In utero bisphenol A exposure disturbs germ cell cyst breakdown through the PI3k/Akt signaling pathway and BDNF expression.

PURPOSE: To determine the influence of the environmental endocrine disruptor bisphenol A (BPA) on germ cell cyst breakdown and explore the possible mechanisms regulating this activity. METHODS: BPA (2 µg/kg/d or 20 µg/kg/d) or tocopherol-stripped corn oil (vehicle control) was administered to pregnant mice by gavage at gestational day 11, and the offspring (prenatally treated mice) were sacrificed and ovariectomized at postnatal day (PND) 4 and PND22. Ovarian morphology was documented in the first filial (F1) generation female offspring, and the follicles were analyzed and classified morphologically on PND 4. To discover differentially expressed genes and associated target pathways, we used RNA-seq, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Ontology (GO) analysis. The mRNA expression of key steroid hormone synthesis-related genes was evaluated by Q-PCR in forskolin-induced KGN cells. Western blotting (WB) and qRTPCR were used to determine the protein and gene expression levels of brain-derived neurotrophic factor (BDNF). RESULTS: BPA, a typical endocrine disrupting chemical (EDC), decreased the expression of the key steroid hormone synthesis-related genes P450scc and aromatase, while the expression of Star increased significantly and caused no significant difference in the expression of Cyp17a1 or HSD3ß in forskolin-induced KGN cells. Moreover, we confirmed that in utero exposure to environmentally relevant concentrations of BPA (2 µg/kg/d and 20 µg/kg/d) could significantly disrupt germ cell cyst breakdown, leading to the generation of fewer primordial follicles than in the control group. The factors mediating the inhibitory effects included the PI3K-Akt signaling pathway and a significant downregulation of BDNF. CONCLUSIONS: These findings indicate that in utero exposure to BPA at low doses, which are lower than recommended as 'safe' dosages, may influence the formation of primordial follicles by inhibiting the expression of steroid hormone synthesis-related genes and partly by regulating the BDNF-mediated PI3K/Akt pathway.

Effects of hormone replacement therapy on glucose and lipid metabolism in peri- and postmenopausal women with a history of menstrual disorders.

BACKGROUND: Previous studies have indicated that women with a history of menstrual disorders have an increased risk of metabolic and cardiovascular diseases. This has been attributed to the high proportion of polycystic ovary syndrome (PCOS) among this group. The favorable effects of hormone replacement therapy (HRT) on serum lipid profiles and glucose homeostasis in postmenopausal women is widely accepted. Whether HRT can also show positive effects on metabolic homeostasis in menopausal women with prior menstrual disorders (a putative PCOS phenotype) has not been reported yet. The aim of the study was to compare the effects of HRT on glucose and lipid metabolism in peri- and postmenopausal women with prior menstrual disorders and controls who did not have prior menstrual disorders. METHODS: A retrospective multicenter study was conducted including 595 peri- and postmenopausal women who received HRT at four hospitals in the Zhejiang Province from May 31, 2010 to March 8, 2021. Participants were divided into the Normal menstruation group and the Menstrual disorders group according to their prior usual menstrual cycle pattern. Glucose and lipid metabolism indicators were assessed at baseline and after HRT. The results were compared between and within the groups, and data from peri- and postmenopausal women were analyzed separately. RESULTS: HRT significantly decreased fasting insulin and homeostasis model assessment of insulin resistance in perimenopausal users, and fasting plasma glucose levels in postmenopausal users with prior menstrual disorders, compared with baseline. Furthermore, HRT decreased low-density lipoprotein cholesterol, total cholesterol, fasting insulin, fasting plasma glucose and homeostasis model assessment of insulin resistance in both peri- and postmenopausal controls, compared with baseline. Nevertheless, no significant differences were observed in any of the glucose or lipid metabolism indicators at baseline and follow-up, as well as changes from baseline levels between menopausal women with and without prior menstrual disorders. CONCLUSIONS: HRT shows more obvious within-group improvements in glucose and lipid metabolism in controls, but there is no significant between-group difference. Further prospective studies are required for confirmation.

Associations of age at natural menopause and occupations in Chinese female workers: A cross-sectional study.

