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Non-coding RNA (ncRNA) cargo of extracellular vesicles (EVs) in the male reproductive tract play critical roles in semen quality and emerging evidence suggests their susceptibility to environmental factors. Male phthalate exposures have been linked to poor semen quality, sperm DNA methylation profiles and embryo development; however, there is limited evidence on their potential impact on EV ncRNAs profiles. We evaluated the association between urinary phthalate metabolites and small ncRNAs (sncRNAs) of seminal plasma EVs (spEV) among men receiving clinical infertility care. We conducted sncRNA sequencing of EVs in 96 seminal plasma samples collected from the Sperm Environmental Epigenetics and Development Study (SEEDS). Sequencing reads were mapped to human transcriptome databases using STAR. Urinary metabolite concentrations of thirteen phthalates and two DiNCH, a phthalate alternative, were measured via tandem mass spectrometry. Associations with normalized counts were assessed using EdgeR (FDR<0.05) adjusting for urinary dilution via specific gravity, age, BMI, batch, and biotype-specific total counts. Select metabolites, MEOHP, MECPP, ∑DEHP, MCPP, MCNP, MCOP, were negatively (p < 0.05) correlated with miRNA relative abundance. Similarly, nine metabolites including MEOHP, MECPP, MEHP, MCPP, MHBP, MHiNCH, MiBP, MEHHP, MCOP and ∑DEHP were associated (q < 0.05) with normalized counts from 23 unique ncRNA transcripts (7 miRNAs (pre & mature); 6 tRFs; and 10 piRNAs), most (78%) of which displayed increased expression patterns. miRNA and tRFs gene targets were enriched in vesicle-mediated transport and developmental-related ontology terms, such as tyrosine kinase, head development, and cell morphogenesis. Six genes (MAPK1, BMPR1A/2, PTEN, TGFBR2, TP53 and APP) were present in all the ontology terms and predicted to form protein association networks. piRNAs were annotated to pseudogenes of genes important in EV cargo transfer and embryonic development. This is the first study to associate phthalate exposures to altered spEV sncRNA profiles. Future studies are needed to determine their impact on reproductive outcomes. [Display omitted] • Urinary phthalate metabolites were correlated with spEV miRNA and piRNA abundance. • Urinary phthalate metabolites were associated with altered expression of 23 unique spEV sncRNAs. • Gene targets of phthalate-associated spEV sncRNAs were enriched in pathways related to early-life developmental processes. • SpEV sncRNA signatures may act as biomarkers of adult male exposure to phthalates. [ABSTRACT FROM AUTHOR]

Objective: To determine whether assisted reproductive technology (ART) cycles involving cryopreserved-warmed embryos are associated with the development of preeclampsia.Design: Retrospective cohort study.Setting: IVF clinics and hospitals.Patient(s): A total of 15,937 births from ART: 9,417 singleton and 6,520 twin.Intervention(s): We used linked ART surveillance, birth certificate, and maternal hospitalization discharge data, considering resident singleton and twin births from autologous or donor eggs from 2005-2010.Main Outcome Measure(s): We compared the frequency of preeclampsia diagnosis for cryopreserved-warmed versus fresh ET and used multivariable logistic regression to adjust for confounders.Result(s): Among pregnancies conceived with autologous eggs resulting in singletons, preeclampsia was greater after cryopreserved-warmed versus fresh ET (7.51% vs. 4.29%, adjusted odds ratio = 2.17 [95% CI 1.67-2.82]). Preeclampsia without and with severe features, preeclampsia with preterm delivery, and chronic hypertension with superimposed preeclampsia were more frequent after cryopreserved-warmed versus fresh ET (3.99% vs. 2.55%; 2.95% vs. 1.41%; 2.76 vs. 1.48%; and 0.95% vs. 0.43%, respectively). Among pregnancies from autologous eggs resulting in twins, the frequency of preeclampsia with severe features (9.26% vs. 5.70%) and preeclampsia with preterm delivery (14.81% vs. 11.74%) was higher after cryopreserved versus fresh transfers. Among donor egg pregnancies, rates of preeclampsia did not differ significantly between cryopreserved-warmed and fresh ET (10.78% vs. 12.13% for singletons and 28.0% vs. 25.15% for twins).Conclusion(s): Among ART pregnancies conceived using autologous eggs resulting in live births, those involving transfer of cryopreserved-warmed embryos, as compared with fresh ETs, had increased risk for preeclampsia with severe features and preeclampsia with preterm delivery. [ABSTRACT FROM AUTHOR]

