Gender and sex hormone effects on neonatal innate immune function.

OBJECTIVES: Scientific evidence provides a widened view of differences in immune response between male and female neonates. The X-chromosome codes for several genes important in the innate immune response and neonatal innate immune cells express receptors for, and are inhibited by, maternal sex hormones. We hypothesized that sex differences in innate immune responses may be present in the neonatal population which may contribute to the increased susceptibility of premature males to sepsis. We aimed to examine the in vitro effect of pro-inflammatory stimuli and hormones in neutrophils and monocytes of male and female neonates, to examine the expression of X-linked genes involved in innate immunity and the miRNA profiles in these populations. METHODS: Preterm infants (n = 21) and term control (n = 19) infants were recruited from the Coombe Women and Infants University Hospital Dublin with ethical approval and explicit consent. The preterm neonates (eight female, 13 male) were recruited with a mean gestation at birth (mean ± SD) of 28 ± 2 weeks and corrected gestation at the time of sampling was 30 + 2.6 weeks. The mean birth weight of preterm neonates was 1084 ± 246 g. Peripheral blood samples were used to analyze immune cell phenotypes, miRNA human panel, and RNA profiles for inflammasome and inflammatory genes. RESULTS: Dividing neutrophil results by sex showed no differences in baseline CD11b between sexes among either term or preterm neonates. Examining monocyte CD11b by sex shows, that at baseline, total and classical monocytes have higher CD11b in preterm females than preterm males. Neutrophil TLR2 did not differ between sexes at baseline or following lipopolysaccharide (LPS) exposure. CD11b expression was higher in preterm male non-classical monocytes following Pam3CSK treatment when compared to females, a finding which is unique to our study. Preterm neonates had higher TLR2 expression at baseline in total monocytes, classical monocytes and non-classical monocytes than term. A sex difference was evident between preterm females and term females in TLR2 expression only. Hormone treatment showed no sex differences and there was no detectable difference between males and females in X-linked gene expression. Two miRNAs, miR-212-3p and miR-218-2-3p had significantly higher expression in preterm female than preterm male neonates. CONCLUSIONS: This study examined immune cell phenotypes and x-linked gene expression in preterm neonates and stratified according to gender. Our findings suggest that the responses of females mature with advancing gestation, whereas male term and preterm neonates have very similar responses. Female preterm neonates have improved monocyte activation than males, which likely reflects improved innate immune function as reflected clinically by their lower risk of sepsis. Dividing results by sex showed changes in preterm and term infants at baseline and following LPS stimulation, a difference which is reflected clinically by infection susceptibility. The sex difference noted is novel and may be limited to the preterm or early neonatal population as TLR2 expression on monocytes of older children does not differ between males and females. The differences shown in female and male innate immune cells likely reflect a superior innate immune defense system in females with sex differences in immune cell maturation. Existing human studies on sex differences in miRNA expression do not include preterm patients, and most frequently use either adult blood or cord blood. Our findings suggest that miRNA profiles are similar in neonates of opposite sexes at term but require further investigation in the preterm population. Our findings, while novel, provide only very limited insights into sex differences in infection susceptibility in the preterm population leaving many areas that require further study. These represent important areas for ongoing clinical and laboratory study and our findings represent an important contribution to exiting literature.

Insulin-like growth factor 1 and sex hormones for assessment of anthropometric and pubertal growth of Egyptian children and adolescents with type 1 diabetes mellitus (single center study).

BACKGROUND: This study aimed to assess the anthropometric measures and pubertal growth of children and adolescents with Type 1 diabetes mellitus (T1DM) and to detect risk determinants affecting these measures and their link to glycemic control. PATIENTS AND METHODS: Two hundred children and adolescents were assessed using anthropometric measurements. Those with short stature were further evaluated using insulin-like growth factor 1 (IGF-1), bone age, and thyroid profile, while those with delayed puberty were evaluated using sex hormones and pituitary gonadotropins assay. RESULTS: We found that 12.5% of our patients were short (height SDS < -2) and IGF-1 was less than -2 SD in 72% of them. Patients with short stature had earlier age of onset of diabetes, longer duration of diabetes, higher HbA1C and urinary albumin/creatinine ratio compared to those with normal stature (p < 0.05). Additionally, patients with delayed puberty had higher HbA1c and dyslipidemia compared to those with normal puberty (p < 0.05). The regression analysis revealed that factors associated with short stature were; age at diagnosis, HbA1C > 8.2, and albumin/creatinine ratio > 8 (p < 0.05). CONCLUSION: Children with uncontrolled T1DM are at risk of short stature and delayed puberty. Diabetes duration and control seem to be independent risk factors for short stature.

Phthalates and sex steroid hormones across the perimenopausal period: A longitudinal analysis of the Midlife Women's Health Study.

