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Study Question: Does hypo-glycosylated human recombinant FSH (hFSH18/21) have greater in vivo bioactivity that drives follicle development in vivo compared to fully-glycosylated human recombinant FSH (hFSH24)?Summary Answer: Compared with fully-glycosylated hFSH, hypo-glycosylated hFSH has greater bioactivity, enabling greater follicular health and growth in vivo, with enhanced transcriptional activity, greater activation of receptor tyrosine kinases (RTKs) and elevated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and Mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling.What Is Known Already: Glycosylation of FSH is necessary for FSH to effectively activate the FSH receptor (FSHR) and promote preantral follicular growth and formation of antral follicles. In vitro studies demonstrate that compared to fully-glycosylated recombinant human FSH, hypo-glycosylated FSH has greater activity in receptor binding studies, and more effectively stimulates the PKA pathway and steroidogenesis in human granulosa cells.Study Design, Size, Duration: This is a cross-sectional study evaluating the actions of purified recombinant human FSH glycoforms on parameters of follicular development, gene expression and cell signaling in immature postnatal day (PND) 17 female CD-1 mice. To stimulate follicle development in vivo, PND 17 female CD-1 mice (n = 8-10/group) were treated with PBS (150 µl), hFSH18/21 (1 µg/150 µl PBS) or hFSH24 (1 µg/150 µl PBS) by intraperitoneal injection (i.p.) twice daily (8:00 a.m. and 6:00 p.m.) for 2 days. Follicle numbers, serum anti-Müllerian hormone (AMH) and estradiol levels, and follicle health were quantified. PND 17 female CD-1 mice were also treated acutely (2 h) in vivo with PBS, hFSH18/21 (1 µg) or hFSH24 (1 µg) (n = 3-4/group). One ovary from each mouse was processed for RNA sequencing analysis and the other ovary processed for signal transduction analysis. An in vitro ovary culture system was used to confirm the relative signaling pathways.Participants/materials, Setting, Methods: The purity of different recombinant hFSH glycoforms was analyzed using an automated western blot system. Follicle numbers were determined by counting serial sections of the mouse ovary. Real-time quantitative RT-PCR, western blot and immunofluorescence staining were used to determine growth and apoptosis markers related with follicle health. RNA sequencing and bioinformatics were used to identify pathways and processes associated with gene expression profiles induced by acute FSH glycoform treatment. Analysis of RTKs was used to determine potential FSH downstream signaling pathways in vivo. Western blot and in vitro ovarian culture system were used to validate the relative signaling pathways.Main Results and the Role Of Chance: Our present study shows that both hypo- and fully-glycosylated recombinant human FSH can drive follicular growth in vivo. However, hFSH18/21 promoted development of significantly more large antral follicles compared to hFSH24 (P < 0.01). In addition, compared with hFSH24, hFSH18/21 also promoted greater indices of follicular health, as defined by lower BAX/BCL2 ratios and reduced cleaved Caspase 3. Following acute in vivo treatment with FSH glycoforms RNA-sequencing data revealed that both FSH glycoforms rapidly induced ovarian transcription in vivo, but hypo-glycosylated FSH more robustly stimulated Gαs and cAMP-mediated signaling and members of the AP-1 transcription factor complex. Moreover, hFSH18/21 treatment induced significantly greater activation of RTKs, PI3K/AKT and MAPK/ERK signaling compared to hFSH24. FSH-induced indices of follicle growth in vitro were blocked by inhibition of PI3K and MAPK.Large Scale Data: RNA sequencing of mouse ovaries. Data will be shared upon reasonable request to the corresponding author.Limitations, Reasons For Caution: The observations that hFSH glycoforms have different bioactivities in the present study employing a mouse model of follicle development should be verified in nonhuman primates. The gene expression studies reflect transcriptomes of whole ovaries.Wider Implications Of the Findings: Commercially prepared recombinant human FSH used for ovarian stimulation in human ART is fully-glycosylated FSH. Our findings that hypo-glycosylated hFSH has greater bioactivity enabling greater follicular health and growth without exaggerated estradiol production in vivo, demonstrate the potential for its development for application in human ART.Study Funding/competing Interest(s): This work was supported by NIH 1P01 AG029531, NIH 1R01 HD 092263, VA I01 BX004272, and the Olson Center for Women's Health. JSD is the recipient of a VA Senior Research Career Scientist Award (1IK6 BX005797). This work was also partially supported by National Natural Science Foundation of China (No. 31872352). The authors declared there are no conflicts of interest. [ABSTRACT FROM AUTHOR]

