Higher E2 Levels Research Articles

Does the elevated estradiol level on the day of human chorionic gonadotropin administration affect embryo quality among women undergoing in vitro fertilization?

To evaluate the association between estradiol (E2 ) levels on the day of human chorionic gonadotropin (hCG) administration and embryo quality during in vitro fertilization (IVF) cycles. A retrospective study of 6676 IVF cycles among women treated at the Reproductive Center of The First Affiliated Hospital of USTC, Hefei, China, from June 2014 to May 2017. E2 levels on hCG day were divided into four groups by 25th percentile: 0-1763pg/mL (group I), 1763-3692pg/mL (group II), 3692-4800pg/mL (group III), and higher than 4800pg/mL (group IV). Analysis of variance and multiple linear regression were used to test associations. There were significant differences in the frequency of high-quality embryos between group I (51.6±1.1%) and groups II (65.6±0.8%), III (62.1±0.7%), and IV (62.3±0.7%). Using E2 as a dummy variable and group II as a control, multiple linear regression showed that E2 levels were associated with the frequency of high-quality embryos obtained (P<0.05). Serum E2 on hCG day had an impact on embryo quality. Higher E2 levels did not produce the most high-quality embryos; the highest frequencies were achieved for E2 levels within 1763-3692pg/mL.

Associations among urinary triclosan and bisphenol A concentrations and serum sex steroid hormone measures in the Canadian and U.S. Populations

Exposure to triclosan, an antimicrobial agent, and bisphenol A (BPA), the monomer of polycarbonate plastics, is widespread. Endocrine-disrupting impacts of these chemicals have been demonstrated in in vitro studies, rodent toxicology studies, and some human observational studies. Here we compared urinary concentrations of triclosan and BPA in the Canadian and U.S. populations using nationally-representative data from the 2012–2015 Canadian Health Measures Survey (CHMS) and the 2013–2016 National Health and Nutrition Examination Survey (NHANES). We then examined the cross-sectional associations of urinary triclosan or BPA with serum sex steroid hormones, including estradiol (E2), progesterone (P4), and testosterone (T), using multivariable regression. We observed differences in creatinine-standardized chemical concentrations between countries; urinary triclosan was higher in Canadian females aged 12–19 years, while BPA was higher in U.S. females aged 20–49 years. We also found significant associations among urinary chemicals and serum E2 and T, but not P4. Increasing triclosan was associated with higher levels of E2 in 6–11-year-old girls, but with lower levels of E2 and T in adolescent boys aged 12–19 years. Increasing BPA was associated with lower levels of E2 in 6–11-year-old boys and in adolescents aged 12–19 years of either sex. We observed a U-shaped association between urinary triclosan and E2 in male adults aged 50–79 years; no associations between BPA and hormones were detected in adults. These results, in accordance with the in vitro and animal literature, suggest that triclosan and BPA exposures may be cross-sectionally associated with altered reproductive hormone levels, especially in children and adolescents. Further research and prospective studies are necessary to elucidate country-specific differences in chemical exposures and the potential public health significance of these findings.

Interactions of Cortisol and Prolactin with Other Selected Menstrual Cycle Hormones Affecting the Chances of Conception in Infertile Women.

One of the major problems of success in infertility treatment could depend on the understanding how the potential factors may affect the conception. The aim of this study was to evaluate present understanding of such factors or hormonal causes that may induce infertility. We studied the interactions between the two menstrual cycle hormones i.e., cortisol (COR) and prolactin (PRL), along with the ultrasonographic ovulation parameters in a group of N = 205 women with diagnosed infertility. The control group consisted of N = 100 women with confirmed fertility. In both groups, follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), thyroid stimulating hormone (TSH), PRL, COR were examined on the third day of the cycle, and estradiol (E2), progesterone (P), and COR were examined during ovulation and 7-days afterwards. In the infertile group, higher levels of PRL and COR were observed than that of in the control group. Cortisol levels at all phases of the menstrual cycle and PRL negatively correlated with E2 secretion during and after ovulation, thus contributed to the attenuation of the ovulatory LH surge. Infertile women who conceived presented with higher levels of E2 during and after ovulation, higher P after ovulation, and thicker endometrium than that of the women who failed to conceive. In conclusion, elevated secretion of COR and PRL in infertile women impairs the menstrual cycle by decreasing the pre-ovulatory LH peak and E2 and postovulatory E2 levels that affect the endometrial growth, and consequently reduce the chances to conceive.