BACKGROUND: The menopausal transition involves significant sex hormone changes. Environmental chemicals, such as urinary phthalate metabolites, are associated with sex hormone levels in cross-sectional studies. Few studies have assessed longitudinal associations between urinary phthalate metabolite concentrations and sex hormone levels during menopausal transition. METHODS: Pre- and perimenopausal women from the Midlife Women's Health Study (MWHS) (n = 751) contributed data at up to 4 annual study visits. We quantified 9 individual urinary phthalate metabolites and 5 summary measures (e.g., phthalates in plastics (∑Plastic)), using pooled annual urine samples. We measured serum estradiol, testosterone, and progesterone collected at each study visit, unrelated to menstrual cycling. Linear mixed-effects models and hierarchical Bayesian kernel machine regression analyses evaluated adjusted associations between individual and phthalate mixtures with sex steroid hormones longitudinally. RESULTS: We observed associations between increased concentrations of certain phthalate metabolites and lower testosterone and higher sub-ovulatory progesterone levels, e.g., doubling of monoethyl phthalate (MEP), monobenzyl phthalate (MBzP), di-2-ethylhexyl phthalate (∑DEHP) metabolites, ∑Plastic, and ∑Phthalates concentrations were associated with lower testosterone (e.g., for ∑DEHP: -4.51%; 95% CI: -6.72%, -2.26%). For each doubling of MEP, certain DEHP metabolites, and summary measures, we observed higher mean sub-ovulatory progesterone (e.g., ∑AA (metabolites with anti-androgenic activity): 6.88%; 95% CI: 1.94%, 12.1%). Higher levels of the overall time-varying phthalate mixture were associated with lower estradiol and higher progesterone levels, especially for 2nd year exposures. CONCLUSIONS: Phthalates were longitudinally associated with sex hormone levels during the menopausal transition. Future research should assess such associations and potential health impacts during this understudied period.

Creating machine learning models that interpretably link systemic inflammatory index, sex steroid hormones, and dietary antioxidants to identify gout using the SHAP (SHapley Additive exPlanations) method.

Background: The relationship between systemic inflammatory index (SII), sex steroid hormones, dietary antioxidants (DA), and gout has not been determined. We aim to develop a reliable and interpretable machine learning (ML) model that links SII, sex steroid hormones, and DA to gout identification. Methods: The dataset we used to study the relationship between SII, sex steroid hormones, DA, and gout was from the National Health and Nutrition Examination Survey (NHANES). Six ML models were developed to identify gout by SII, sex steroid hormones, and DA. The seven performance discriminative features of each model were summarized, and the eXtreme Gradient Boosting (XGBoost) model with the best overall performance was selected to identify gout. We used the SHapley Additive exPlanation (SHAP) method to explain the XGBoost model and its decision-making process. Results: An initial survey of 20,146 participants resulted in 8,550 being included in the study. Selecting the best performing XGBoost model associated with SII, sex steroid hormones, and DA to identify gout (male: AUC: 0.795, 95% CI: 0.746- 0.843, accuracy: 98.7%; female: AUC: 0.822, 95% CI: 0.754- 0.883, accuracy: 99.2%). In the male group, The SHAP values showed that the lower feature values of lutein + zeaxanthin (LZ), vitamin C (VitC), lycopene, zinc, total testosterone (TT), vitamin E (VitE), and vitamin A (VitA), the greater the positive effect on the model output. In the female group, SHAP values showed that lower feature values of E2, zinc, lycopene, LZ, TT, and selenium had a greater positive effect on model output. Conclusion: The interpretable XGBoost model demonstrated accuracy, efficiency, and robustness in identifying associations between SII, sex steroid hormones, DA, and gout in participants. Decreased TT in males and decreased E2 in females may be associated with gout, and increased DA intake and decreased SII may reduce the potential risk of gout.

Association between secondhand smoke exposure and serum sex hormone concentrations among US female adults: a cross-sectional analysis using data from the National Health and Nutrition Examination Survey, 2013-2016.

OBJECTIVE: To estimate the association between secondhand smoke (SHS) exposure and serum sex hormone concentrations in female adults (never smokers and former smokers). DESIGN: Cross-sectional analysis. SETTING: US National Health and Nutrition Examination Survey, 2013-2016. OUTCOME MEASURES: Serum sex hormone measures included total testosterone (TT) and oestradiol (E2), sex hormone-binding globulin (SHBG), the ratio of TT and E2 and free androgen index (FAI). Isotope dilution-liquid chromatography tandem mass spectrometry was used to measure serum TT and E2. SHBG was measured using immunoassay. The ratio of TT and E2 and FAI were calculated. SHS exposure was defined as serum cotinine concentration of 0.05-10 ng/mL. PARTICIPANTS: A total of 622 female participants aged ≥20 years were included in the analysis. RESULTS: For never smokers, a doubling of serum cotinine concentration was associated with a 2.85% (95% CI 0.29% to 5.47%) increase in TT concentration and a 6.29% (95% CI 0.68% to 12.23%) increase in E2 in fully adjusted models. The never smokers in the highest quartile (Q4) of serum cotinine level exhibited a 10.30% (95% CI 0.78% to 20.72%) increase in TT concentration and a 27.75% (95% CI 5.17% to 55.17%) increase in E2 compared with those in the lowest quartile (Q1). For former smokers, SHBG was reduced by 4.36% (95% CI -8.47% to -0.07%, p for trend=0.049) when the serum cotinine level was doubled, and the SHBG of those in Q4 was reduced by 17.58% (95% CI -31.33% to -1.07%, p for trend=0.018) compared with those in Q1. CONCLUSION: SHS was associated with serum sex hormone concentrations among female adults. In never smokers, SHS was associated with increased levels of TT and E2. In former smokers, SHS was associated with decreased SHBG levels.