AIMS: To investigate the impact of occupation types on age at natural menopause. METHODS: This is a nation-wide cross-sectional study based on 17,948 female workers aged over 40, who come from different industries or organizations. A face-to-face standardized questionnaire was conducted in all participants with the help of occupational hygienists. Occupational titles were coded according to the International Standard Classification of Occupations (2008) (ISCO08). Cox regression model was used to assess the association between each independent occupation and menopausal timing. Models were adjusted for marriage, education, average annual family income, parity, cigarette smoking, alcohol consumption. RESULTS: Higher risks of earlier age at natural menopause was found among legislators and senior officials (ISCO Minor group:111, HR = 2.328, P < 0.001), among other health associated professionals (ISCO Minor group: 325, HR = 1.477, P = 0.003), the workers involved in mining and mineral processing (ISCO Minor group: 811, HR = 1.515, P = 0.048) and metal processing and finishing (ISCO Minor group: 812, HR = 1.722, P < 0.001). Reduced risks of earlier age at natural menopause, including: finance professionals (ISCO Minor group: 241, HR = 0.751, P = 0.021), manufacturing and construction supervisors (ISCO Minor group: 312, HR = 0.477, P = 0.002), administrative and specialized secretaries (ISCO Minor group: 334, HR = 0.788, P = 0.045), cleaners and helpers (ISCO Minor group: 911, HR = 0.633, P = 0.01). CONCLUSIONS: This is the first study to address the influence of occupation types on reproductive aging, showing some specific occupations could be associated with age at natural menopause. Further investigations are necessary to clarify whether it is chance finding or a true association.

Urinary trace elements in association with premature ovarian insufficiency and reproductive hormones in a Chinese population.

Homeostasis disturbance of trace elements has been linked to adverse reproductive consequences, including premature ovarian insufficiency (POI) in women, but limited evidence has been reported so far. This case-control study evaluated the associations between 5 common urinary trace elements [copper (Cu), manganese (Mn), Iron (Fe), Selenium (Se), and zinc (Zn)] and the odds for POI. Urinary concentrations of these 5 metals and serum levels of POI-related reproductive hormones of 169 cases and 209 healthy controls were measured. The urinary levels of Cu and Se in women with POI were significantly higher than those in the controls. The positive associations were observed between Cu levels and the odds of POI [for the medium tertile: odds ratio (OR) = 3.79, 95% CI: 1.98-7.27, p < 0.001; for the highest tertile: OR = 3.85, 95% CI: 2.00-7.41, p < 0.001]. The highest tertile of urinary Se levels was associated with increasing POI risk (for the highest tertile: OR = 2.54, 95% CI: 1.38-4.70, compared with the lowest tertile, p for trend = 0.001). In POI patients, urinary concentrations of Zn and Fe were negatively associated with serum levels of follicle-stimulating hormone (FSH). Our findings suggested that higher exposure levels of Cu and Se might lead to an increased risk of POI.

SHP2 protects endothelial cell barrier through suppressing VE-cadherin internalization regulated by MET-ARF1.

Vascular endothelial (VE)-cadherin junctional localization is known to play a central role in vascular development, endothelial barrier integrity, and homeostasis. The sarcoma homology domain containing protein tyrosine phosphatase (SHP)2 has been shown to be involved in regulating endothelial barrier function; however, the mechanisms remain largely unknown. In this work SHP2 knockdown in an HUVEC monolayer increased VE-cadherin internalization and endothelial barrier permeability. Loss of SHP2 specifically augmented the GTPase activity of ADP-ribosylation factor (ARF)-1. ARF1 knockdown or inhibition of its guanine nucleotide exchange factors (GEFs) markedly attenuated VE-cadherin internalization and barrier hyperpermeability induced by SHP2 deficiency. SHP2 knockdown increased the total and phosphorylated levels of MET, whose activity was necessary for ARF1 activation and VE-cadherin internalization. Furthermore, constitutive endothelium-specific deletion of Shp2 in mice led to disrupted endothelial cell junctions, massive hemorrhage, and lethality in embryos. Induced and endothelium-specific deletion of Shp2 in adult mice resulted in lung hyperpermeability. Inhibitors for ARF1-GEF or MET used in pregnant mice prevented the vascular leakage in endothelial Shp2-deleted embryos. Together, our findings define a novel role of SHP2 in stabilizing junctional VE-cadherin in the resting endothelial barrier through suppressing MET and ARF1 activation.-Zhang, J., Huang, J., Qi, T., Huang, Y., Lu, Y., Zhan, T., Gong, H., Zhu, Z., Shi, Y., Zhou, J., Yu, L., Zhang, X., Cheng, H., Ke, Y. SHP2 protects endothelial cell barrier through suppressing VE-cadherin internalization regulated by MET-ARF1.

