Maternal Estradiol Levels Research Articles

Elevated prenatal maternal sex hormones, but not placental aromatase, are associated with child neurodevelopment

Fetal exposure to testosterone may contribute to vulnerability for autism spectrum disorder (ASD). It is hypothesized that placental aromatase prevents fetal exposure to maternal testosterone, however, this pathway and the implications for child neurodevelopment have not been fully explored. We examined the relationships between prenatal maternal testosterone and estradiol at 19.2 ± 1.3 weeks, cord blood testosterone and estradiol at birth, placental aromatase mRNA expression, and neurodevelopment using the Social Communication Questionnaire (SCQ), the Behavioral Assessment System for Children, 3rd Edition (BASC-3), and the Empathizing Quotient for Children (EQ-C) at 4.5–6.5 years of age in a sample of 270 Nulliparous-Mothers-to-be (nuMoM2b) study participants. Maternal testosterone levels were positively associated with SCQ scores, but the association was not significant after adjusting for maternal age at delivery, nor was there a significant interaction with sex. Maternal estradiol levels were negatively associated with BASC-3 Clinical Probability scores among males (n = 139). We report a significant interaction effect of cord blood testosterone and fetal sex on both total SCQ scores and t-scores on the Developmental Social Disorders subscale. Placental aromatase was not associated with any neurodevelopmental or hormone measure, but under conditions of low placental aromatase expression, high maternal testosterone was positively associated with SCQ scores in males (n = 46). No other associations between hormone levels and neurodevelopment were significant. Our findings provide a foundation for further investigation of the mechanisms through which maternal sex hormones and placental steroidogenesis may affect fetal hormone production and neurobehavior.

SUPRAPHYSIOLOGIC SERUM ESTRADIOL NEGATIVELY IMPACTS EUPLOID EMBRYO IMPLANTATION

Euploid embryo transfer failure remains a frustrating clinical conundrum for patients and providers. Emerging research now focuses on optimizing the embryo (beyond euploidy) versus maternal environment, though many questions remain. This study evaluated how maternal estradiol level at time of embryo transfer influences the success of single euploid embryo transfer.

Maternal steroid levels and the autistic traits of the mother and infant

BackgroundPrenatal sex steroids have been associated with autism in several clinical and epidemiological studies. It is unclear how this relates to the autistic traits of the mother and how early this can be detected during pregnancy and postnatal development.MethodsMaternal serum was collected from pregnant women (n = 122) before or during their first ultrasound appointment [mean = 12.7 (SD = 0.7) weeks]. Concentrations of the following were measured via immunoassays: testosterone, estradiol, dehydroepiandrosterone sulphate, progesterone; and sex hormone-binding globulin which was used to compute the free fractions of estradiol (FEI) and testosterone (FTI). Standardised human choriogonadotropin (hCG) and pregnancy-associated plasma protein A (PAPP-A) values were obtained from clinical records corresponding to the same serum samples. Mothers completed the Autism Spectrum Quotient (AQ) and for their infants, the Quantitative Checklist for Autism in Toddlers (Q-CHAT) when the infants were between 18 and 20 months old.ResultsFEI was positively associated with maternal autistic traits in univariate (n = 108, Pearson’s r = 0.22, p = 0.019) and multiple regression models (semipartial r = 0.19, p = 0.048) controlling for maternal age and a diagnosis of PCOS. Maternal estradiol levels significantly interacted with fetal sex in predicting infant Q-CHAT scores, with a positive relationship in males but not females (n = 100, interaction term: semipartial r = 0.23, p = 0.036) after controlling for maternal AQ and other covariates. The opposite was found for standardised hCG values and Q-CHAT scores, with a positive association in females but not in males (n = 151, interaction term: r = −0.25, p = 0.005).LimitationsSample size of this cohort was small, with potential ascertainment bias given elective recruitment. Clinical covariates were controlled in multiple regression models, but additional research is needed to confirm the statistically significant findings in larger cohorts.ConclusionMaternal steroid factors during pregnancy are associated with autistic traits in mothers and their infants.