Associations among neighborhood walkability, metal exposure, and sex steroid hormone levels: Results from Hangzhou Birth Cohort Study â ¡.

BACKGROUND: Neighborhood walkability may influence maternal-fetal exposure to environmental hazards and maternal-fetal health (e.g., fetal growth restriction, reproductive toxicity). However, few studies have explored the association between neighborhood walkability and hormones in pregnant women. METHODS: We included 533 pregnant women from the Hangzhou Birth Cohort Study II (HBCS-II) with testosterone (TTE) and estradiol (E2) measured for analysis. Neighborhood walkability was evaluated by calculating a walkability index based on geo-coded addresses. Placental metals were measured using inductively coupled plasma mass spectrometry (ICP-MS). TTE and E2 levels in umbilical cord blood were measured using chemiluminescence microparticle immunoassay (CMIA). Linear regression model was used to estimate the relationship between the walkability index, placental metals, and sex steroid hormones. Effect modification was also assessed to estimate the effect of placental metals on the associations of neighborhood walkability with TTE and E2. RESULTS: Neighborhood walkability was significantly linked to increased E2 levels (P trend=0.023). Compared with participants at the first quintile (Q1) of walkability index, those at the third quintiles (Q3) had lower chromium (Cr) levels (ß = -0.212, 95% CI = -0.421 to -0.003). Arsenic (As), cobalt (Co), manganese (Mn), molybdenum (Mo), nickel (Ni), lead (Pb), antimony (Sb), selenium (Se), tin (Sn), and vanadium (V) were linked to decreased TTE levels, and cadmium (Cd) was linked to increased TTE levels. No metal was significantly associated with E2 levels in trend analysis. In the analysis of effect modification, the associations of neighborhood walkability with TTE and E2 were significantly modified by Mn (P = 0.005) and Cu (P = 0.049) respectively. CONCLUSION: Neighborhood walkability could be a favorable factor for E2 production during pregnancy, which may be inhibited by maternal exposure to heavy metals.

Dopamine as a potential diagnostic biomarker in women's sexual dysfunction.

Dopamine and prolactin are the key mediators involved in sexual function in both males and females, but the role of dopamine in female sexual dysfunction (FSD) is still unclear. The aim was to investigate the possible role of dopamine and their relationship with sex steroid hormones (estrogen, progesterone and dehydroepiandrosterone; DHEA) and prolactin levels in Egyptian women suffering from sexual dysfunction. This study included 84 women having sexual dysfunction (FSD group) and 84 normal sexual function (control group). All women were subjected to the questionnaire to assess their demographic and gynecological data as well as female sexual function index (FSFI). Blood samples were collected from all women for measuring serum estradiol, progesterone, DHEA, prolactin and dopamine levels. FSD patients had significantly higher serum progesterone and DHEA and prolactin levels; while significantly lower dopamine and estradiol levels versus controls (p < 0.001). In all women, dopamine level appeared as a predictor of FSD at cut-off point ≤8.8 ng/mL with sensitivity (75%), specificity (92%) and accuracy (83%) (p < 0.001). The low levels of dopamine were associated with significantly higher prevalence in patients with low estradiol (p < 0.001) and high progesterone (p < 0.001), DHEA (p < 0.001) and prolactin (p = 0.004). Also, dopamine was significantly positive correlation with arousal score (r = 0.16, p = 0.04), and negative correlation with age (r = -0.31, p < 0.001), pain score (r = -0.19, p = 0.01), DHEA (r = -0.45, p < 0.001) and prolactin (r = -0.28, p < 0.001). Low serum dopamine level is a potential diagnostic biomarker in women's sexual dysfunction and their association with high prolactin and sex steroid hormones dysfunction.

Associations between sex hormones, receptors, binding proteins and inflammatory bowel disease: a Mendelian randomization study.

