Sex hormone-binding globulin may explain sex differences for glucose homeostasis and incidence of type 2 diabetes: the KORA study.

Research has indicated that sex hormone-binding globulin (SHBG) is associated with glucose homeostasis and may play a role in the etiology of type 2 diabetes (T2D). While it is unclear whether SHBG may mediate sex differences in glucose control and subsequently, incidence of T2D. We used observational data from the German population-based KORA F4 study (n = 1937, mean age: 54 years, 41% women) and its follow-up examination KORA FF4 (median follow-up 6.5 years, n = 1387). T2D was initially assessed by self-report and validated by contacting the physicians and/ or reviewing the medical charts. Mediation analyses were performed to assess the role of SHBG in mediating the association between sex (women vs. men) and glucose- and insulin-related traits (cross-sectional analysis) and incidence of T2D (longitudinal analysis). After adjustment for confounders, (model 1: adjusted for age; model 2: model 1 + smoking + alcohol consumption + physical activity), women had lower fasting glucose levels compared to men (ß = -4.94 (mg/dl), 95% CI: -5.77, -4.11). SHBG levels were significantly higher in women than in men (ß = 0.47 (nmol/l), 95% CI:0.42, 0.51). Serum SHBG may mediate the association between sex and fasting glucose levels with a proportion mediated (PM) of 30% (CI: 22-41%). Also, a potential mediatory role of SHBG was observed for sex differences in incidence of T2D (PM = 95% and 63% in models 1 and 2, respectively). Our novel findings suggest that SHBG may partially explain sex-differences in glucose control and T2D incidence.

Sex hormone-binding globulin is a valuable diagnostic indicator of gestational diabetes mellitus.

Objective: To assess the performance of the Sex Hormone-Binding Globulin (SHBG) assay as a diagnostic indicator of Gestational Diabetes Mellitus (GDM) in the study population. Design: Analytical cross-sectional study. Setting: Hospital-based, Benue State University Teaching Hospital (BSUTH), Makurdi, Nigeria. Participants: Women with singleton pregnancies at 24 to 28 weeks gestational age attending Antenatal care at BSUTH, Makurdi. Intervention: Serum SHBG levels were assayed by ELISA during a diagnostic 75-gram Oral Glucose Tolerance Test (OGTT) for assessment of GDM in the cohort of consecutively selected participants who met the inclusion criteria. Main Outcome Measures: Serum levels of SHBG and presence of GDM in the participants. Result: Serum SHBG was significantly negatively correlated (rpb = - 0.534, p-value < 0.001) with the presence of GDM. It had an area under the ROC curve of 0.897 (95% Confidence Interval = 0.858-0.935; p-value < 0.001). A cut-off value of 452.0 nmol/L indicative of GDM had a diagnostic odds ratio of 21.4 in the study population. Conclusion: SHBG is a valuable diagnostic indicator for GDM in the study population. Funding: None declared.

High bioavailable testosterone levels increase the incidence of isolated REM sleep behavior disorder: Results from multivariable and network Mendelian randomization analysis.

OBJECTIVES: To explore the causal relationships between sex hormone levels and incidence of isolated REM sleep behavior disorder (iRBD). METHODS: In our study, we utilized Genome-Wide Association Studies (GWAS) data for iRBD, including 9447 samples with 1061 cases of iRBD provided by the International RBD Study Group. Initially, we conducted a two-sample univariate MR analysis to explore the impact of sex hormone-related indicators on iRBD. This was followed by the application of multivariable MR methods to adjust for other hormone levels and potential confounders. Finally, we undertook a network MR analysis, employing brain structure Magnetic Resonance Imaging (MRI) characteristics as potential mediators, to examine whether sex hormones could indirectly influence the incidence of iRBD by affecting brain structure. RESULTS: Bioavailable testosterone (BioT) is an independent risk factor for iRBD (Odds Ratio [95 % Confidence Interval] = 2.437 [1.308, 4.539], P = 0.005, corrected-P = 0.020), a finding that remained consistent even after adjusting for other sex hormone levels and potential confounders. Additionally, BioT appears to indirectly increase the risk of iRBD by reducing axial diffusivity and increasing the orientation dispersion index in the left cingulum and cingulate gyrus. CONCLUSIONS: Our research reveals that elevated levels of BioT contribute to the development of iRBD. However, the specific impact of BioT on different sexes remains unclear. Furthermore, high BioT may indirectly lead to iRBD by impairing normal pathways in the left cingulum and cingulate gyrus and fostering abnormal pathway formation.

Exploiting gender-based biomarkers and drug targets: advancing personalized therapeutic strategies in hepatocellular carcinoma.