Further evidence that a supraphysiologic estradiol level during ovarian stimulation affects birthweight: findings of fresh and frozen embryo transfer with comparable estradiol levels on human chorionic gonadotropin trigger

Studies have reported a supraphysiologic estradiol (E2) level during ovarian stimulation may be related to low birthweight after fresh embryo transfer (ET), but whether a high E2 level in the stimulation cycle affects birthweight via frozen ET remained controversial. The study was to investigate whether a supraphysiologic E2 level in ovarian stimulation cycle affects birth weight in infants conceived via subsequent FET. In this retrospective cohort study, 2525 singletons conceived via FET and 2668 singletons conceived via fresh ET were analyzed. The birthweight and incidences of small for gestational age (SGA) in infants conceived via FET in groups with low and high levels of E2 did not differ significantly. Multivariate analyses showed that the peak E2 level was not predictive of SGA in infants conceived via FET. Singletons conceived via fresh ET had a higher risk of SGA than those conceived via FET even after comparable previous exposure to a high level of E2 > 3000 pg/mL. Our study results indicated that the increased risk of SGA was at least partly a result of the supraphysiologic E2 exposure to the intrauterine environment.

Melatonin stimulates aromatase expression and estradiol production in human granulosa-lutein cells: relevance for high serum estradiol levels in patients with ovarian hyperstimulation syndrome

Ovarian hyperstimulation syndrome (OHSS) is one of the most life-threatening and potentially fatal complications associated with controlled ovarian hyperstimulation (COH) during in vitro fertilization (IVF) treatment. Although the pathogenesis of OHSS remains unclear, elevated serum estradiol (E2) levels before human chorionic gonadotropin (hCG) administration are associated with the risk of OHSS. The pineal hormone melatonin and its receptors are expressed in human granulosa cells and have been shown to stimulate E2 production. However, the effect of melatonin on the expression of aromatase, an enzyme responsible for a key step in the biosynthesis of E2, in human granulosa cells remains to be determined. Here, we demonstrate that melatonin upregulates aromatase expression in primary cultured human granulosa-lutein (hGL) cells through the melatonin receptor-mediated PKA-CREB pathway. Using a mouse model of OHSS, we demonstrate that administration of the melatonin receptor inhibitor luzindole inhibits the development of OHSS. In addition, the expression of ovarian aromatase and serum E2 levels are upregulated in OHSS mice compared to control mice, but this upregulation is attenuated by inhibition of the function of melatonin. Moreover, clinical results reveal that aromatase expression levels are upregulated in hGL cells from OHSS patients. Melatonin and E2 levels in the follicular fluid are significantly higher in OHSS patients than in non-OHSS patients. Furthermore, melatonin levels are positively correlated with E2 levels in follicular fluid. This study helps to elucidate the mechanisms mediating the expression of aromatase in hGL cells and provides a potential mechanism explaining the high E2 levels in patients with OHSS.

Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17β-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4+ T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

Follicle stimulating hormone and estradiol trajectories from menopausal transition to late postmenopause in indigenous Chinese women

Objective The aim of this study was to examine follicle stimulating hormone (FSH) and estradiol (E2) trajectories in indigenous Chinese women through the ovarian aging process from 10 years before the final menstrual period (FMP) to 20 years after. Methods A prospective community-based longitudinal cohort study of 362 Chinese middle-aged women with a clearly determined FMP was performed. Results FSH and E2 trajectories were identified according to years from FMP and the Stages of Reproductive Aging Workshop + 10 (STRAW + 10), and further classified by body mass index. E2 decreases relatively steadily from Stage −2 to +1c, while FSH stabilizes quickly from Stage −2 to +1a. Obese women have higher E2 levels and lower FSH levels during menopausal transition, which last for decades after the FMP. There was no obvious decline in FSH levels for at least 20 years after the FMP. Conclusions The FSH and E2 trajectories in this indigenous Chinese cohort appear similar to those discussed in the Study of Women’s Health Across the Nation, with ethnic differences. STRAW + 10 criteria may be used to ascertain the ovarian aging process in Chinese women. Obese women may experience different levels of hormonal fluctuations during the menopause transition, while FSH levels in all women appear to remain high even at late postmenopause.

Resolution of Pulmonary Inflammation Induced by Carbon Nanotubes and Fullerenes in Mice: Role of Macrophage Polarization.

Pulmonary exposure to certain engineered nanomaterials (ENMs) causes chronic lesions like fibrosis and cancer in animal models as a result of unresolved inflammation. Resolution of inflammation involves the time-dependent biosynthesis of lipid mediators (LMs)—in particular, specialized pro-resolving mediators (SPMs). To understand how ENM-induced pulmonary inflammation is resolved, we analyzed the inflammatory and pro-resolving responses to fibrogenic multi-walled carbon nanotubes (MWCNTs, Mitsui-7) and low-toxicity fullerenes (fullerene C60, C60F). Pharyngeal aspiration of MWCNTs at 40 μg/mouse or C60F at a dose above 640 μg/mouse elicited pulmonary effects in B6C3F1 mice. Both ENMs stimulated acute inflammation, predominated by neutrophils, in the lung at day 1, which transitioned to histiocytic inflammation by day 7. By day 28, the lesion in MWCNT-exposed mice progressed to fibrotic granulomas, whereas it remained as alveolar histiocytosis in C60F-exposed mice. Flow cytometric profiling of whole lung lavage (WLL) cells revealed that neutrophil recruitment was the greatest at day 1 and declined to 36.6% of that level in MWCNT- and 16.8% in C60F-treated mice by day 7, and to basal levels by day 28, suggesting a rapid initiation phase and an extended resolution phase. Both ENMs induced high levels of proinflammatory leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) with peaks at day 1, and high levels of SPMs resolvin D1 (RvD1) and E1 (RvE1) with peaks at day 7. MWCNTs and C60F induced time-dependent polarization of M1 macrophages with a peak at day 1 and subsequently of M2 macrophages with a peak at day 7 in the lung, accompanied by elevated levels of type 1 or type 2 cytokines, respectively. M1 macrophages exhibited preferential induction of arachidonate 5-lipoxygenase activating protein (ALOX5AP), whereas M2 macrophages had a high level expression of arachidonate 15-lipoxygenase (ALOX15). Polarization of macrophages in vitro differentially induced ALOX5AP in M1 macrophages or ALOX15 in M2 macrophages resulting in increased preferential biosynthesis of proinflammatory LMs or SPMs. MWCNTs increased the M1- or M2-specific production of LMs accordingly. These findings support a mechanism by which persistent ENM-induced neutrophilic inflammation is actively resolved through time-dependent polarization of macrophages and enhanced biosynthesis of specialized LMs via distinct ALOX pathways.