Background: Gender differences existed in inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Observational studies have revealed associations between sex hormones and IBD, such as estrogen and testosterone. However, the exact relationship between these sex hormones and IBD is unclear. Method: Based on the genome-wide association studies data of eight sex hormones, two sex hormone receptors, sex hormone-binding globulin (SHBG), total IBD and its two subtypes, we performed a two-sample Mendelian randomization (MR) study to analyze their mutual relationship. For estradiol (E2), progesterone (PROG), bioavailable testosterone (BAT), total testosterone (TT) and SHBG, sex-stratified MR analyses were also performed. Inverse variance weighted method, MR-Egger regression and Weighted median method were used for causal analyses. Sensitivity analyses were conducted to test the stability of causal relationships. Besides, a reverse MR analysis was performed to estimate the reverse causation. Results: E2 (P=0.028) and TT (P=0.034) had protective effects on CD. Sex-stratified analyses revealed protective roles of E2 in males on total IBD (P=0.038) and CD (P=0.020). TT in females had protective effects on total IBD (P=0.025) and CD (P=0.029), and BAT in females decreased the risk of developing CD (P=0.047) and UC (P=0.036). Moreover, SHBG in males was also associated with a decreased risk of CD (P=0.021). The reversed MR analysis showed that CD was negatively correlated with estrogen receptor (P=0.046). UC was negatively correlated with PROG in females (P=0.015) and positively correlated with SHBG levels in males (P=0.046). Conclusion: Findings of this study revealed the mutual causal associations between sex hormones and the risk of developing IBD.

Associations of sex hormone ratios with metabolic syndrome and inflammation in US adult men and women.

Background: Sex hormones play a critical role in sex differences and cardiovascular disease risk associated with metabolic syndrome (MS) and inflammation. However, the associations of sex hormone ratios with metabolic and inflammatory markers are unclear according to sex and age differences. We evaluated the associations of sex hormone ratios with MS and inflammation among males and females. Methods: A retrospective cross-sectional study was conducted by including all adults from the National Health and Nutrition Examination Survey cycles 2013-2016 and excluding any pregnant women, heart disease, diabetes, and those currently taking insulin. MS was defined using the National Cholesterol Education Program criteria and a high-sensitivity C-reactive protein (CRP) level>3 mg/L was defined as a high CRP. Measures of MS components and CRP concentrations were also analyzed. The primary exposures were testosterone to estradiol (excess androgen index), testosterone to sex hormone-binding globulin (free androgen index), and estradiol to sex hormone-binding globulin (free estradiol index). The adjusted associations were summarized with a relative risk (RR) and 95% confidence interval (CI). Results: This study included 9167 subjects with 4360 males and 4807 females. Increases in free estradiol index were positively associated with MS (RR=1.48; 95%CI: 1.39, 1.58; RR=1.31; 95%CI: 1.22, 1.40) and high CRP (RR=1.49; 95%CI: 1.25, 1.77; RR=1.26; 95%CI: 1.06, 1.50) in men with age<50 years and age≥50 years, respectively. Similarly, higher free estradiol index was also robustly associated with increased prevalence of MS (RR=1.22; 95%CI: 1.15, 1.28) and high CRP (RR=1.68; 95%CI: 1.48, 1.90) in women with age ≥50 years. Among women with age<50 years, a higher free androgen index was associated with MS (RR=1.34; 95%CI: 1.25, 1.42) and high CRP (RR=1.13; 95%CI: 1.02, 1.25). These associations were unchanged even after adjusting for all sex hormones. Conclusion: Free estradiol index was consistently and positively associated with MS and high CRP in males of all ages and older females. Free androgen index was positively associated with MS and high CRP in females with age<50 years.

Causal Relationship between Sex Hormones and Risk of Developing Common Neurodegenerative Diseases: A Mendelian Randomization Study.

BACKGROUND: Neurodegenerative diseases are a group of unexplained disorders of the central nervous system, and studies have shown that a large number of genetic and environmental factors are associated with these diseases. Since these diseases show significant gender differences in epidemiology, sex hormones are thought to be strongly associated with these diseases. In this study, we used Mendelian randomization to explore the causal relationship between sex hormones and the risk of developing neurodegenerative diseases. METHODS: We obtained genetic instrumental variables for sex hormones (sex hormone-binding globulin [SHBG], estradiol levels [EL], and bioavailable testosterone [BT]) separately through the Integrative Epidemiology Unit (IEU) database (https://gwas.mrcieu.ac.uk/). We analyzed the causal relationship of each with the risk of developing neurodegenerative diseases (Amyotrophic Lateral Sclerosis [ALS], Parkinson's disease [PD], and Alzheimer's disease [AD]) using inverse variance weighted (IVW) in Mendelian randomization. Data were then analyzed for sensitivity. RESULTS: BT was negatively associated with the risk of developing ALS (odds ratio [OR] = 0.794; 95% confidence interval [95% CI] = 0.672-0.938; p = 0.006). EL and SHBG were not associated with a risk for developing neurodegenerative diseases (ALS, PD, AD). CONCLUSIONS: Elevated BT is associated with a reduced risk of developing ALS. Further research is needed to investigate the underlying mechanisms of action for this correlation and how it can be used as a potential target of action to reduce the risk of developing ALS.

