upregulated in T3, 10 male-exclusive DEGs upregulated in T1, and 20 male-exclusive DEGs upregulated in T3. DISCUSSION: This is the largest cohort of placentas across gestation from healthy pregnancies defining the normative sex dimorphic gene expression and sex common, sex specific and sex exclusive gene expression across gestation. The first trimester has the most sexually dimorphic transcripts, and the majority were upregulated in females compared to males in both trimesters. The short arm of the X chromosome and the pseudoautosomal region is particularly critical in defining sex differences in the first trimester placenta. As pregnancy is a dynamic state, sex specific DEGs across gestation may contribute to sex dimorphic changes in overall outcomes.

Alterations in nonesterified free fatty acid trafficking rather than hyperandrogenism contribute to metabolic health in obese women with polycystic ovary syndrome.

OBJECTIVE: To determine whether alterations in nonesterified fatty acid (NEFA) dynamics or degree of hyperandrogenism (HA) contribute to the difference in insulin sensitivity between women with metabolically healthy obese polycystic ovary syndrome (PCOS) (MHO-PCOS) and women with metabolically unhealthy obese PCOS (MUO-PCOS). DESIGN: Prospective cross-sectional study. SETTING: Tertiary-care academic center. PATIENTS: One hundred twenty-five obese women with PCOS. INTERVENTION: Consecutive obese (body mass index [BMI] ≥ 30 kg/m2) oligo-ovulatory women (n = 125) with PCOS underwent an oral glucose tolerance test and a subgroup of 16 participants underwent a modified frequently sampled intravenous glucose tolerance test to determine insulin-glucose and -NEFA dynamics. MAIN OUTCOME MEASURES: Degree of insulin resistance (IR) in adipose tissue (AT) basally (Adipo-IR) and dynamically (the nadir in NEFA levels observed [NEFAnadir], the time it took for NEFA levels to reach nadir [TIMEnadir], and the percent suppression in plasma NEFA levels from baseline to nadir [%NEFAsupp]); peak lipolysis rate (SNEFA) and peak rate of NEFA disposal from plasma pool (KNEFA); whole-body insulin-glucose interaction (acute response of insulin to glucose [AIRg], insulin sensitivity index [Si], glucose effectiveness [Sg], and disposition index [Di]); and HA (hirsutism score, total and free testosterone levels, and dehydroepiandrosterone sulfate levels). RESULTS: A total of 85 (68%) women were MUO-PCOS and 40 (32%) were MHO-PCOS using the homeostasis model of assessment of IR. Subjects with MUO-PCOS and MHO-PCOS did not differ in mean age, BMI, waist-to-hip ratio, HA, and lipoprotein levels. By a modified frequently sampled intravenous glucose tolerance test, eight women with MUO-PCOS had lesser Si, KNEFA, and the percent suppression in plasma NEFA levels from baseline to nadir (%NEFAsupp) and greater TIMEnadir, NEFAnadir, and baseline adipose tissue IR index (Adipo-IR) than eight subjects with MHO-PCOS, but similar fasting NEFA levels and SNEFA. Women with MUO-PCOS had a higher homeostasis model of assessment-ß% and fasting insulin levels than women with MHO-PCOS. In bivalent analysis, Si correlated strongly and negatively with Adipo-IR and NEFAnadir, weakly and negatively with TIMEnadir, and positively with KNEFA and %NEFAsupp, in women with MUO-PCOS only. CONCLUSION: Independent of age and BMI, women with MUO-PCOS have reduced NEFA uptake and altered insulin-mediated NEFA suppression, but no difference in HA, compared with women with MHO-PCOS. Altered insulin-mediated NEFA suppression, rather than HA or lipolysis rate, contributes to variations in insulin sensitivity among obese women with PCOS.

High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester†.

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.

A systematic review of genome-wide analyses of methylation changes associated with assisted reproductive technologies in various tissues.