Hormonal and biochemical studies on female dromedary camels affected with multiple ovarian cysts

Abstract The purpose of the present study was to investigate the hormonal and biochemical profile of dromedary she-camels with multiple ovarian cysts (MOC). Seventeen she-camels suffering from MOC and 10 control animals were enrolled in this study. Blood samples were collected from all animals. Progesterone (P4), estradiol 17-β (E2), Testosterone, tri-iodothyronine (T3), Thyroxine (T4), glucose, total protein, albumin, total cholesterol, triglycerides, HDL, nitric oxide (NO), malondialdehyde (MDA) and glutathione peroxidase (GPX) levels were estimated in blood serum. Results revealed the presence of three or more large follicular ovarian cysts either on one (n = 6) or both ovaries (n = 11) of MOC cases with absence of any luteal structure. She-camels with multiple MOC had significantly (P ≤ 0.001) lower levels of P4 (0.24 ± 0.02 vs. 0.40 ± 0.03 ng/mL, respectively) and significantly higher levels of E2 and T3 (19.62 ± 0.62 vs. 13.74 ± 0.67 pg/mL, P ≤ 0.001 and 1.85 ± 0.09 vs. 1.44 ± 0.10 ng/mL, P ≤ 0.012, respectively) as compared with control. There were no significant differences between the two groups regarding testosterone and T4 levels (0.031 ± 0.002 vs. 0.026 ± 0.001 and 10.93 ± 0.24 vs. 10.17 ± 0.28 ng/mL, respectively). She-camels having MOC had significantly higher levels of glucose, cholesterol, triglycerides, HDL, total lipids and MDA and lower levels of GPX and NO as compared with control group. There were no significant differences between the two groups in levels of total proteins, albumin and globulin. In conclusion, the hormonal imbalances, metabolic disorders and oxidative stress are involved in the formation and/or persistence of multiple ovarian cysts in dromedary camels.

Impact of Supraphysiological Estradiol Serum Levels on Birth Weight in Singletons Born After Fresh Embryo Transfer

In assisted reproductive technology, high estradiol (E2) levels at trigger may increase the risk of low birth weight (LBW). Our objective was to investigate the impact of supra-physiological E2 levels at trigger, on the rate of LBW in singleton pregnancies following fresh embryo transfers (ET), in a center that typically employs the 'freeze-all' strategy in case of high E2 levels, to prevent ovarian hyper stimulation syndrome risk. A cohort study was conducted in a university hospital between November 2012 and January 2017. The main inclusion criterion was having a live birth (LB) singleton (≥ 24weeks of gestation) after a fresh-ET. Four groups were defined according to the E2 level at trigger, as quartiles of the entire patient population. The main measured outcome was the rate of LBW. 497 fresh-ET led to LB. Mean E2 level was 1608.4 ± 945.5pg/ml. The groups were allocated as follows: 124LB in the Group E2 < 25 percentile(p) (1106.5pg/ml), 124LB in the Group E2 [25p-50p] (1106.5-1439pg/ml), 124LB in the Group E2[50p-75p] (1440-1915pg/ml), and 125LB in the Group E2 > 75p (>1915pg/ml). There was no significant difference in the rate of LBW (Group E2 < 25p, n = 8/124, (6.5%); Group E2[25p-50p], n = 15/124, (12.1%); Group E2 [50p-75p], n = 13/124, (10.4%); and Group E2 > 75p, n = 10/12, (8.1%); (p = 0.43)). After multivariate analysis, E2 level at trigger was not significantly correlated to the rate of LBW. In our cohort, E2 level on the day of hCG trigger was not associated with increased odds of LBW after fresh embryo transfers.

Association between higher levels of serum estradiol and elevated levels of fibrin (fibrinogen) degradation products in late pregnancy following assisted reproductive technology treatment