Study Question: Is there an association between peak serum estradiol (E2) level during controlled ovarian stimulation (COS) and neonatal birthweight in freeze-all cycles?Summary Answer: Peak serum E2 level during ovarian stimulation is not associated with neonatal birthweight in freeze-all cycles.What Is Known Already: Supraphysiologic E2 levels during COS have been demonstrated to generate a suboptimal peri-implantation endometrial environment and thus lead to adverse neonatal outcomes in fresh embryo transfer cycles. Previous experimental studies also suggested a potential influence of superovulation on oocyte epigenetic programming, but whether it translates into altered phenotypes of fetal growth and development remains unclear in clinical practice. By segmenting the process of COS and embryo transfer, the freeze-all policy provides a novel model to investigate the sole impact of ovarian stimulation on oocytes after ruling out the effects of hyperestrogenic milieu on endometrium in fresh cycles.Study Design, Size, Duration: A retrospective cohort study of 8501 patients who underwent their first COS cycles with a freeze-all strategy and delivered live-born singletons in subsequent frozen-thawed embryo transfer cycles from January 2007 to December 2016 at a tertiary-care academic medical center.Participants/materials, Setting, Methods: Patients were categorized into six groups according to E2 level on trigger day in regular increments of 1000 pg/mL: <1000, 1000-1999, 2000-2999, 3000-3999, 4000-4999 and ≥5000 pg/mL. Univariable and multivariable linear regression and logistic regression analysis were performed to assess the independent association between peak E2 level and measures of neonatal birthweight including absolute birthweight, Z-score, low birthweight (LBW) and small-for-gestational age (SGA).Main Results and the Role Of Chance: The six groups did not differ significantly in birthweight, Z-score or the incidence of LBW and SGA. Compared with the E2 <1000 pg/mL group, the adjusted mean difference (95% confidence interval [CI]) of stratified higher E2 groups was 17.2 (-31.0-65.5), 12.3 (-35.9-60.5), -4.1 (-51.9-43.7), -0.6 (-48.9-47.8) and -3.6 (-50.0-42.8) g for birthweight, and 0 (-0.11-0.10), 0.02 (-0.08-0.12), 0.04 (-0.06-0.14), -0.01 (-0.11-0.10) and -0.04 (-0.14-0.06) for Z-score, respectively. Regarding the outcomes of LBW and SGA, no increased risks were observed in each E2 category, with the adjusted odds ratio (95% CI) being 1.21 (0.68-2.16), 1.0 (0.58-1.90), 0.90 (0.50-1.63), 0.93 (0.51-1.69) and 1.08 (0.61-1.90) for LBW, and 0.97 (0.58-1.64), 1.06 (0.63-1.77), 0.77 (0.46-1.31), 0.71 (0.41-1.22) and 1.00 (0.60-1.65) for SGA, respectively.Limitations, Reasons For Caution: The study was retrospective in design, and other unknown confounding factors may not be included for adjustment. Furthermore, the generalization of the study finding could be limited to some extent by the majority of double cleavage-stage embryo transfer and difference in birthweight reference percentiles between Chinese and other populations.Wider Implications Of the Findings: Our observations suggest that the hyperestrogenic milieu during COS does not seem to pose adverse effects on neonatal birthweight after frozen-thawed embryo transfer, which provides reassuring information for high ovarian responders in freeze-all cycles concerning their offspring's health.Study Funding/competing Interest(s): This study was funded by the National Key Research and Development Program of China (SQ2018YFC100163) and National Natural Science Foundation of China (81571397, 81771533). The authors declare no conflict of interest. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to analyse the associations of left-hand digit ratio (2D:4D), digit length and puberty characteristics to show the role of prenatal hormones in development among Chinese girls.Method: A total of 318 Chinese girls aged 8-15 years were recruited using a stratified cluster sampling method. The index finger (2D), ring finger (4D) of the left hand, oestradiol and testosterone were measured, and age at menarche (AAM), breast (high and low) and pubic hair (high and low) development were recorded.Results: Girls who had experienced menarche had longer left digits (2D and 4D) and higher oestradiol, testosterone than those who had not. The high breast group had longer digits (2D and 4D), and higher oestradiol than the low breast group. With regard to pubic hair development, the high group had high 2D:4D, longer 2D and higher oestradiol, testosterone than the low group. After adjusting for oestradiol and testosterone, 4D length was positively related to occurrence of menarche. In addition, 2D and 2D:4D were significantly correlated with pubic hair development after adjusting for oestradiol, respectively.Conclusion: Prenatal hormone level may be related to the development of puberty characteristics among Chinese girls. [ABSTRACT FROM AUTHOR]

Background: The second-to-fourth digit ratio (2D:4D) is a marker of prenatal hormone exposure, which is negatively correlated with prenatal androgen and positively correlated with prenatal estrogen. The study was to analyze the association between 2D:4D and the first spermatorrhea to indirectly show the possible role of prenatal hormone during puberty development among boys.Method: The total of 367 boys aged 8-15 years were enrolled by using the stratified cluster sampling method. The variables of index finger (2D), ring finger (4D), height, weight, waist circumference (WC), skinfold thickness, testosterone and estradiol were measured, and the age at the first spermatorrhea was surveyed.Results: The average age at the first spermatorrhea was 12.15 years. The 2D:4D was not related to first spermatorrhea, circulating testosterone in boys (P > 0.05), however, was positively correlated with circulating estradiol (P < 0.05). The direct association (OR value) between 4D, average of index finger and ring finger (AIR) and first spermatorrhea were 2.79 and 2.29, and the mediating effect (OR value) of which were 1.95 and 2.01 by testosterone, accounting for 41.18% and 46.73% of the total effect, respectively. The 2D, MIDRL, lean body mass (LBM) were indirectly related to first spermatorrhea by testosterone, the mediating effects (OR value) were 2.11, 1.71 and 2.41, respectively.Conclusion: The prenatal androgen exposure may be directly and indirectly related to first spermatorrhea. In addition, the high prenatal estrogen exposure may be indirectly associated with first spermatorrhea by testosterone. [ABSTRACT FROM AUTHOR]

Objectives: To observe the effectiveness and safety of menopause-related hormone therapy (MHT) to prevent bone loss in Chinese women during the menopausal transition and early menopause, as well as to evaluate the effects of 5-year MHT on overall health to add Level I evidence for the prevention of osteoporosis using MHT.Design: This clinical study was a prospective, double-blind, randomized, parallel placebo-controlled study. Chinese women in the menopausal transition and early menopause were randomly allocated to the MHT group or the placebo group. All subjects received a 5-year intervention. The effectiveness of MHT for bone mineral density (BMD) and bone metabolism and the safety of MHT in relation to glycolipid metabolism, breast cancer, and cardiovascular disease were studied.Results: In the MHT group, women in both transition and early menopause showed a significant increase in lumbar and femoral neck BMD after the 1st year of therapy; BMD tended to decrease in the 3rd year but ultimately was sustained at stable levels that were near the baseline levels. In the placebo group, BMD decreased at both sites. Metabolism indexes and breast ultrasound examination findings did not differ significantly between the MHT and placebo groups. Three cases of breast cancer and three cases of cardiovascular disease were diagnosed during follow-up. One breast cancer case and two cardiovascular disease cases occurred in the MHT group.Conclusions: Five-year sequential therapy with estrogen and progesterone can increase or maintain the BMD of women in their menopausal transition and early menopause. This regimen had no negative effect on glycolipid metabolism and did not increase the risk of breast cancer or cardiovascular events. [ABSTRACT FROM AUTHOR]