IMPORTANCE: Because analytic technologies improve, increasing amounts of data on methylation differences between assisted reproductive technology (ART) and unassisted conceptions are available. However, various studies use different tissue types and different populations in their analyses, making data comparison and integration difficult. OBJECTIVE: To compare and integrate data on genome-wide analyses of methylation differences due to ART, allowing exposure of overarching themes. EVIDENCE REVIEW: All studies undertaking genome-wide analysis of human methylation differences due to ART or infertility in any tissue type across the lifespan were assessed for inclusion. FINDINGS: Seventeen studies were identified that met the inclusion criteria. One study assessed trophectoderm biopsies, 2 first-trimester placenta, 1 first-trimester fetal tissue, 2 term placenta, 7 cord blood, 3 newborn dried blood spots, 1 childhood buccal smears, 1 childhood peripheral blood, and 2 adult peripheral blood. Eleven studies compared tissues from in vitro fertilization (IVF) conceptions with those of unassisted conceptions, 4 compared intracytoplasmic sperm injection with unassisted conceptions, 4 compared non-IVF fertility treatment (NIFT) with unassisted conceptions, 4 compared NIFT with IVF, and 5 compared an infertile population (conceiving via various methods) with an unassisted presumably fertile population. In studies assessing placental tissue, 1 gene with potential methylation changes due to IVF when compared with unassisted conceptions was identified by 2 studies. In blood, 11 potential genes with methylation changes due to IVF compared with unassisted conceptions were identified by 2 studies, 1 of which was identified by 3 studies. Three potentially affected genes were identified by 2 studies involving blood between intracytoplasmic sperm injection and unassisted populations. There were no overlapping genes identified in any tissue type between NIFT and unassisted populations, between NIFT and IVF, or the infertility combined population when compared with the unassisted fertile population. CONCLUSIONS: Comparing studies is challenging due to differing variables between analyses. However, even in similar tissue types and populations, overlapping methylation changes are limited, suggesting that differences due to ART are minimal. RELEVANCE: Information from this systematic review is significant for providers and patients who provide and use ART to understand methylation risks that may be associated with the technology.

Testicular ACE regulates sperm metabolism and fertilization through the transcription factor PPARγ.

Testis angiotensin-converting enzyme (tACE) plays a critical role in male fertility, but the mechanism is unknown. By using ACE C-domain KO (CKO) mice which lack tACE activity, we found that ATP in CKO sperm was 9.4-fold lower than WT sperm. Similarly, an ACE inhibitor (ACEi) reduced ATP production in mouse sperm by 72%. Metabolic profiling showed that tACE inactivation severely affects oxidative metabolism with decreases in several Krebs cycle intermediates including citric acid, cis-aconitic acid, NAD, α-ketoglutaric acid, succinate, and L-malic acid. We found that sperms lacking tACE activity displayed lower levels of oxidative enzymes (CISY, ODO1, MDHM, QCR2, SDHA, FUMH, CPT2, and ATPA) leading to a decreased mitochondrial respiration rate. The reduced energy production in CKO sperms leads to defects in their physiological functions including motility, acrosine activity, and fertilization in vitro and in vivo. Male mice treated with ACEi show severe impairment in reproductive capacity when mated with female mice. In contrast, an angiotensin II receptor blocker (ARB) had no effect. CKO sperms express significantly less peroxisome proliferators-activated receptor gamma (PPARγ) transcription factor, and its blockade eliminates the functional differences between CKO and WT sperms, indicating PPARγ might mediate the effects of tACE on sperm metabolism. Finally, in a cohort of human volunteers, in vitro treatment with the ramipril or a PPARγ inhibitor reduced ATP production in human sperm and hence its motility and acrosine activity. These findings may have clinical significance since millions of people take ACEi daily, including men who are reproductively active.

High-throughput mRNA-seq atlas of human placenta shows vast transcriptome remodeling from first to third trimester.

Background: 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. Methods: 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. Results: 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). Conclusion: 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.

Racial and ethnic disparities in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that impacts women worldwide. There are several racial and ethnic differences in PCOS phenotypes and in PCOS- associated metabolic dysfunction. In this review, we summarize the current literature on disparities in the diagnosis and outcomes associated with PCOS in the United States. Future studies are needed to address gaps in knowledge for racial and ethnic-specific differences in PCOS, and include a large number of non-White and/or Hispanic participants in PCOS studies.

Regional Variation in Hormonal and Metabolic Parameters of White and Black Women With PCOS in the United States.

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.

Ovarian volume as an independent marker for metabolic dysfunction in women with suspected androgen excess.