Objective: The current study examined whether age after menopause impacted the effect of estradiol (E2) on mood after a psychosocial stress manipulation. Background: Previous studies have shown that E2 improves mood in women around the menopause transition but does not improve mood for older postmenopausal women. We have previously shown that E2 treatment in nondepressed women resulted in increased negative mood after psychosocial stress. Design: Participants were 22 postmenopausal women placed on either oral placebo or 17β-estradiol (1 mg/day for 1 month, then 2 mg/day for 2 months). Method: At the end of the 3-month treatment phase, the participants performed the Trier Social Stress Test followed by mood ratings. To examine the effects of age on the estrogen-stress interaction, we performed a median split on age and created four groups of participants: younger-placebo (mean age: 55.5 years), younger-E2 (mean age: 55.5 years), older-placebo (mean age: 73.0 years), and older-E2 (mean age: 76.8 years). Results: The results showed that both older and younger E2-treated participants exhibited a significant and similar increase in negative mood after psychosocial stress compared with placebo-treated women. Conclusions: These results suggest that E2 may play a significant role in modulating emotional reactivity to stressful events and that this effect persists in older women. Furthermore, responsivity to E2 effects on emotional processing appears to be intact even years after menopause in contrast with other cognitive and behavioral effects of E2, which may be limited to the early postmenopausal years. [ABSTRACT FROM AUTHOR]

Objective: To determine whether a supplement of soy protein improves body composition, body fat distribution, and glucose and insulin metabolism in postmenopausal women without diabetes compared with an isocaloric casein placebo.Design: Randomized, double-blind, placebo-controlled 3-month trial.Setting: Clinical Research Center.Patient(s): Fifteen postmenopausal women.Intervention(s): Computed tomographic scans at L4/L5, dual energy x-ray absorptiometry, hyperglycemic clamps.Main Outcome Measure(s): Total fat, total abdominal fat, visceral fat, subcutaneous abdominal fat, and insulin secretion.Result(s): Weight by dual energy x-ray absorptiometry did not change between groups (+1.38 +/- 2.02 kg for placebo vs. +0.756 +/- 1.32 kg for soy, mean +/- SD). Total and subcutaneous abdominal fat increased more in the placebo group than in the soy group (for differences between groups in total abdominal fat: +38.62 +/- 22.84 cm(2) for placebo vs. -11.86 +/- 31.48 cm(2) for soy; subcutaneous abdominal fat: +22.91 +/- 28.58 cm(2) for placebo vs. -14.73 +/- 22.26 cm(2) for soy). Insulin secretion, visceral fat, total body fat, and lean mass did not differ between groups. Isoflavone levels increased more in the soy group.Conclusion(s): A daily supplement of soy protein prevents the increase in subcutaneous and total abdominal fat observed with an isocaloric casein placebo in postmenopausal women. [ABSTRACT FROM AUTHOR]