Exposure to topiramate and acetazolamide causes endocrine disrupting effects in female rats during estrus.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a disease characterized by elevated intracranial pressure (ICP) and is a disease of young females. The first line pharmacological treatments include acetazolamide and topiramate and given the nature of IIH patients and the dosing regimen of these drugs, their effect on the endocrine system is important to evaluate. We aimed to assess the effects of acetazolamide and topiramate on steroid profiles in relevant endocrine tissues. METHODS: Female Sprague Dawley rats received chronic clinically equivalent doses of acetazolamide or topiramate by oral gavage and were sacrificed in estrus. Tissue specific steroid profiles of lateral ventricle CP, 4th ventricle CP, CSF, serum, uterine horn and fundus, ovaries, adrenal glands and pituitary glands were assessed by quantitative targeted LC-MS/MS. We determined luteinizing hormone (LH) and follicle stimulating hormones (FSH) levels in paired serum by ELISA. RESULTS: Topiramate increased the concentration of estradiol and decreased the concentration of DHEA in lateral choroid plexus. Moreover, it decreased the concentration of androstenediol in the pituitary gland. Topiramate increased serum LH. Acetazolamide decreased progesterone levels in serum and uterine fundus and increased corticosteroid levels in the adrenal glands. CONCLUSION: These results demonstrate that both acetazolamide and topiramate have endocrine disrupting effects in rats. Topiramate primarily targeted the choroid plexus and the pituitary gland while acetazolamide had broader systemic effects. Furthermore, topiramate predominantly targeted sex hormones, whereas acetazolamide widely affected all classes of hormones. A similar effect in humans has not yet been documented but these concerning findings warrants further investigations.

Association between sex hormones and gout: An analysis of the UK Biobank cohort.

OBJECTIVES: To investigate the associations between sex hormones and gout. METHODS: A total of 448,836 individuals free of gout at baseline were included from the UK Biobank. Cox regression models were used to estimate hazard ratios (HRs) for gout. Besides, we investigated the causal relationship between bioavailable testosterone (BAT) and gout using mendelian randomization (MR). RESULTS: There were differential effects in different testosterone active states in gout. One-unit higher log-transformed total testosterone (TT) was associated with a 52 % [95 % CI, 0.39-0.58] lower risk of gout in males. In contrast, free testosterone (FT) and BAT were associated with a 74 % [95 % CI, 1.38-2.20] and a 78 % [95 % CI, 1.41-2.25] higher risk of gout in males respectively. For MR, the weighted median [OR, 1.70; 95 % CI, 1.14-2.56;] and inverse variance-weighted [OR, 1.25; 95 % CI, 0.96-1.62; P = 0.09] method revealed significant and approximately significant positive effect of genetic liability to BAT levels on the risk of gout respectively. CONCLUSIONS: Sex hormones were potentially associated with gout. Notably, we were the first to explore different testosterone states on gout and found that FT and BAT may increase the risk of gout in males, which is opposite to TT. And the former are active states of androgens, may be more accurately reflect the association between androgens and gout.

Associations of per- and polyfluoroalkyl substances with maternal early second trimester sex-steroid hormones.

BACKGROUND/AIMS: Pregnant women are exposed to persistent environmental contaminants, including per- and polyfluoroalkyl substances (PFAS) that disrupt thyroid function. However, it is unclear if PFAS alter maternal sex-steroid hormone levels, which support pregnancy health and fetal development. METHODS: In Illinois women with relatively high socioeconomic status (n = 460), we quantified perfluorononanoic (PFNA), perfluorooctane sulfonic (PFOS), perfluorooctanoic (PFOA), methyl-perfluorooctane sulfonamide acetic acid, perfluorohexanesulphonic (PFHxS), perfluorodecanoic (PFDeA), and perfluoroundecanoic (PFUdA) acid concentrations in fasting serum samples at median 17 weeks gestation, along with plasma progesterone, testosterone, and estradiol. We evaluated covariate-adjusted associations of ln-transformed hormones with each ln-transformed PFAS individually using linear regression and with the PFAS mixture using quantile-based g-computation (QGComp). RESULTS: Interquartile range (IQR) increases in PFOS were associated with higher progesterone (%Δ 3.0; 95%CI: -0.6, 6.6) and estradiol (%Δ: 8.1; 95%CI: 2.2, 14.4) levels. Additionally, PFHxS was positively associated with testosterone (%Δ: 10.2; 95%CI: 4.0, 16.7), whereas both PFDeA and PFUdA were inversely associated with testosterone (%Δ: -5.7; 95%CI: -10.3, -0.8, and %Δ: -4.1; 95%CI: -7.6, -0.4, respectively). The IQR-standardized PFAS mixture was not associated with progesterone (%Δ: 1.6; 95%CI: -5.8, 9.2), due equal partial positive (%Δ: 9.2; driven by PFOA) and negative (%Δ: -7.4; driven by PFOS) mixture associations. Similarly, the mixture was not associated with testosterone (%Δ: 5.3; 95%CI: -9.0, 20.1), due to similar partial positive (%Δ: 23.6; driven by PFHxS) and negative (%Δ: -17.4; driven by PFDeA) mixture associations. However, we observed a slightly stronger partial positive (%Δ: 25.6; driven by PFOS and PFUdA) than negative (%Δ: -16.3; driven by PFOA) association resulting in an overall non-significant positive trend between the mixture and estradiol (%Δ: 8.5; 95%CI: -3.7, 20.9). CONCLUSION: PFAS mixture modeled using QGComp was not associated with maternal sex-steroid hormones due to potential opposing effects of certain PFAS. Additional prospective studies could corroborate these findings.