Reduced Intellectual Ability in Offspring of Ovarian Hyperstimulation Syndrome: A Cohort Study

BackgroundOvarian hyperstimulation syndrome (OHSS), a complication of ovarian stimulation, has various adverse effects on both pregnant women and their offspring. However, whether OHSS will affect intellectual ability in offspring is still unknown. MethodsWe recruited 86 Chinese children born to OHSS women and 172 children conceived with non-OHSS In Vitro Fertilization (IVF) in this cohort study. Their intellectual ability was assessed according to the Revised Chinese Version of the Wechsler Intelligence Scale for Children (C-WISC). Verbal Intelligence Quotient (VIQ), Performance Intelligence Quotient (PIQ), and Full Intelligence Quotient (FIQ) were calculated. The investigation was registered in Chinese Clinical Trial Registry (ChiCTR-SOC-16009555). FindingsOHSS offspring scored less on C-WISC (mean (standard deviation [SD]): (VIQ=92.7 (14.7), PIQ=108.9 (13.1), FIQ=100.6 (13.4)) compared with non-OHSS IVF offspring (VIQ=100.1 (13.2), PIQ=113.7 (10.8), FIQ=107.4 (11.5)). The prevalence of low IQ (<80) children was 4.7 times higher in OHSS offspring compared with non-OHSS offspring. Maternal estradiol level on hCG administration day was negatively associated with FIQ in offspring. InterpretationOHSS offspring displayed reduced intellectual ability. Prenatal estradiol exposure might be involved in underlying mechanism.

The Steroid Hormone Environment During Primordial Follicle Formation in Perinatal Mouse Ovaries1

Primordial follicle assembly is essential for reproduction in mammalian females. Oocytes develop in germ cell cysts that in late fetal development begin break down into individual oocytes and become surrounded by pregranulosa cells, forming primordial follicles. As they separate, many oocytes are lost by apoptosis. Exposure to steroid hormones delays cyst breakdown, follicle formation, and associated oocyte loss in some species. One model for regulation of follicle formation is that steroid hormones in the maternal circulation keep cells in cysts and prevent oocyte death during fetal development but that late in pregnancy hormone levels drop, triggering cyst breakdown and associated oocyte loss. However, herein we found that, while maternal circulating levels of progesterone drop during late fetal development, maternal estradiol levels remain high. We hypothesized that fetal ovaries were the source of hormones and that late in fetal development their production stops. To test this, mRNA and protein levels of steroidogenic enzymes required for estradiol and progesterone synthesis were measured. We found that aromatase and 3-beta-hydroxysteroid dehydrogenase mRNA levels drop before cyst breakdown. The 3-beta-hydroxysteroid dehydrogenase protein levels also dropped, but we did not detect a change in aromatase protein levels. The steroid content of perinatal ovaries was assayed, and both estradiol and progesterone were detected in fetal ovaries before cyst breakdown. To determine the role of steroid hormones in oocyte development, we examined the effects of blocking steroid hormone production in organ culture and found that the number of oocytes was reduced, supporting our model that steroid hormones are important for fetal oocyte survival.

Effects of Estrogen Coadministration on Epoxiconazole Toxicity in Rats

Epoxiconazole (EPX; CAS-No. 133855-98-8) is a triazole class-active substance of plant protection products. At a dose level of 50 mg/kg bw/day, it causes a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (gestation day [GD] 7-18 or 21), as reported previously (Taxvig et al., 2007, 2008) and confirmed in these studies. Late fetal resorptions occurred in the presence of significant maternal toxicity such as clear reduction of corrected body weight gain, signs of anemia, and, critically, a marked reduction of maternal estradiol plasma levels. Furthermore, estradiol supplementation at dose levels of 0.5 or 1.0 μg/animal/day of estradiol cyclopentylpropionate abolished the EPX-mediated late fetal resorptions. No increased incidences of external malformations were found in rats cotreated with 50 mg/kg bw/day EPX and estradiol cyclopentylpropionate, indicating that the occurrence of malformations was not masked by fetal mortality under the study conditions. Overall, the study data indicate that fetal mortality observed in rat studies with EPX is not the result of direct fetal toxicity but occurs indirectly via depletion of maternal estradiol levels. The clarification of the human relevance of the estrogen-related mechanism behind EPX-mediated late fetal resorptions in rats warrants further studies. In particular, this should involve investigation of the placenta (Rey Moreno et al., 2013), since it is the materno-fetal interface and crucial for fetal maintenance. The human relevance is best addressed in a species which is closer to humans with reference to placentation and hormonal regulation of pregnancy, such as the guinea pig (Schneider et al., 2013).