IntroductionAssisted reproductive technology (ART) treatment is a risk factor for pregnancy-related venous thromboembolism (VTE). This study aims to explore the risk factors for elevated fibrin (fibrinogen) degradation products (FDPs), an indicator of hypercoagulability, in late pregnancy among women who underwent ART treatment. Materials and methodsThis retrospective case-control study recruited 227 women who spontaneously conceived and 214 women who underwent ART treatment and gave birth. A subgroup analysis of the 214 pregnant women after ART treatment was performed. 156 women with elevated FDP levels and 58 women with normal FDP levels were designated as the case and control groups, respectively. ResultsWe found that ART treatment was a risk factor for higher FDP. After adjustments were made for confounders in the group of 214 women after ART treatment, fresh embryo transfer (adjusted odds ratio (aOR) = 3.33, 95% confidence interval (CI), 1.57–7.03) and >10 oocytes retrieved (aOR = 2.09, 95% CI, 1.10-3.99) were associated with elevated FDP in late pregnancy. Serum estradiol (E2) levels on human chorionic gonadotropin (hCG) trigger day were higher in the high-FDP group. A positive correlation between E2 on hCG trigger day and FDP was found for both fresh embryo transfer (r = 0.67, p < 0.001) and frozen embryo transfer (FET) (r = 0.53, p < 0.001). ConclusionsA higher E2 level on hCG trigger day is closely associated with dysfunction of coagulation and fibrinolysis in late pregnancy. When performing the thromboprophylaxis assessment during pregnancy, clinicians should pay more attention to patients who had previous ART treatment and had a high E2 level on hCG trigger day.

Analysis of the Relationship between the Levels of Androgens and Biochemical Bone Markers in Men Aged 60-75 Years.

Introduction: The purpose of this study was to analyze the relationship between the parameters of bone turnover and the levels of hormonal parameters, such as total testosterone (TT), bioavailable and free testosterone (FT), and estradiol (E2) in men. Material and methods: The study group included 63 men with testosterone deficiency syndrome (TDS). The control group consisted of 112 patients without TDS. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of osteocalcin (OC), parathyroid hormone (PTH), E2, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEAS), insulin (I), Serum CrossLaps (CtX-I), human procollagen I N-terminal peptide (PINP), and TT. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Results: The groups with TSD and without TDS differed in terms of the following parameters: body weight (p = 0.001), BMI (p = 0.003), TT (p = 0.001), FT (p = 0.004), bioavailable testosterone (p = 0.001), E2 (p = 0.003), SHBG (p = 0.003), and PINP (p = 0.004). In the group without TDS, higher PINP levels were accompanied by higher levels of E2 (beta = 0.360, p = 0.002) and TT (beta = 0.389, p = 0.001). In the group without TDS, PINP was positively correlated with E2 (beta = 0.726, p <0.001). Patients with TDS had significantly lower PINP levels (p < 0.004). Conclusions: Analysis of sex hormones and biochemical bone markers in reflecting the quality of the bone tissue in men may suggest a relationship between these parameters. Nevertheless, further research based on a larger sample size is necessary to better describe this relationship.

Field survey of environmental estrogen pollution in the coastal area of Tokyo Bay and Nagasaki City using the Japanese common goby Acanthogobius flavimanus

Endocrine disrupting chemicals (EDCs) are common pollutants in coastal waters. To investigate the estrogen risk of EDCs in the coastal areas of Japan, the Japanese common goby, which is a commonly observed species in these waters, was used as the target fish. Plasma 17β-estradiol (E2) and vitellogenin (VTG) levels were analyzed and the gonads of fish collected from the Taira River (northern Nagasaki, reference site), Nagasaki Port, and two sites in Tokyo Bay were observed. Abnormal levels (>150 ng/mL, p < 0.05) of plasma VTG and high levels of plasma E2 were detected in the fish from Nagasaki Port and Tokyo Bay, whereas the levels of both were low in the fish from the Taira River. The target EDCs, including natural estrogen [estrone (E1), and E2] and alkylphenols [4-t-octylphenol (4-t-OP), 4-nonylphenol (4-NP), and bisphenol-A (BPA)] in water samples were quantified using gas chromatography tandem mass spectrometry (GC/MS/MS), respectively. It was observed that the E2-equivalent (EEQ) in Nagasaki Port and Tokyo Bay, which was calculated from the actual EDC measurement value, were almost 20- and 150-fold higher, respectively, than that at the reference site (Taira River, 0.021 ng/L). The EEQs mostly comprised natural estrogen in the sampling sites, although there was some influence of alkylphenols. There was an association between the EEQ and the E2 in environmental water, suggesting a high estrogen risk in Japan coastal waters. Moreover, the results indicated that abnormal VTG synthesis was induced by environmental estrogen (EE) pollution in Nagasaki Port and Tokyo Bay.