Objective: Aging is associated with reduced tissue sensitivity to insulin. In women, these age-related changes may be accelerated by menopause. The effect of ovarian hormone deficiency on tissue insulin sensitivity in humans, however, has not been defined clearly. Thus, the goal of this study was to evaluate the effect of suppression of endogenous ovarian hormone production on insulin-stimulated glucose disposal.Design: Randomized, single-blind, placebo-controlled trial.Setting: General clinical research center.Patients: Thirteen healthy, nonobese premenopausal women.Intervention(s): Insulin-stimulated glucose disposal was determined by hyperinsulinemic (40 mU/m(2)/min) clamp during the early to midfollicular and midluteal phase of the menstrual cycle. Volunteers then received 2 months of treatment with the GnRH agonist (GnRHa) leuprolide acetate (n = 6) or placebo (n = 7) and were retested.Main Outcome Measure(s): Total, oxidative, and nonoxidative insulin-stimulated glucose disposal.Result(s): Because no effect of cycle phase was found on total, oxidative, or nonoxidative glucose disposal, pretreatment follicular and luteal phase values were averaged. Treatment with GnRHa had no effect on total glucose disposal (GnRHa: 10.6 +/- 0.9 to 10.8 +/- 0.9 vs. placebo: 10.2 +/- 0.7 to 10.4 +/- 1.0 mg/kg fat-free mass/min, P = .99). Similarly, there was no effect of GnRHa administration on oxidative (GnRHa: 2.77 +/- 0.58 to 3.89 +/- 0.58 vs. placebo: 2.74 +/- 0.42 to 3.33 +/- 0.62 mg/kg fat-free mass/min, P = .52; n = 6 and 6, respectively) or nonoxidative (GnRHa: 7.82 +/- 0.68 to 6.91 +/- 0.66 vs. placebo: 7.94 +/- 0.72 to 7.79 +/- 0.99 mg/kg fat-free mass/min, P = .59; n = 6 and 6, respectively) components of glucose disposal.Conclusion(s): Our results suggest that endogenous ovarian hormones do not regulate tissue responsiveness to insulin or intracellular pathways of glucose disposal. [ABSTRACT FROM AUTHOR]

Objective: To determine the effect of ovarian hormone deficiency on peripheral vascular function. Design: Randomized, single-blind, placebo-controlled. Setting: General clinical research center. Patient(s): Twelve healthy, lean, premenopausal women with regular menstrual cycles. Intervention(s): Measurements were made during the early to midfollicular and midluteal phases of the menstrual cycle. Patients were then randomized to an 8-week course of gonadotropin-releasing hormone agonist (GnRHa) (n = 6) or placebo (n = 6) and retested. On each occasion, blood flow was assessed in the basal postabsorptive state and under euglycemic-hyperinsulinemic-hyperaminoacidemic conditions. Main Outcome Measure(s): Calf blood flow by venous occlusion plethysmography. Result(s): No differences in calf blood flow under postabsorptive (1.65 ± 0.09 vs. 1.73 ± 0.16 mL/100 g tissue per minute) or insulin-stimulated conditions (2.24 ± 0.20 vs. 2.30 ± 0.18 mL/100 g tissue per minute) were found between the follicular and luteal phases of the menstrual cycle, respectively; therefore, pretreatment data were averaged. Ovarian hormone suppression did not alter postabsorptive calf blood flow (GnRHa: 1.68 ± 0.13 to 1.69 ± 0.15; placebo: 1.69 ± 0.21 to 1.64 ± 0.14 mL/100 g tissue per minute) or the blood flow response to insulin infusion (GnRHa: 2.40 ± 0.21 to 2.37 ± 0.29; placebo: 2.10 ± 0.28 to 2.19 ± 0.35 mL/100 g tissue per minute). Conclusion(s): Variation in ovarian hormones associated with the menstrual cycle or short-term ovarian hormone deficiency induced by GnRHa do not affect calf blood flow under postabsorptive conditions or the response to hyperinsulinemia. [Copyright &y& Elsevier]