Loss of muscle mass in women with premature ovarian insufficiency as compared with healthy controls.

OBJECTIVE: Menopausal transition has been known to be associated with the loss of muscle mass. However, muscle health in women with premature menopause, that is, premature ovarian insufficiency (POI), remains unclear. We aimed to investigate and compare muscle mass parameters and the prevalence of low muscle mass between patients with spontaneous POI and healthy controls. METHODS: In this cross-sectional study, 59 women with spontaneous POI and 57 premenopausal controls with normal ovarian function were enrolled at the Women's Hospital, Zhejiang University School of Medicine (Hangzhou, China) from June 17, 2020, to August 20, 2021. Muscle mass parameters were measured by dual-energy x-ray absorptiometry, and low muscle mass was diagnosed using the Asian Working Group for Sarcopenia criteria. In addition, participants provided their sociodemographic data, menstrual and reproductive history, lifestyle factors, and medical history. Multivariate linear regression analysis was conducted. RESULTS: Muscle mass parameters, including appendicular skeletal muscle mass (ASM), ASM/height2, ASM/weight, ASM/body mass index, total skeletal muscle mass (TSM), and TSM/weight, were significantly lower in women with POI as compared with healthy controls (ASM: 14.62 ± 2.08 vs 15.97 ± 1.78, P < 0.001; ASM/height2: 5.71 ± 0.64 vs 6.15 ± 0.62, P < 0.001; ASM/weight: 0.27 [0.25, 0.28] vs 0.28 [0.27, 0.29], P = 0.002; ASM/BMI: 0.68 ± 0.07 vs 0.73 ± 0.06, P = 0.001; TSM: 33.85 ± 4.08 vs 36.43 ± 3.56, P < 0.001; TSM/weight: 0.63 [0.59, 0.65] vs 0.64 [0.61, 0.67], P = 0.02). The prevalence of low muscle mass in POI patients was significantly higher than that in controls (32.20% vs 8.77%, χ2 = 9.70, P = 0.002). Furthermore, multivariate linear regression analyses demonstrated that POI status was an independent risk factor for ASM (ß = -1.13; 95% CI, -1.62 to -0.65), ASM/height2 (-0.35, -0.47 to -0.22), ASM/weight (-0.01, -0.02 to -0.009), ASM/BMI (-0.05, -0.07 to -0.02), TSM (-2.16, -3.14 to -1.17), and TSM/weight (-0.03, -0.04 to -0.02). CONCLUSIONS: Women with POI exhibit significant loss of muscle mass as compared with healthy controls. Early diagnosis and long-term health management in POI patients are important.

Occupational hazards and the onset of natural menopause.

OBJECTIVE: To identify occupational hazards associated with earlier onset of natural menopause. STUDY DESIGN: A national cross-sectional study was conducted to explore the reproductive health of Chinese female workers. The final sample size was 17,948. MAIN OUTCOME MEASURES: Participants completed a self-report instrument that recorded working conditions, chemical and physical agents in the occupational environment, socioeconomic factors, lifestyle, reproductive history, and occupational information. A Cox regression model was used to examine the association between each occupational hazard and onset of menopause. RESULTS: Abnormal workload (19.31 %), aromatic compounds (7.95 %), and noise (24.94 %) were the three most frequently self-reported occupational hazards in the three categories of working conditions, chemical agents, and physical agents, respectively. Abnormal workload (HR = 1.133, p = 0.038), noise (HR = 1.233, p < 0.001), and heat stress (HR = 1.178, p = 0.041) were associated with earlier age at natural menopause in the analyses of each hazard, after adjustment. Only noise (HR = 1.187, p = 0.003) remained statistically significant after including all possible occupational hazards. CONCLUSIONS: In a national survey of 17,948 female workers, this study investigated the association of age at natural menopause with multiple occupational hazards, some of which have not been addressed. Occupational noise was identified as a risk factor for reproductive senescence for the first time. However, further research is needed to confirm our findings.