Sex-specific associations between sex hormones and clinical symptoms in late-life schizophrenia.

The prevalence of late-life schizophrenia is increasing with high burden. It is well-documented that schizophrenia affects men and women differently in terms of symptoms. Sex hormones, which play a role in the pathology and symptoms of schizophrenia, are greatly affected by aging. To the best of our knowledge, this is a study to examine the sex differences in psychiatric symptoms and their correlation with sex hormones in participants with late-life schizophrenia. Positive and Negative Syndrome Scale (PANSS) factors were evaluated. Testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and prolactin were measured. Male participants with late-life schizophrenia had more severe negative symptoms than female participants (z = -2.56, P = 0.010), while female participants had more severe anxiety/depression compared to male participants (z = 2.64, P = 0.008). Testosterone levels in male participants were positively associated with negative symptoms (ß = 0.23, t = 2.27, P = 0.025), while there was no significant association between sex hormones and symptoms in female participants. In conclusion, higher testosterone levels were associated with more severe negative symptoms in male participants with late-life schizophrenia, suggesting that attention should be paid to the sex differences in late-life schizophrenia in clinical practice.

Disturbed sex hormone milieu in males and females with major depressive disorder and low-grade inflammation.

Sex hormones have biological effects on inflammation, and these might contribute to the sex-specific features of depression. C-reactive protein (CRP) is the most widely used inflammatory biomarker and consistent evidence shows a significant proportion (20-30 %) of patients with major depressive disorder (MDD) have CRP levels above 3 mg/L, a threshold indicating at least low-grade inflammation. Here, we investigate the interplay between sex hormones and CRP in the cross-sectional, observational Biomarkers in Depression Study. We measured serum high-sensitivity (hs-)CRP, in 64 healthy controls and 178 MDD patients, subdivided into those with hs-CRP below 3 mg/L (low-CRP; 53 males, 72 females) and with hs-CRP above 3 mg/L (high-CRP; 19 males, 34 females). We also measured interleukin-6, testosterone, 17-ß-estradiol (E2), progesterone, sex-hormone binding globulin (SHBG), follicle-stimulating and luteinising hormones, and calculated testosterone-to-E2 ratio (T/E2), free androgen and estradiol indexes (FAI, FEI), and testosterone secretion index. In males, high-CRP patients had lower testosterone than controls (p = 0.001), and lower testosterone (p = 0.013), T/E2 (p < 0.001), and higher FEI (p = 0.015) than low-CRP patients. In females, high-CRP patients showed lower SHGB levels than controls (p = 0.033) and low-CRP patients (p = 0.034). The differences in testosterone, T/E2 ratio, and FEI levels in males survived the Benjamini-Hochberg FDR correction. In linear regression analyses, testosterone (ß = -1.069 p = 0.033) predicted CRP concentrations (R2 = 0.252 p = 0.002) in male patients, and SHBG predicted CRP levels (ß = -0.628 p = 0.009, R2 = 0.172 p = 0.003) in female patients. These findings may guide future research investigating interactions between gonadal and immune systems in depression, and the potential of hormonal therapies in MDD with inflammation.

Impact of Physiological Fluctuations of Sex Hormones During the Menstrual Cycle on Glucose Metabolism and the Gut Microbiota.