Objective: To examine the effect of ovarian hormones on the regulation of cardiac growth.Design: Ovariectomized rat model with replacement of 17β-estradiol (E2) and progesterone (P).Setting: University research laboratory.Patient(s): Female Sprague-Dawley rats (7–8 weeks old).Intervention(s): Rats were separated into five groups: [1] sham-operated (S; n = 6), [2] ovariectomized plus placebo (OVX; n = 8), [3] OVX plus 17β-E2 (OVX+E2; n = 8), [4] OVX plus P (OVX+P; n = 8), and [5] OVX+E2+P (n = 7).Main outcome measure(s): Cardiac muscle protein synthesis rates, steroid hormone receptor protein expression, and plasma volume.Result(s): Cardiac protein synthesis was greater in OVX+P (mean ± SE; 11.4 ± 1.5% per day) rats compared with S (5.9 ± 0.6%/day), OVX (6.9 ± 0.5%/day), OVX+E2 (5.2 ± 0.4%/day), and OVX+E2+P (6.8 ± 0.3%/day) groups. Treatment of OVX+P rats with the P receptor antagonist RU 486 (n = 9) reduced protein synthesis rates to control levels (7.5 ± 0.5% per day), indicating that P regulates cardiac protein metabolism through a receptor-dependent pathway. Both P and estrogen receptors were found in cardiac tissue homogenates, suggesting the possibility of direct effects of ovarian hormones on the heart. Progesterone replacement had an additional effect of increasing plasma volume. Rats in the OVX+P group had a 20% greater plasma volume compared with animals in the S group (5.24 ± 0.22 vs. 4.19 ± 0.26 mL/100 g). This effect of P replacement to increase plasma volume was not blocked by RU 486 (5.01 ± 0.24 mL/100 g), suggesting that volume expansion was not solely responsible for the effects of P on cardiac protein synthesis.Conclusion(s): Our findings indicate a role for ovarian hormones in the regulation of cardiac growth in female rats. [Copyright &y& Elsevier]

Recent evidence suggest that Sex Steroid Therapy involving estrogen while beneficial, may have adverse effects as well. Both of the known estrogen receptors, estrogen receptor-α (ER-α) and estrogen receptor-β (ER-β) have been found in reproductive tissues as well as bone, liver, and brain. These receptors are important targets for endogenous estrogen, estrogen replacement therapy and pharmacological estrogen agonists allowing specific modulation of sex steroids. This article will review the basic mechanisms of sex steroid biosynthesis and detail our current understanding of the action of these hormones on specific hormone responsive tissues. The properties of tibolone, a synthetic steroid will be outlined and its mechanism reviewed. [Copyright &y& Elsevier]

Background: Contemporary embryo biopsy in the United States involves the removal of several cells from a blastocyst that would become the placenta for preimplantation genetic testing. Embryos are then cryopreserved while patients await biopsy results, with transfers occurring in a subsequent cycle as a single frozen-thawed embryo transfer, if euploid.Objective: We sought to determine if removal of these cells for preimplantation genetic testing was associated with adverse obstetrical or neonatal outcomes after frozen-thawed single embryo transfer.Study Design: We linked assisted reproductive technology surveillance data from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System to birth certificates and maternal and neonatal hospitalization discharge diagnoses in Massachusetts from 2014 to 2017, considering only singleton births after frozen-thawed single embryo transfers. We compared outcomes of cycles having embryo biopsy (n=585) to those having no biopsy (n=2191) using chi-square for categorical and binary variables and logistic regression for adjusted odds ratios and 95% confidence intervals, adjusting for mother's age, race, education, parity, body mass index, birth year, insurance, and all infertility diagnoses.Results: Considering no biopsy as the reference, there was no difference between groups with respect to preeclampsia (adjusted odds ratio, 0.82; 95% confidence interval, 0.42-1.61; P=.5685); pregnancy-induced hypertension (adjusted odds ratio, 0.85; 95% confidence interval, 0.46-1.59; P=.6146); placental disorders, including placental abruption, placenta previa, placenta accreta, placenta increta, and placenta percreta (adjusted odds ratio, 1.16; 95% confidence interval, 0.60-2.24; P=.6675); preterm birth (adjusted odds ratio, 1.22; 95% confidence interval 0.73-2.03; P=.4418); low birthweight (adjusted odds ratio, 1.12; 95% confidence interval, 0.58-2.15; P=.7355); cesarean delivery (adjusted odds ratio, 1.04; 95% confidence interval, 0.79-1.38; P=.7762); or gestational diabetes mellitus (adjusted odds ratio, 0.83; 95% confidence interval, 0.50-1.38; P=.4734). In addition, there was no difference between the groups for prolonged hospital stay for mothers (adjusted odds ratio, 1.23; 95% confidence interval, 0.83-1.80; P=.3014) or for infants (95% confidence interval, 1.29; 95% confidence interval, 0.72-2.29; P=.3923).Conclusion: Embryo biopsy for preimplantation genetic testing does not increase the odds for diagnoses related to placentation (preeclampsia, pregnancy-related hypertension, placental disorders, preterm delivery, or low birthweight), maternal conditions (gestational diabetes mellitus), or maternal or infant length of stay after delivery. [ABSTRACT FROM AUTHOR]