Oocyte exposure to supraphysiological estradiol during ovarian stimulation increased the risk of adverse perinatal outcomes after frozen-thawed embryo transfer: a retrospective cohort study.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22-3.06; aOR2 = 2.05, 95% CI: 1.33-3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30-3.11; aOR2 = 2.51, 95% CI: 1.69-3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03-2.45; aOR2 = 1.99, 95% CI: 1.05-3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

Human chorionic gonadotropin-induced amphiregulin stimulates aromatase expression in human granulosa-lutein cells: a mechanism for estradiol production in the luteal phase.

Does amphiregulin (AREG), the most abundant and important epidermal growth factor receptor (EGFR) ligand in the follicular fluid, regulate aromatase expression in human granulosa-lutein (hGL) cells? AREG mediates the hCG-induced up-regulation of aromatase expression and estradiol (E2) production in hGL cells. AREG expression and secretion are rapidly induced by hCG in hGL cells and mediate physiological functions of LH/hCG in the ovary. EGFR protein is expressed in follicles not only in the pre-ovulatory phase but also throughout the luteal phase of the menstrual cycle. After the LH surge, the human corpus luteum secretes high levels of E2, which regulates various luteal cell functions. Aromatase is an enzyme responsible for a key step in the biosynthesis of E2. However, whether AREG regulates aromatase expression and E2 production in hGL cells remains unexplored. This study is an experimental study performed over a 1-year period. In vitro investigations examined the role of AREG in the regulation of aromatase expression and E2 production in primary hGL cells. Primary hGL cells were obtained from women undergoing IVF treatment in an academic research center. Aromatase mRNA and protein levels were examined after exposure of hGL cells to recombinant human AREG, hCG or LH. The EGFR tyrosine kinase inhibitor AG1478, PI3K inhibitor LY294002 and siRNAs targeting EGFR, LH receptor, StAR and AREG were used to verify the specificity of the effects and to investigate the underlying molecular mechanisms. Reverse transcription quantitative real-time PCR (RT-qPCR) and western blot were used to measure the specific mRNA and protein levels, respectively. Follicular fluid and serum were collected from 65 infertile women during IVF treatment. Pearson's correlation analysis was performed to examine the correlation coefficient between two values. Treatment of hGL cells with AREG-stimulated aromatase expression and E2 production. Using pharmacological inhibitors and specific siRNAs, we revealed that AREG-stimulated aromatase expression and E2 production via EGFR-mediated activation of the protein kinase B (AKT) signaling pathway. In addition, inhibition of EGFR activity and AREG knockdown attenuated hCG-induced up-regulation of aromatase expression and E2 production. Importantly, the protein levels of AREG in the follicular fluid were positively correlated with the E2 levels in serum after 2days of oocyte pick-up and in the follicular fluid of IVF patients. N/A. The in vitro setting of this study is a limitation that may not reflect the real intra-ovarian microenvironment. Clinical data were obtained from a small sample size. Our results provide the first evidence that hCG-induced AREG contributes to aromatase expression and E2 production in the luteal phase of the menstrual cycle. A better understanding of the hormonal regulation of female reproductive function may help to develop new strategies for the treatment of clinical infertility. This work was supported by the National Natural Science Foundation of China for Young Scientists (81601253), the specific fund of clinical medical research of Chinese Medical Association (16020160632) and the Foundation from the First Affiliated Hospital of Zhengzhou University for Young Scientists to Lanlan Fang. This work was also supported by an operating grant from the National Natural Science Foundation of China (81820108016) to Ying-Pu Sun. All authors declare no conflict of interest.