This review systematically examines gender differences in hepatocellular carcinoma (HCC), identifying the influence of sex hormones, genetic variance, and environmental factors on the disease's epidemiology and treatment outcomes. Recognizing the liver as a sexually dimorphic organ, we highlight how gender-specific risk factors, such as alcohol consumption and obesity, contribute differently to hepatocarcinogenesis in men and women. We explore molecular mechanisms, including the differential expression of androgen and estrogen receptors, which mediate diverse pathways in tumor biology such as cell proliferation, apoptosis, and DNA repair. Our analysis underscores the critical need for gender-specific research in liver cancer, from molecular studies to clinical trials, to improve diagnostic accuracy and therapeutic effectiveness. By incorporating a gender perspective into all facets of liver cancer research, we advocate for a more precise and personalized approach to cancer treatment that acknowledges gender as a significant factor in both the progression of HCC and its response to treatment. This review aims to foster a deeper understanding of the biological and molecular bases of gender differences in HCC and to promote the development of tailored interventions that enhance outcomes for all patients.

Effect of occupational exposure to vat-textile dyes on follicular and luteal hormones in female dye workers in Abeokuta, Nigeria.

Background: Some synthetic dyes used mainly in textile industries have been associated with endocrine disruption, resulting in infertility, among other disorders. It is unknown if occupational exposure to Vat textile dyes among premenopausal dyers alters hormonal levels. Objectives: We aimed at determining the probable effects of occupational exposure to Vat dyes on reproductive hormones of female textile dyers in the follicular and luteal phases while relating this to age categories and duration of exposure. Methods: Thirty-three premenopausal Vat textile dyers at "Itoku", Abeokuta, Nigeria, among a population of about 80 female dyers were age and sex-matched with 55 non-exposed (control) female participants. Using semi-structured questionnaires, socio-demographic, occupational details and the LMP of participants were obtained. Serum samples were collected in follicular and luteal phases and assayed for female sex hormones using Enzyme Immunoassay. Mann-Whitney U and Z- statistic were used for comparison of the two groups. P-value < 0.05 was considered to be significant. Results: In the follicular phase, the result showed a lower mean FSH ranking (in age category ≤20 years) and higher (p<0.05) Estradiol ranking (in age category 31-40 years) in the exposed than the unexposed. Mean ranks of Progesterone and Estradiol in the luteal phase (age category 31-40 years) were higher (p<0.05) in the exposed, while Estradiol (age category ≥41years) ranked lower (p<0.05). Prolactin demonstrated a significant inverse relationship with the duration of exposure. Conclusion: Occupational exposure to Vat dye among female dyers in Abeokuta is associated with some sex hormone disruption which appears to be age and duration of exposure-related.

Crustacean endocrinology: Sexual differentiation and potential application for aquaculture.

Crustaceans, which represent a significant subset of arthropods, are classified into three major classes: Ostracoda, Malacostraca, and Branchiopoda. Among them, sex manipulation in decapod species from the Malacostraca class has been extensively researched for aquaculture purposes and to study reproductive physiology and sexual plasticity. Some decapods exhibit sexual dimorphism that influences their biological and economic value. Monosex culture, in which only one sex is cultivated, increases production yields while reducing the risk of invasiveness, as genetic leakage into natural waters is less likely to occur. Differences in yield are also observed when cultivating different sexes, with all-male cultures of Macrobrachium rosenbergii being more profitable than both mixed and all-female cultures. Research on decapod sexual differentiation has led to a better understanding of sex determination and sexual differentiation processes in arthropods. Similar to most mammals and other vertebrate classes, Malacostraca crustaceans, including decapods, exhibit a cell-non-autonomous mode of sexual development. Genetic factors (e.g., sex chromosomes) and endocrine factors (e.g., insulin-like androgenic gland factor and crustacean female sex hormone) play pivotal roles in the development of sexually dimorphic traits. This review synthesizes the existing understanding of sex determination mechanisms and the role of sex hormones in decapod species. Additionally, it provides an overview of the methyl farnesoate, which has been suggested to be involved in male sex differentiation in some crab species, as well as the phenomenon of male-to-female sex reversal in host decapods caused by parasitic crustaceans.

Hyperglycemia Inhibits Hepatic SHBG Synthesis Through the NGBR-AMPK-HNF4 Pathway in Rats with Polycystic Ovary Syndrome Induced by Letrozole in Combination with a High-Fat Diet.