Little is known about the effects of human embryo cryopreservation on developmental potential. Initial beta-HCG, indicating embryo implantation, was measured in 322 single embryo transfer cycles (246 fresh and 76 thawed–warmed). Median initial beta-HCG was higher for fresh compared with thawed–warmed transfers (126 versus 100 mIU/ml; P = 0.04). Blastocyst slow cooling resulted in a lower initial beta-HCG compared with vitrification ( P = 0.01). Live birth rates were lower for blastocyst slow cooling (25%) compared with vitrification (71%) and fresh transfer (70%). We conclude that cryopreservation may impair an embryo's ability to produce beta-HCG, but that vitrification does not impair developmental potential. [ABSTRACT FROM AUTHOR]

Background: Transfer of cryopreserved-warmed embryos into an appropriately prepared uterus unaffected by controlled ovarian hyperstimulation is common in the practice of in vitro fertilization. There is limited information on the effect of blastocyst vitrification and warming on perinatal outcomes.Objective: We sought to determine if perinatal outcomes are affected after the transfer of vitrified-warmed blastocysts compared to the transfer of fresh blastocysts, by comparing preeclampsia rate, birthweight, percentage of low birthweight, and preterm delivery rate between embryo transfer types.Study Design: We performed a retrospective database cohort study of 289 fresh and 109 vitrified-warmed blastocyst transfer cycles at an academic medical center. Cycles were performed from July 2, 2009, through Dec. 8, 2014, and included infants born at ≥20 weeks gestational age, excluding donor egg cycles. We examined the association between transfer type (fresh or vitrified-warmed) and proportion of deliveries complicated by preeclampsia, preterm delivery (gestational age <37 weeks), and low birthweight (<2500 g). We assessed associations using generalized linear models, both unadjusted and adjusted, for maternal age, newborn sex, diabetes status, and parity.Results: We observed more pregnancies complicated by preeclampsia following vitrified-warmed transfers (7.6%) compared to fresh embryo transfers (2.6%) (P = .023) (adjusted odds ratio, 3.1; 95% confidence interval, 1.2-8.4). Newborns resulting from vitrified-warmed embryo transfer cycles were similar to those resulting from fresh embryo transfer cycles with regard to low birthweight (7.4% vs 5.3%, P = .421), mean birthweight (3443 vs 3431 g, P = .865), and preterm delivery rate (9.2% vs 8.7%, P = .869).Conclusion: We conclude that embryo vitrification with warming may affect some perinatal outcomes since preeclampsia is increased compared to fresh blastocyst transfer. However, other perinatal outcomes such as low birthweight and preterm delivery rate are not affected. Fresh blastocyst transfers should be considered when possible as they may reduce the incidence of preeclampsia. [ABSTRACT FROM AUTHOR]

Objective: We sought to examine regional and black-white differences in mean age at self-reported menopause among community-dwelling women in the United States. Study Design: This was a cross-sectional survey conducted in the context of the REasons for Geographic And Racial Differences in Stroke and Myocardial Infarction study. Results: We studied 22,484 menopausal women. After controlling for covariates, Southern women reported menopause 10.8 months earlier than Northeastern women, 8.4 months earlier than Midwestern women, and 6.0 months earlier than Western women (P < .05 for all). No difference was observed in menopausal age between black and white women after controlling for covariates (P = .69). Conclusion: Women in the South report earlier menopause than those in other regions, but the cause remains unclear. Our study''s large sample size and adjustment for multiple confounders lends weight to our finding of no racial difference in age at menopause. More study is needed of the implications of these findings with regard to vascular health. [Copyright &y& Elsevier]