Diabetes mellitus is one of the most prevalent chronic diseases. Previous studies have shown differences in glucose metabolism between males and females. Moreover, difficulties in medication adherence have been reported in females with type 2 diabetes. These observations are believed to be caused by fluctuations in sex hormone concentrations during the menstrual cycle. Furthermore, gut microbiota is linked to female host metabolism and sex hormone production. Understanding the interactions between fluctuating hormone concentrations during the menstrual cycle, gut microbiota, and glucose metabolism in humans is significant because of the increasing prevalence of diabetes and the consequent need to expand preventive efforts. A literature search was performed to determine and summarize the existing evidence, deduce future research needs to maintain female health, and investigate the relationship between the physiological menstrual cycle and glucose metabolism. Studies from 1967 to 2020 have already examined the relationship between variations during the menstrual cycle and glucose metabolism in healthy female subjects using an oral-glucose tolerance test or intravenous glucose tolerance test. However, the overall number of studies is rather small and the results are contradictory, as some studies detected differences in glucose concentrations depending on the different cycle phases, whereas others did not. Some studies reported lower glucose levels in the follicular phase than in the luteal phase, whereas another study detected the opposite. Data on gut microbiota in relation to the menstrual cycle are limited. Conflicting results exist when examining the effect of hormonal contraceptives on the gut microbiota and changes in the course of the menstrual cycle. The results indicate that the menstrual cycle, especially fluctuating sex hormones, might impact the gut microbiota composition.The menstrual cycle may affect the gut microbiota composition and glucose metabolism. These results indicate that glucose tolerance may be the greatest in the follicular phase; however, further well-conducted studies are needed to support this assumption.

Sex-steroid hormones and risk of postmenopausal estrogen receptor-positive breast cancer: a case-cohort analysis.

PURPOSE: Sex-steroid hormones are associated with postmenopausal breast cancer but potential confounding from other biological pathways is rarely considered. We estimated risk ratios for sex-steroid hormone biomarkers in relation to postmenopausal estrogen receptor (ER)-positive breast cancer, while accounting for biomarkers from insulin/insulin-like growth factor-signaling and inflammatory pathways. METHODS: This analysis included 1208 women from a case-cohort study of postmenopausal breast cancer within the Melbourne Collaborative Cohort Study. Weighted Poisson regression with a robust variance estimator was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs) of postmenopausal ER-positive breast cancer, per doubling plasma concentration of progesterone, estrogens, androgens, and sex-hormone binding globulin (SHBG). Analyses included sociodemographic and lifestyle confounders, and other biomarkers identified as potential confounders. RESULTS: Increased risks of postmenopausal ER-positive breast cancer were observed per doubling plasma concentration of progesterone (RR: 1.22, 95% CI 1.03 to 1.44), androstenedione (RR 1.20, 95% CI 0.99 to 1.45), dehydroepiandrosterone (RR: 1.15, 95% CI 1.00 to 1.34), total testosterone (RR: 1.11, 95% CI 0.96 to 1.29), free testosterone (RR: 1.12, 95% CI 0.98 to 1.28), estrone (RR 1.21, 95% CI 0.99 to 1.48), total estradiol (RR 1.19, 95% CI 1.02 to 1.39) and free estradiol (RR 1.22, 95% CI 1.05 to 1.41). A possible decreased risk was observed for SHBG (RR 0.83, 95% CI 0.66 to 1.05). CONCLUSION: Progesterone, estrogens and androgens likely increase postmenopausal ER-positive breast cancer risk, whereas SHBG may decrease risk. These findings strengthen the causal evidence surrounding the sex-hormone-driven nature of postmenopausal breast cancer.

Sex steroid and cognitive function among community-dwelling older men with or without vascular risk factors: a cross-sectional study.

BACKGROUND: The relationship of testosterone and estradiol concentrations with cognitive function among community-dwelling older men was inconclusive. To examine the association of serum testosterone and estradiol concentrations with cognitive function in older men with or without vascular risk factors (VRFs). METHODS: This cross-sectional study consisted of 224 community-dwelling men aged 65-90 years in the Songjiang District of Shanghai, China. Serum testosterone and estradiol were measured by electrochemiluminescence immunoassay. The following five factors were defined as VRFs in this study: obesity, history of hypertension, diabetes, stroke, and coronary heart disease. Multivariable linear regression was used to examine the association of testosterone and estradiol with the Mini-Mental State Examination (MMSE) in participants with or without VRF. Restricted cubic spline (RCS) regression was performed to account for the nonlinearity of these associations. RESULTS: An inverted "U" shaped non-linear relationship was found between testosterone concentration and MMSE score in men with one VRF (P overall =.003, non-linear P =.002). Estradiol showed an inverted "U" shaped non-linear relationship with MMSE score independent of VRFs (men without VRF, P overall =.049, non-linear P =.015; men with one VRF, overall P =.007, non-linear P =.003; men with two or more VRFs, overall P =.009, non-linear P =.005). CONCLUSION: In older men, an optimal level of sex steroid concentration may be beneficial to cognitive function and the VRFs should be considered when interpreting the relationship between sex steroid and cognitive function.