Objective: To determine whether ovarian volume (OV) alone is an independent marker for metabolic dysfunction in women with suspected androgen excess. Design: Retrospective cohort study. Setting: Tertiary academic reproductive endocrinology clinic. Patients: Women aged ≥21 years recruited/referred for symptoms related to androgen excess. Interventions: Transvaginal ovarian ultrasound, physical and medical evaluation, 2-hour 75-g oral glucose tolerance test (oGTT), and blood sampling. Main Outcome Measures: Prevalence of hyperandrogenism and metabolic dysfunction. Results: This study included 666 women, of whom 412 (61.9%) and 254 had OVs of >10 and ≤10 mL, respectively. An OV of >10 mL was associated with a higher prevalence of hirsutism (65.1% vs. 51.5%) than an OV of ≤10 mL. Polycystic ovary syndrome by the National Institutes of Health 1990 criteria was found in 67.3% and 51.4% of women with OVs of >10 and ≤10 mL, respectively. Metabolic parameters, including body mass index, waist circumference, and 1-hour insulin levels during the oGTT (odds ratio, 1.98; 95% confidence interval, 1.18-3.31), were significantly higher in women with an OV of >10 mL than in those with an OV of ≤10 mL. An OV of ≤10 mL had a 76.3% negative predictive value for hyperinsulinemia at 1 hour. Conclusions: In women with suspected androgen excess, an OV of >10 mL in at least 1 ovary is not associated with metabolic syndrome but is associated with younger age; an increased body mass index and waist circumference; a higher prevalence of hirsutism, oligoovulation, and polycystic ovary syndrome; and a higher 60-minute insulin level during the oGTT. Overall, an increased OV appears to be a good marker for hyperinsulinemia and hyperandrogenism in women suspected of having an androgen excess disorder.

Subclinical cardiovascular disease and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) impacts approximately 6%-10% of women worldwide, with hallmark features of hyperandrogenism, irregular menses, infertility, and polycystic appearing ovaries on ultrasound. In addition, PCOS is associated with several endocrine and metabolic disorders, including obesity, insulin resistance and diabetes mellitus, hypertension, dyslipidemia and metabolic syndrome, which all increase the risk for subclinical cardiovascular disease (CVD), the presence of altered vascular endothelium without overt CVD. In this review, we summarize the most recent literature regarding subclinical CVD in women with PCOS, including markers such as flow-mediated dilation, arterial stiffness, coronary artery calcium scores, carotid intima-media thickness and visceral and epicardial fat.

Sex differences in microRNA expression in first and third trimester human placenta†.

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.

High-throughput miRNA sequencing of the human placenta: expression throughout gestation.

Aim: To understand miRNA changes across gestation in healthy human placentae. This is essential before miRNAs can be used as biomarkers or prognostic indicators during pregnancy. Materials & methods: Using next-generation sequencing, we characterize the normative human placenta miRNome in first (n = 113) and third trimester (n = 47). Results & conclusion: There are 801 miRNAs expressed in both first and third trimester, including 182 with similar expression across gestation (p ≥ 0.05, fold change ≤2) and 180 significantly different (false discovery rate <0.05, fold change >2). Of placenta-specific miRNA clusters, chromosome 14 miRNA cluster decreases across gestation and chromosome 19 miRNA cluster is overall highly expressed. Chromosome 13 clusters are upregulated in first trimester. This work provides a rich atlas of healthy pregnancies to direct functional studies investigating the epigenetic differences in first and third trimester placentae.

Lay abstract The human body produces miRNAs which affect the expression of genes and proteins. This study uses next-generation sequencing to identify the miRNA profile of first and third trimester human placentae using a large cohort (n = 113 first trimester; n = 47 third trimester). All pregnancies resulted in healthy babies. We identify miRNAs with significantly different expression between first and third trimester, as well as stably expressed miRNAs. This work provides a baseline for future studies which may use miRNAs to monitor maternal­fetal health throughout pregnancy.

Clinical utility of the endometrial receptivity analysis in women with prior failed transfers.

PURPOSE: To determine the utility of the endometrial receptivity analysis (ERA) in women with prior failed embryo transfers (ET). METHODS: This 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. RESULTS: A 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). CONCLUSION: Women 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.

Screening for Androgen Excess in Women: Accuracy of Self-Reported Excess Body Hair Growth and Menstrual Dysfunction.

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.

Differences in First-Trimester Maternal Metabolomic Profiles in Pregnancies Conceived From Fertility Treatments.

Context: Maternal metabolic status reflects underlying physiological changes in the maternal-placental-fetal unit that may help identify contributors to adverse pregnancy outcomes associated with infertility and treatments used. Objective: To determine if maternal metabolomic profiles differ between spontaneous pregnancies and pregnancies conceived with fertility treatments that may explain the differences in pregnancy outcomes. Design: Metabolon metabolomic analysis and ELISAs for 17-ß-estradiol and progesterone were performed during the late first trimester of pregnancy. Setting: Academic institution. Subjects: Women in the Spontaneous/Medically Assisted/Assisted Reproductive Technology cohort (N = 409), 208 of whom conceived spontaneously and 201 with infertility [non in vitro fertilization treatments (NIFT), n=90; in vitro fertilization (IVF), n=111]. Intervention: Mode of conception. Main Outcome Measures: Levels of of 806 metabolites within eight superpathways, 17-ß-estradiol, and progesterone in maternal plasma in the late first trimester. Results: Metabolomic differences in the lipid superpathway (i.e., steroid metabolites, lipids with docosahexaenoyl acyl chains, acyl cholines), and xanthine and benzoate metabolites (P < 0.05) were significant among the spontaneous and two infertility groups, with greatest differences between the spontaneous and IVF groups. 17-ß-estradiol and progesterone levels were significantly elevated in the infertility groups, with greatest differences between the spontaneous and IVF groups. Conclusion: Metabolomic profiles differ between spontaneous and infertility pregnancies, likely driven by IVF. Higher levels of steroids and their metabolites are likely due to increased hormone production from placenta reprogrammed from fertility treatments, which may contribute to adverse outcomes associated with infertility and the treatments used.