In this review, we summarize existing research on a variety of environmental factors potentially involved in the etiology, prevalence, and modulation of polycystic ovary syndrome (PCOS), and we suggest avenues for future research. The main environmental factors we consider include environmental toxins, diet and nutrition, socioeconomic status, and geography. There is some evidence that environmental toxins play a role in disrupting reproductive health, but there is limited research as to how these toxins may affect the development of PCOS. Although research has also shown that PCOS symptoms are reduced with certain dietary supplements and with weight loss among obese women, additional research is needed to compare various approaches to weight loss, as well as nutritional factors that may play a role in preventing or mitigating the development of PCOS. Limited studies indicate some association of low socioeconomic status with certain PCOS phenotypes, and future research should consider socioeconomic conditions during childhood or adolescence that may be more relevant to the developmental onset of PCOS. Finally, the limited scope of comparable international studies on PCOS needs to be addressed, because global patterns of PCOS are potentially valuable indicators of cultural, environmental, and genetic factors that may contribute to excess risk in certain regions of the world. [ABSTRACT FROM AUTHOR]

Abstract Research question To examine associations between sperm mitochondrial DNA copy number (mtDNAcn), sperm mitochondrial DNA deletions (mtDNAdel), semen parameters and clinical infertility in an IVF setting. Design A total of 125 sperm samples were collected from men undergoing assisted reproductive procedures in an IVF clinic in Western Massachusetts, USA. Sperm mtDNAcn and mtDNAdel were measured by probe-based quantitative polymerase chain reaction. Semen parameters, clinical diagnoses of infertility, and infertility based on consecutive semen parameters, were fitted with mtDNAcn and mtDNAdel in linear models. The utility of sperm mtDNAcn and mtDNAdel to predict infertility was assessed by receiver operating characteristic curves. Results Adjusting for relevant covariates, both sperm mtDNAcn and mtDNAdel were associated with lower sperm concentration, count, motility and morphology (P ≤ 0.03). Sperm mtDNAcn and mtDNAdel were also associated with increased risks of clinical infertility based on current and consecutive semen samples. Sperm mtDNAcn had high predictive accuracy for consecutive diagnoses of clinical infertility (C-statistic: 0.91), whereas sperm mtDNAdel had moderate predictive accuracy (C-statistic: 0.75). Conclusions Sperm mtDNAcn is a measure of consecutive abnormal semen parameters and has promise as a diagnostic test. [ABSTRACT FROM AUTHOR]

Objective: To determine racial differences in self-reported infertility and in risk factors for infertility in a cohort of black and white women.Design: A cross-sectional analysis of data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective, epidemiologic investigation of the determinants and evolution of cardiovascular risk factors among black and white young adults and from the ancillary CARDIA Women's Study (CWS).Setting: Population-based sample from four US communities (Birmingham, AL; Chicago, IL; Minneapolis, MN; Oakland, CA).Patient(s): Women aged 33-44 years who had complete data (n = 764).Intervention(s): None.Main Outcome Measure(s): Self-report of ever having unprotected sexual intercourse for at least 12 months without becoming pregnant.Result(s): Among nonsurgically sterile women, blacks had a twofold increased odds (95% confidence interval [CI] 1.3-3.1) of infertility compared with whites after adjustment for socioeconomic position (education and ability to pay for basics), correlates of pregnancy intent (marital status and hormonal contraceptive use), and risk factors for infertility (age, smoking, T, fibroid presence, and ovarian volume). The corresponding odds ratio among all women was 1.5 (95% CI 1.0-2.2). Difficulty paying for basics and ovarian volume were associated with infertility among black but not white women.Conclusion(s): In this population-based sample, black women were more likely to have experienced infertility. This disparity is not explained by common risk factors for infertility, such as smoking and obesity, and among nonsurgically sterile women, it is not explained by gynecologic risk factors such as fibroids and ovarian volume. [ABSTRACT FROM AUTHOR]