Change in metabolic parameters and reproductive hormones from baseline to 6-month hormone therapy.

ABSTRACT: Adequate evidence showed hormone therapy (HT) reduces the risk of new-onset diabetes in midlife women by decreasing fasting glucose and insulin. However, the improvement of these diabetic biomarkers varied with each individual in clinical observations. The objective of our study was to investigate potential baseline factors associated with the change of fasting glucose and insulin during HT.A retrospective cohort study was performed among 263 midlife participants aged 40 to 60 years with menopausal symptoms who have received 6-month individualized HT. Demographic information and laboratory indicators including reproductive hormone, lipid profiles, diabetic indicators were collected and measured at baseline and were followed-up. A series of statistical analyses were performed to confirm the effectiveness of HT and compare the baseline factors between participants with different glycemic or insulinemic response. Multivariable linear regression model with stepwise variable selection was further used to identify the associated factor with the change of fasting glucose and insulin.Of all participants, fasting glucose (P = .001) and fasting insulin (P < .001) were significantly decreased after individualized HT. Significant differences in baseline reproductive hormones were observed in participants with different glycemic response to HT (P < .001 for both follicle stimulating hormone [FSH] and estradiol). Stepwise linear regression model showed that in addition to baseline fasting glucose levels, baseline FSH was also independently associated with the change of fasting glucose (ß = -0.145, P = .019 for baseline FSH) but not fasting insulin. Greater reduction in fasting glucose in women with higher FSH levels was observed even though they have already been in better metabolic conditions (P = .037).Midlife women with higher baseline FSH levels have greater reduction in fasting glucose but not fasting insulin. FSH could be an independent predictor of glycemic response to HT in peri- and postmenopausal women.

Menopausal symptoms in women with premature ovarian insufficiency: prevalence, severity, and associated factors.

OBJECTIVE: To comprehensively investigate and evaluate the prevalence, severity, and associated factors of menopausal symptoms in women with premature ovarian insufficiency (POI). In this study, the specific symptomatology experienced by women with POI and women with natural menopause was also compared. METHODS: In this cross-sectional study, 293 Chinese women with POI from an outpatient clinic were recruited between June 2014 and January 2019. The prevalence and severity of menopausal symptoms were assessed with modified Kupperman Menopausal Index. Participants completed a structured questionnaire, including medical history, menstrual characteristics, and sociodemographic data. Serum levels of reproductive hormones were measured. RESULTS: Among 293 women with POI (33.76 ±â€Š5.47 y), the most prevalent symptoms were mood swings (73.4%), insomnia (58.7%), sexual problems (58.7%), and fatigue (57.3%). Moderate-to-severe mood swings were most frequently reported (23.9%), followed by formication (17.4%) and hot flashes/sweating (17.1%). Compared with women with natural menopause, women with POI exhibited significantly higher risks for fatigue (odds ratio  = 1.42; 95% confidence interval, 1.04-1.94), melancholia (3.12; 1.94-5.01), mood swings (3.57; 2.33-5.45), insomnia (1.41; 1.02-1.96), and significantly lower risks for moderate-to-severe sexual problems (0.40; 0.23-0.69), any and moderate-to-severe muscle/joint pain (0.41; 0.27-0.62 and 0.45; 0.25-0.78, respectively). Living in urban areas and higher gravidity were independently associated with menopausal symptoms in women with POI. CONCLUSIONS: Women with POI experienced a high prevalence of menopausal symptoms, particularly related to psychological and sexual domains. Furthermore, women with POI tended to have more distressing menopausal symptoms compared with women with natural menopause.

Metabolic profile of women with premature ovarian insufficiency compared with that of age-matched healthy controls.

OBJECTIVE: . To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. STUDY DESIGN: . A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. MAIN OUTCOME MEASURES: . Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. RESULTS: . Women with POI were more likely to exhibit increased serum levels of TG (ß, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. CONCLUSION: . Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.