Effects of Pasturella Multocida B: 2 and its immunogens (LPS and OMP) on reproductive hormones in Nili-Ravi Buffaloes / Efeitos de Pasteurella multocida B: 2 e seus imunógenos (LPS e OMP) em hormônios reprodutivos em búfalos Nili-Ravi

Abstract Livestock is a fundamental part of the agriculture industry in Pakistan and contributes more than 11.53% to GDP. Among livestock species, the buffaloes are regarded as the black gold of Pakistan. Being the highest milk producers globally, Nili-Ravi buffaloes are the most famous ones. Buffaloes are affected by many endemic diseases, and "Hemorrhagic septicemia" (HS) is one of them. This study was designed to ascertain the effects of experimental exposure ofP. multocida B:2 (oral) and its immunogens, i.e., LPS (oral and intravenous) and OMP (oral and subcutaneous) on reproductive hormonal profiles in Nili-Ravi buffaloes. Repeated serum samples were collected from the jugular vein of experimental animals for 21 days (0, 02, 04, 08, 12, 16, 20, 24, 36, 48, 72, 120, 168, 216, 264, 360, 456 and 504 hours). Hormonal assays to determine the serum concentrations of Gonadotropin-releasing hormone (GnRH), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), Estrogen (E2) and progesterone (P4) were performed using (MyBioSource) commercial Elisa kits. The hormonal profile of all treatment groups of the buffalo heifers exhibited significant (P<0.05) variations as compared to the control group (G-1). These results indicate suppression in Nili-Ravi buffaloes' reproductive hormonal profile on exposure to P. multocida B:2 and its immunogens. This influence warrants that exposure to H.S may be a possible reason for delayed puberty and poor reproduction performance in Nili-Ravi buffaloes.

Resumo A pecuária é uma parte fundamental da indústria agrícola no Paquistão e contribui com 11,53% do PIB nacional. Entre as espécies de gado, os búfalos são considerados o ouro negro do Paquistão. Sendo os maiores produtores de leite em todo o mundo, os búfalos Nili-Ravi são os mais famosos. Os búfalos são afetados por muitas doenças endêmicas, entre as quais a "septicemia hemorrágica" (SH). Este estudo busca verificar os efeitos da exposição experimental de P. multocida B:2 (oral) e seus imunógenos, ou seja, LPS (oral e intravenoso) e OMP (oral e subcutâneo), nos perfis hormonais reprodutivos em búfalos Nili-Ravi. Amostras de soro repetidas foram coletadas da veia jugular de animais experimentais por 21 dias (0, 2, 4, 8, 12, 16, 20, 24, 36, 48, 72, 120, 168, 216, 264, 360, 456 e 504 horas). Os ensaios hormonais para determinar as concentrações séricas do hormônio liberador de gonadotrofina (GnRH), hormônio foliculoestimulante (FSH), hormônio luteinizante (LH), estrogênio (E2) e progesterona (P4) foram realizados usando kits comerciais Elisa (MyBioSource). O perfil hormonal de todos os grupos de tratamento das novilhas bubalinas apresentou variações significativas (P < 0,05) em relação ao grupo controle (G-1). Esses resultados indicam supressão no perfil hormonal reprodutivo de búfalos Nili-Ravi na exposição a P. multocida B:2 e seus imunógenos. Essa influência garante que a exposição à SH possa ser uma possível razão para o atraso da puberdade e o baixo desempenho reprodutivo em búfalos Nili-Ravi.

Adolescence is a sensitive period for acrylamide-induced sex hormone disruption: Evidence from NHANES populations and experimental mice.

Acrylamide (AA) is widely contaminated in environment and diet. However, the association of AA and sex hormones has rarely been investigated, especially in adolescents, a period of particular susceptibility to sex hormone disruption. In this study, survey-weighted multivariate linear regression models were conducted to determine the association between AA Hb biomarkers [HbAA and glycidamide (HbGA)] and sex hormones [total testosterone (TT) and estradiol (E2)] in a total of 3268 subjects from National Health and Nutrition Examination Survey (NHANES) 2013-2016 waves. Additionally, adult and pubertal mice were treated with AA to assess the effect of AA on sex hormones and to explore the potential mechanisms. Among all the subjects, significant negative patterns for HbGA and sex hormones were identified only in youths (6-19 years old), with the lowest ß being - 0.53 (95% CI: -0.80 to -0.26) for TT in males and - 0.58 (95% CI: -0.93 to -0.23) for E2 in females. Stratified analysis further revealed significant negative associations between HbGA and sex hormones in adolescents, with the lowest ß being - 0.58 (95% CI: -1.02 to -0.14) for TT in males and - 0.54 (95% CI: -1.03 to -0.04) for E2 in females, while there were no significant differences between children or late adolescents. In mice, the levels of TT and E2 were dramatically reduced in AA-treated pubertal mice but not in adult mice. AA disturbed the expression of genes in the hypothalamic-pituitary-gonadal (HPG) axis, induced apoptosis of hypothalamus-produced gonadotropin-releasing hormone (GnRH) neurons in the hypothalamus and reduced serum and hypothalamic GnRH levels in pubertal mice. Our study indicates AA could reduce TT and E2 levels by injuring GnRH neurons and disrupting the HPG axis in puberty, which manifested as severe endocrine disruption on adolescents. Our findings reinforce the idea that adolescence is a vulnerable stage in AA-induced sex hormone disruption.