Risk factors for sexual dysfunction in BRCA mutation carriers after risk-reducing salpingo-oophorectomy.

OBJECTIVE: The aim of the study was to identify risk factors for sexual dysfunction in BRCA mutation carriers who have undergone risk-reducing salpingo-oophorectomy (RRSO). METHODS: A cross-sectional study was performed. BRCA1/2 mutation carriers with and without RRSO were surveyed to determine sexual function (Female Sex Function Index [FSFI]), demographics, medical history, sleep quality, depression, and anxiety scores. Characteristics of patients with the lowest quartile of FSFI scores (<14 ±â€Š8.8) were analyzed to identify risk factors for the most severe phenotype. RESULTS: In the 804 women surveyed, 764 underwent RRSO. Of the 529 (69%) carriers with completed FSFI questionnaires in the RRSO cohort, sexual dysfunction was reported in 77.3%. Poor sleep (P = 0.002), hot flashes (P = 0.002), lack of current systemic hormone therapy (HT) use (P = 0.002), depression (P < 0.001), and anxiety (P = 0.001) were associated with sexual dysfunction. In adjusted analyses, depression (adjusted odds ratio [aOR] 2.4, 95% CI, 1.4-4.1) and hot flashes (aOR 1.9, 95% CI, 1.2-3.0) remained significantly associated with sexual dysfunction. Depression was also a significant risk factor for the most severe degree of sexual dysfunction (OR 2.1, 95% CI, 1.3-3.5) and had the greatest impact on Arousal and Satisfaction domain scores of the FSFI. Current systemic HT use seemed to decrease the risk for sexual dysfunction (aOR 0.6, 95% CI, 0.4-1.0). CONCLUSIONS: Sexual dysfunction is highly prevalent in BRCA mutation carriers after RRSO. Depression seems to be a significant risk factor for sexual dysfunction in this patient population and may be under-recognized and undertreated. Patient and provider education on sexual side effects after surgery and risk factors for sexual dysfunction is necessary to decrease postoperative sexual distress. HT may be associated with improved sexual function after surgery.

Genetics and Epigenetics of Infertility and Treatments on Outcomes.

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.

Mode of conception does not affect fetal or placental growth parameters or ratios in early gestation or at delivery.

PURPOSE: Ratio of fetal weight to placenta size varies by mode of conception (fertility treatments utilized) in animals. Our objective was to assess whether fertility treatments also affect these ratios in humans. METHODS: In this retrospective study, we assessed two cohorts: (a) early gestation cohort, women with singleton pregnancies who underwent first trimester vaginal ultrasound and (b) delivered cohort, women who delivered a live-born, singleton infant with placenta disposition to pathology. Crown rump length (CRL) and estimated placental volume (EPV) were calculated from first trimester ultrasound images using a validated computation. Infant birth weight (BW), pregnancy data, placental weight (PW), and placental histopathology were collected. Fetal growth-to-placental weight ratios (CRL/EPV; BW/PW) and placentas were compared by mode of conception. Linear regression was used to adjust for confounding variables. RESULTS: Two thousand one hundred seventy patients were included in the early gestation cohort and 1443 in the delivered cohort. Of the early gestation cohort (a), 85.4% were spontaneous conceptions, 5.9% Non-IVF Fertility (NIFT), and 8.7% IVF. In the delivered cohort (b), 92.4% were spontaneous, 2.1% NIFT, and 80 5.5% IVF. There were no significant differences between fetal growth-to-placental weight parameters, ratios, and neonatal birth measurements based on mode of conception. Placenta accreta was significantly higher in the patients receiving fertility treatments (1.2 versus 3.6%, p < 0.05). CONCLUSIONS: Mode of conception does not appear to influence fetal growth-to-placental weight ratios throughout gestation. In addition, findings in animal models may not always translate into human studies of infertility treatment outcomes.