Sex Hormone Phenotypes in Young Girls and the Age at Pubertal Milestones.

The age of pubertal onset is influenced by many variables in young girls. Previous studies have not examined sex hormones longitudinally around the time of breast development and their relationship to pubertal onset. We sought to use an unbiased statistical approach to identify phenotypes of sex hormones in young girls and examine their relationship with pubertal milestones. Longitudinal observational study. In 269 girls, serum concentrations of steroid sex hormones [estradiol (E2), estrone, testosterone, and dehydroepiandrosterone sulfate] were measured by HPLC-mass spectrometry at time points before, at, and after thelarche. Girls were classified into four hormone phenotypes using objective principal components and cluster analyses of longitudinal hormone data. The association between the identified phenotypes and age of pubertal milestones was estimated using Cox proportional hazards modeling. Mean ages at thelarche, pubarche, and menarche were 9.02, 9.85, and 12.30 years, respectively. Girls with low levels of all four hormones, phenotype 3b, were youngest at thelarche (8.67 years); those in phenotype 2, with the highest E2 levels and E2 surge 6 months after thelarche, were youngest at menarche (11.87 years) with shortest pubertal tempo. When controlling for race, maternal age of menarche, caregiver education, and body mass, different phenotypes were associated with the age of pubertal events. Hormone phenotypic clustering can identify clinically relevant subgroups with differing ages of thelarche, pubarche, and menarche. These findings may enhance the understanding of timing of pubertal milestones and risk of adult disease.

Distinctive reproductive tactics between sympatric specimens of Astyanax aff. fasciatus in the wild and in captivity

Astyanax fasciatus is a group of neotropical fish with two different diploid chromosome numbers, and in the wild, these individuals are found in sympatry. The annual reproductive cycles of adult females of species with different numbers of chromosomes (G1: 46 chromosomes, low responsiveness to induced spawning; G2: 48 chromosomes, responsive to induced spawning) were investigated in the wild and in captivity. Plasma estradiol (E2) levels, relative fecundity (RF), oocyte diameter, gonadosomatic index, and ovarian morpho-histology were evaluated to identify the ovarian maturation stage. The G1 females in both environments began the vitellogenic phase during winter, concurrent with increased plasma E2 levels. In wild G1 females, large numbers of vitellogenic oocytes were observed during spring and summer, when plasma E2 levels remained high. In contrast, captive G1 females showed higher E2 levels during the winter. They also retained significantly higher RF and vitellogenic oocyte numbers than wild females, but showed no spawning and slow yolk reabsorption. Wild G2 females began the vitellogenic phase in autumn and had progressively increasing E2 levels that peaked in the spring, with spawning occurring during the summer. In captive G2 females, the E2 levels and RF remained high throughout the year. These data suggest that A. aff. fasciatus with different numbers of chromosomes differ in their reproductive performance in the wild and show altered sensitivity to environmental cues in captivity. Our results indicate that G1 females likely respond best to artificial spawning just after winter, whereas G2 females should respond year-round.

Initiation of the Hypothalamic-Pituitary-Gonadal Axis in Young Girls Undergoing Central Precocious Puberty Exerts Remodeling Effects on the Prefrontal Cortex.