Light exposure at night, sleep duration and sex hormone levels in pregnant Japanese women

The association between light exposure at night and sex hormone levels in utero has scarcely reported. We assessed the associations between sleep duration or being awake in the late evening hours, which can be as indicator of light exposure at night, and the maternal and umbilical blood hormone levels during pregnancy and at delivery among Japanese women. The data for 236 women and their newborns who visited a maternal clinic in Gifu, Japan, between May 2000 and October 2001 were analyzed. Maternal blood samples were obtained at approximately the 10th weeks, 29th weeks of gestation, and at delivery. Umbilical cord artery blood was immediately drawn after birth. Information for sleep during pregnancy was obtained by a self-administered questionnaire. The levels of estradiol and testosterone were measured using radioimmunoassay. Maternal serum testosterone level in the 10th week was higher among those who were awake at or after 1:00 a.m. than among those who were asleep at that time (P = 0.032). Maternal estradiol level in the 29th week was inversely associated with sleep duration on weekends (P = 0.043). Umbilical testosterone level at delivery inversely correlated with sleep duration on weekdays (P = 0.030). These associations were somewhat stronger among mothers with female offspring than those with male offspring. These results suggested that exposure to light at night might increase sex hormone levels during pregnancy.

Developmental Programming: Impact of Excess Prenatal Testosterone on Intrauterine Fetal Endocrine Milieu and Growth in Sheep1

Prenatal testosterone excess in sheep leads to reproductive and metabolic disruptions that mimic those seen in women with polycystic ovary syndrome. Comparison of prenatal testosterone-treated sheep with prenatal dihydrotestosterone-treated sheep suggests facilitation of defects by androgenic as well as androgen-independent effects of testosterone. We hypothesized that the disruptive impact of prenatal testosterone on adult pathology may partially depend on its conversion to estrogen and consequent changes in maternal and fetal endocrine environments. Pregnant Suffolk sheep were administered either cottonseed oil (control) or testosterone propionate in cottonseed oil (100 mg, i.m. twice weekly), from Day 30 to Day 90 of gestation (term is ~147 d). Maternal (uterine) and fetal (umbilical) arterial samples were collected at Days 64-66, 87-90, and 139-140 (range; referred to as D65, D90, and D140, respectively) of gestation. Concentrations of gonadal and metabolic hormones, as well as differentiation factors, were measured using liquid chromatography/mass spectrometer, radioimmunoassay, or ELISA. Findings indicate that testosterone treatment produced maternal and fetal testosterone levels comparable to adult males and D65 control male fetuses, respectively. Testosterone treatment increased fetal estradiol and estrone levels during the treatment period in both sexes, supportive of placental aromatization of testosterone. These steroidal changes were followed by a reduction in maternal estradiol levels at term, a reduction in activin A availability, and induction of intrauterine growth restriction in D140 female fetuses. Overall, our findings provide the first direct evidence in support of the potential for both androgenic as well as estrogenic contribution in the development of adult reproductive and metabolic pathology in prenatal testosterone-treated sheep.

Association of maternal fat and alcohol intake with maternal and umbilical hormone levels and birth weight

High levels of estrogen during pregnancy have been hypothesized to increase the risk of breast cancer in offspring. Some studies have reported a positive association of estrogen level during pregnancy with fetal size, which has been linked to the subsequent risk of breast cancer in offspring. We examined whether maternal diet, including fat and alcohol intake, was associated with hormone levels during pregnancy, as well as with birth weight. The concentrations of estradiol, estriol, and testosterone were measured in the maternal serum and umbilical cord blood of 189 women during pregnancy and at delivery. Intakes of fat, alcohol, and other nutrients were assessed by 5-day diet records at approximately the 29th week of pregnancy before blood sampling. Intake of polyunsaturated fatty acids was moderately but significantly positively correlated with the umbilical cord estriol level (r = 0.17, P = 0.03) after controlling for covariates. The positive association between intake of polyunsaturated fatty acids and birth weight was of borderline significance (r = 0.14, P = 0.06). Intake of long-chain n-3 fatty acids was significantly inversely correlated with the umbilical cord estradiol and testosterone levels (r = -0.18, P = 0.02 and r = -0.24, P = 0.002, respectively). Alcohol intake was significantly positively correlated with the maternal estradiol level in the 29th week of pregnancy (r = 0.19, P = 0.01), but was unrelated to birth weight. Estrogen level during pregnancy may be regulated by dietary polyunsaturated fatty acids and mediate their effects on fetal growth.