Objective: This study made use of the percent abdominal fat to define abdominal obesity (AbO) and examined the differential associations of general obesity (GOb) and AbO with age, metabolic and endocrine factors.Methods: Metabolic, endocrine and anthropometric factors and body composition were measured in 481 Asian men.Results: A DEXA-derived ≥25% abdominal fat (PAbdF) was used to define men with AbO. Age was directly associated with PAbdF and percent total body fat (PBF). Exercise intensity was negatively associated with PBF. Both PBF and PAbdF were associated with HDL and LDL, but have opposite correlation with triglyceride. Furthermore, both PBF and PAbdF were associated with the number of metabolic syndrome (MetS) risk factors. Men with GOb had lower levels of percent lean mass (PLM), testosterone and bioavailable testosterone, and higher insulin and glucose levels. Men with AbO had lower arm and leg fat, higher insulin levels and triglycerides.Conclusions: Men with GOb and AbO had different pattern of body composition. Age may be a contributory factor in AbO and a sedentary lifestyle may contribute to GOb. Both GOb and AbO are associated with an increased risk of MetS, with GOb more predispose to risk of diabetes, while AbO more at risk for cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Purpose: The role of estrogen in cardiovascular health remains contested with discrepancies between findings from randomized controlled trials and observational studies. Mendelian randomization, which assesses the effect of lifelong endogenous exposure, may help elucidate these discrepancies.Methods: We used separate sample instrumental variable analysis to estimate the association of log 17β-estradiol with factors related to cardiovascular disease risk (systolic and diastolic blood pressure, lipids, fasting glucose, body mass index, waist hip ratio, and waist circumference) and Framingham score, a predictor of 10-year risk of ischemic heart disease events, in older Chinese women from the Guangzhou Biobank Cohort Study (GBCS, n = 3092). The estimate was derived using the Wald estimator, that is, the ratio of the association of genetic determinants (rs1008805 and rs2175898) of log 17β-estradiol with cardiovascular disease risk factors and Framingham score in GBCS and the association of these genetic determinants with log 17β-estradiol in a sample of young women from Hong Kong (n = 236).Results: Genetically, higher 17β-estradiol was not associated with any cardiovascular disease-related risk factor or with Framingham score (-0.01, 95% confidence interval = -1.34 to 1.31).Conclusions: Lifetime exposure to estrogen does not appear to be cardioprotective via the cardiovascular disease-related risk factors examined. [ABSTRACT FROM AUTHOR]

Objective. To explore the effects of puerarin to treat endometriosis (EMT) model rats and the possible regulatory mechanisms. Methods. EMT model rats were surgically induced by autotransplantion of endometrial tissues. The appropriate dosage of puerarin to treat EMT model rats was determined by observing the pathologic morphology of ectopic endometrial tissues and by detecting the levels of estradiol (E2) and prostaglandin E2 (PGE2) of both serum and ectopic endometrial tissues. The related genes and proteins of ectopic endometrial tissues were analyzed by Real-time PCR and immunohistochemistry (IHC) to explore the possible mechanisms. Results. Puerarin could reduce the levels of E2 and PGE2 and prevent the growth of ectopic endometrium tissues by inhibiting the expression of aromatase cytochrome P450 (p450arom) and cyclooxygenase-2 (cox-2); puerarin could adjust the anabolism of E2 by upregulating the expression of 17β-hydroxysteroid-2 (17β-hsd-2) and downregulating the expression of 17β- hydroxysteroid-1 (17β-hsd-1) of the ectopic endometrium tissues; puerarin could increase the expression of ERβ and improve the inflammatory microenvironment of EMT model rats. Conclusions. Our data suggest that puerarin has a therapeutic effect on EMT model rats and could be a potential therapeutic agent for the treatment of EMT in clinic. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Although Zuo Gui Yin Decoction has long been used in Traditional Chinese Medicine to treat menopausal symptoms, the underlying mechanism(s) by which these effects are induced remains to be defined. The aim of this study was to investigate the action mechanism of Zuo Gui Yin Decoction on estradiol production in the rat ovary during peri-menopause. Materials and methods: The peri-menopausal animal model was established by natural aging. Peri-menopausal rats were treated by intragastric administration (ig) with low (13.78gkg−1), middle (20.67gkg−1) or high (31gkg−1) dose of Zuo Gui Yin Decoction per day for 8 weeks. At the 8th weekend, the rats were sacrificed for sampling. Estradiol (E 2) levels in rats’ serum were evaluated by radioimmunoassay (RIA). RT-PCR, in situ hybridization and immunohistochemistry were used to determine mRNA and protein expression of relevant genes. Results: Medium- and high-dose of Zuo Gui Yin Decoction could significantly increase serum estradiol concentration, ovarian CYP19 mRNA levels, and P450arom protein expression in rats during peri-menopause. Zuo Gui Yin Decoction at three different dosages all could promote FSHR expression and the effect of low-dose was the greatest. Zuo Gui Yin Decoction could elevate LRH-1 and ERα expression in a dose dependent manner. Conclusions: Taken collectively, these findings suggest that Zuo Gui Yin Decoction could promote estradiol production in rat serum during peri-menopausal period through ovarian ERα →LRH-1→CYP19 pathway as well as the ovarian classical FSHR→CYP19 mechanism. [Copyright &y& Elsevier]

Primary objective: To evaluate the effects of estradiol-pre-treated neural stem cells (NSCs) derived from rat hippocampi post-ischemic neurological recovery and neuronal survival, migration and differentiation in rats with cerebral ischemia. Research design: A controlled laboratory study in animal model. Methods and procedure: NSCs were cultured with (CE) or without (CN) 17 β-estradiol (E2) and transplanted into the lateral ventricles of rats with middle cerebral artery occlusion (MCAO). A MCAO model alone group and treatment control group served as controls. Main outcome and results: Transplantation recipients (CN and CE groups) had ameliorated neurological deficits, less severe morphological changes and reduced total infarct volume, while there were no significant differences in these outcomes or in nestin and glial fibrillary acidic protein expression between the CN and CE groups at all time points. On day 1 post-transplantation, the CE group exhibited significantly higher neuron-specific enolase expression compared to all other groups, but there were no significant differences between the CE group and CN groups on days 4 and 7 post-transplantation. Conclusions: The results indicated no measurable improvements of E2 pre-treatment NSCs in neuronal survival, migration or neurological recovery. The findings provide pre-clinical support for the use of NSC transplantation in ischemic injury. [ABSTRACT FROM AUTHOR]

Objective: To investigate links between psychologic distress and levels of maternal hormones and cortisol during pregnancy and post partum.Method: The study population of 308 pregnant or recently delivered women was divided into 4 equal groups, 3 representing each pregnancy trimester and the fourth one representing the first week of the postpartum period. The women were screened for psychological distress and had blood drawn to measure serum levels of estradiol, progesterone, and total cortisol on the same day.Results: The rates of anxiety and depression were higher in the first trimester and the postpartum groups. Depression was correlated with sharp changes in estradiol and progesterone levels; anxiety was correlated with total cortisol level; and there was a correlation between depression and anxiety.Conclusion: Sharp changes in maternal hormone levels were correlated with depression; depression was correlated with anxiety; and anxiety was correlated with elevated cortisol levels, which may adversely affect the health of mother and offspring. Measuring maternal hormones may be a diagnostic tool to evaluate psychologic stress and associated risks. [ABSTRACT FROM AUTHOR]