Central precocious puberty (CPP) has been shown to exert significant effects on psychosocial development. These early puberty-related hormones and psychosocial functional changes are considered to be associated with specific brain development. However, the biological mechanisms underlying the sculpting of human brain architecture and modulation of psychosocial transformation by puberty-related hormonal maturation remain elusive, especially during the early phase of CPP. The current investigation aims to specify the brain regions in which early hormone-related maturation effects occur during CPP and their relationships with psychological functions. 65 young girls (aged 4.3–8.0 years) underwent structural imaging on a 3T MR system, completed psychological tests and performed the gonadotropin-releasing hormone (GnRH) stimulation test to identify hormonal manifestations of hypothalamic–pituitary–gonadal axis (HPG axis) activation. Based on the GnRH test, 28 young girls were identified with CPP, whereas the other 37 girls were identified with non-central precocious puberty (NCPP). Cortical parameters were calculated and compared between the two groups after adjusting for age, weight, and height. Brain regions showing group differences were extracted and correlated with serum hormone levels and psychological parameters. The CPP girls showed thinner cortices primarily in the right rostral middle frontal cortex. This morphological difference was positively correlated with stimulated estradiol (E2) levels. Further, higher E2 levels were significantly associated with higher hyperactivity scores. Premature HPG axis activation in CPP girls at an early stage appears to exert remodeling effects on brain anatomy, primarily in the prefrontal cortex, which may affect psychological development following the emergence of robust changes in sex hormones.

Association between diminished ovarian reserve and luteal phase deficiency

To determine the association between biomarkers of ovarian reserve and luteal phase deficiency (LPD). Secondary analysis of a prospective time-to-conceive cohort study. Not applicable. Women attempting conception, aged 30-44years, without known infertility. Measurement of early follicular phase serum levels of antimüllerian hormone, FSH, inhibin B, and E2. The primary outcome was LPD, defined by luteal bleeding (LB) (≥1day of LB) or a short luteal phase length (≤11days). Overall, 755 women provided information on 2,171 menstrual cycles and serum for measurement of at least one biomarker of ovarian reserve. There were 2,096 cycles from 754 women in the LB cohort, of which 40% experienced LB. After adjusting for age, race, previous miscarriages, and previous pregnancies, diminished ovarian reserve (DOR) was not significantly associated with LB. Low early follicular phase FSH levels increased the odds of LB (odds ratio [OR] 1.84; 95% confidence interval [CI] 1.25-2.71), as did high early follicular phase E2 levels (OR 1.59; 95% CI 1.26-2.01). A total of 608 cycles from 286 women were included in the analysis of luteal phase length, of which 13% had a short luteal phase. After adjusting for age, there was no significant association between DOR and a short luteal phase. The risk of a short luteal phase decreased with increasing inhibin B (OR 0.61; 95% CI 0.45-0.81). Although DOR is not associated with LPD, hormone dysfunction in the early follicular phase may contribute to LPD in women of older reproductive age.

Effects of obesity on sperm retrieval, early embryo quality and clinical outcomes in men with nonobstructive azoospermia undergoing testicular sperm aspiration-intracytoplasmic sperm injection cycles.

The objective of this study was to assess the effects of body mass index (BMI) on sperm retrieval, early embryo quality and clinical outcomes in patients with nonobstructive azoospermia (NOA) undergoing testicular sperm aspiration-intracytoplasmic sperm injection (TESA-ICSI). A total of 3,005 infertile couples were evaluated between January 2010 and June 2017, including 1585 normal-weight (BMI<25kg/m2 ), 847 overweight (BMI 25-29.99kg/m2 ) and 573 obese (BMI≥30kg/m2 ) patients. We found no significant relationship between BMI and sperm retrieval rate (22.4%, 24.3% and 25.1%, p=0.327) or sperm motility. Among the 705 patients with NOA who underwent TESA-ICSI cycles, obese individuals had lower T levels and higher E2 levels than normal-weight and overweight individuals. However, there were no significant differences in other male hormones (follicle stimulating hormone [FSH], luteinizing hormone [LH], or prolactin [PRL]) among the groups. We also found that the sperm parameters, embryo quality and clinical outcomes of patients with NOA undergoing TESA-ICSI were not influenced by high BMI levels. In conclusion, this study demonstrated a lack of obvious effects of obesity on sperm retrieval, early embryo quality and clinical outcomes in infertile men undergoing TESA-ICSI cycles, although T and E2 levels were affected.