Alcohol consumption and serum hormone levels during pregnancy

Factors that change sex hormone levels during pregnancy may have long-term health consequences for the offspring, including changes in breast cancer risk. A cross-sectional analysis of alcohol consumption and hormone levels in 339 pregnant women sampled from the Child Health and Development Study cohort was undertaken. Alcohol intake was queried from 1959 to 1966, long before any hazards of drinking during pregnancy were publicized. Third trimester serum hormone levels including estradiol and testosterone were analyzed. Among 339 pregnant women, 196 reported some alcohol consumption during pregnancy. The drinkers were divided into three groups with intake levels of 0.2–0.5, 0.6–2.0, and 2.1–12.5 ounces of ethanol per week. The second group corresponds to a median intake of ∼2 drinks per week, and the last group corresponds to a median intake of ∼1 drink per day, which is considered “light” to “moderate” drinking. Maternal estradiol levels were not associated with alcohol intake during pregnancy. However, serum testosterone was significantly lower, by 12.2%, in the latter two groups of drinking pregnant women, [confidence interval (CI) = −3.0 to 25.2] and 25.6% (CI = 9.2–39.5), respectively. The alcohol intakes reported are far below those shown to cause fetal alcohol syndrome, or any of the fetal alcohol effects so far studied. Light alcohol intake during pregnancy is associated with lower maternal testosterone. The health implications are uncertain, but may include an increased breast density in the daughters of drinking mothers.

Effects of 17-β-estradiol treatment of female zebra finches on offspring sex ratio and survival

Treatment of female zebra finches ( Taeniopygia guttata) with 17-β-estradiol leads to a female-biased sex ratio in their offspring at the age of independence [Horm. Behav. 35 (1999) 135]. It is unclear whether this is due to a bias of the primary sex ratio or to sex-specific survival. We replicated this experiment and found again a significantly higher total number of daughters than sons at independence in the estradiol-treated group. This was due to higher embryonic survival of daughters compared with sons in the estradiol-treated group and the reverse in the control group. There was no effect of the hormone treatment on the primary sex ratio. Treatment with 17-β-estradiol led to a significantly shorter hatching time and to heavier offspring at day 7 after hatching. This weight was correlated with maternal plasma estradiol levels on the day of the first egg, which were significantly higher in the estradiol-treated group than in the control group. The results do not support the idea that maternal estradiol levels influence the primary sex ratio. They indicate that maternal estradiol differentially affects survival of sons and daughters via an influence on the embryonic environment, possibly enhancing offspring growth.

Maternal estradiol levels in relation to offspring cognition and behavior among firstborns

Maternal estradiol levels in relation to offspring cognition and behavior among firstborns

Birth order and breast cancer risk

It has been hypothesized that prenatal exposure to maternal estrogens may be a risk factor for breast cancer in the offspring. In two recent studies, maternal estradiol levels in the first pregnancy have been compared to those in the second, and in both studies levels were higher in the first pregnancy. If both the hypothesis and the reported findings were true, women born as their mother's second child would be expected to have lower risk for breast cancer than first-born women. Data from 1,468 cases of breast cancer and 4,175 hospital controls from three previously published studies were modelled through multiple logistic regression to evaluate this possibility. The size of the woman's sibship was not related to breast cancer risk. On the other hand, second-born women had, as predicted, lower breast cancer risk than first-born women, although the difference was nominally significant only among premenopausal women. The relative risk for breast cancer, contrasting second-born to first-born women, and the corresponding 95 per cent confidence intervals, were 0.71 (0.54-0.94) among premenopausal women, 0.94 (0.76-1.17) among postmenopausal women, and 0.86 (0.73-1.02) among all women, controlling for menopausal status.

Maternal estradiol response to alterations in uteroplacental blood flow

Low levels of maternal estrogens are commonly regarded as indicators of fetal stress. We continuously monitored distal aortic blood flow by flowmeter, fetal heart rate, and amniotic fluid pressure in seven pregnant baboons near term. Four of the animals received a constant intravenous infusion of [7-3H]dehydroepiandrosterone and [4-14C]estradiol for 270 minutes. A 50% reduction in mean distal aortic blood flow was imposed after 60 minutes by means of partial occlusion of the aorta with a snare device and released at 180 minutes. Blood was collected at 10-minute intervals from 30 to 60 minutes, 120 to 180 minutes, and 240 to 270 minutes. Concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, estradiol, and cortisol in maternal plasma were determined by radioimmunoassay. Metabolic clearance rates of dehydroepiandrosterone and estradiol were calculated from plasma concentrations of [3H]dehydroepiandrosterone and [14C]estradiol. There was no significant change in maternal levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, or cortisol with alterations in distal aortic blood flow. Three animals exhibited no fetal heart rate evidence of fetal stress; estradiol levels declined during occlusion and returned toward control after release of the snare. Four animals exhibited repetitive late decelerations under conditions of reduced flow; estradiol was unchanged or rose slightly during occlusion but increased three- to 10-fold after release whereas the metabolic clearance rate of both dehydroeplandrosterone and estradiol remained stable. We conclude that (1) placental hypoperfusion without fetal stress results in decreased conversion of aromatizable substrate and (2) elevated maternal estradiol levels during acute hypoxemic fetal stress probably represent increased production of fetal androgen.