SCOPE: Polycystic ovary syndrome (PCOS) is closely related to non-alcoholic fatty liver disease (NAFLD), and sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver. Hepatic lipogenesis inhibits hepatic SHBG synthesis, which leads to hyperandrogenemia and ovarian dysfunction in PCOS. Therefore, this study aims to characterize the mechanism whereby liver lipogenesis inhibits SHBG synthesis. METHODS AND RESULTS: This study establishes a rat model of PCOS complicated by NAFLD using a high-fat diet in combination with letrozole and performs transcriptomic analysis of the liver. Transcriptomic analysis of the liver shows that the expression of neurite growth inhibitor-B receptor (NgBR), hepatocyte nuclear factor 4α (HNF4α), and SHBG is low. Meantime, HepG2 cells are treated with palmitic acid (PA) to model NAFLD in vitro, which causes decreases in the expression of NgBR, HNF4α, and SHBG. However, the expression of HNF4α and SHBG is restored by treatment with the AMP-activated protein kinase (AMPK) agonist AICAR. CONCLUSIONS: NgBR regulates the expression of HNF4α by activating the AMPK signaling pathway, thereby affecting the synthesis of SHBG in the liver. Further mechanistic studies regarding the effect of liver fat on NGBR expression are warranted.

Cardiorespiratory fitness, body composition, diabetes, and longevity: a two-sample Mendelian randomization study.

CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality. OBJECTIVE: We investigated the causality and directionality of the associations of VO2max with body composition, physical activity, diabetes, performance enhancers, and longevity. METHODS: Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional two-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (ß=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max showed no associations. CONCLUSION: Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO2max is not causally associated with T2D or longevity.

Gestational age-specific reference intervals for androgens in pregnancy.

BACKGROUND: Androgen could impact cervical remodelling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval (RI) of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism. METHODS: We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models. RESULTS: A4 and TT levels increased across the gestation, and they closely correlated with each other (R = 0.90, P=<0.001), whereas 17-OHP level decreased from 5th gestational week to 16th gestational week and then increased afterward towards the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with p ≤0.01, whereas mothers carrying male versus female fetuses have comparable levels of A4, TT, and 17-OHP. CONCLUSION: The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.

Sex-Based Mechanisms of Cardiac Development and Function: Applications for Induced-Pluripotent Stem Cell Derived-Cardiomyocytes.

Males and females exhibit intrinsic differences in the structure and function of the heart, while the prevalence and severity of cardiovascular disease vary in the two sexes. However, the mechanisms of this sex-based dimorphism are yet to be elucidated. Sex chromosomes and sex hormones are the main contributors to sex-based differences in cardiac physiology and pathophysiology. In recent years, the advances in induced pluripotent stem cell-derived cardiac models and multi-omic approaches have enabled a more comprehensive understanding of the sex-specific differences in the human heart. Here, we provide an overview of the roles of these two factors throughout cardiac development and explore the sex hormone signaling pathways involved. We will also discuss how the employment of stem cell-based cardiac models and single-cell RNA sequencing help us further investigate sex differences in healthy and diseased hearts.

Impact of hormonal therapy on HIV-1 immune markers in cis women and gender minorities.

BACKGROUND: Although sex hormones are recognized to induce immune variations, the effect of hormonal therapy use on immunity is only poorly understood. Here, we quantified how hormonal therapy use affects HIV-1 immune markers in cis women (CW) and trans women and non-binary people (TNBP) with HIV. METHODS: We considered CD4, CD8 and lymphocyte measurements from cis men (CM), CW and TNBP in the Swiss HIV Cohort Study. We modelled HIV-1 markers using linear mixed-effects models with an interaction between 'gender' (CW, TNBP) and 'hormonal therapy use' (yes/no). Models were adjusted on age, ethnicity, education level, time since start of antiretroviral therapy and use of intravenous drugs. We assessed the inflammatory effect of hormonal therapy use in 31 TNBP using serum proteomics measurements of 92 inflammation markers. RESULTS: We included 54 083 measurements from 3092 CW and 83 TNBP, and 147 230 measurements from 8611 CM. Hormonal therapy use increased CD4 count and CD4:CD8 ratio in TNBP more than in CW (pinteraction = 0.02 and 0.007, respectively). TNBP with hormonal therapy use had significantly higher CD4 counts [median = 772 cells/µL, interquartile range (IQR): 520-1006] than without (617 cells/µL, 426-892). This was similar to the effect of CW versus CM on CD4 T cells. Hormonal therapy use did not affect serum protein concentrations in TNBP. CONCLUSION: This study highlights the potential role of hormonal therapy use in modulating the immune system among other biological and social factors, especially in TNBP with HIV.

Associations of sex-related and thyroid-related hormones with risk of metabolic dysfunction-associated fatty liver disease in T2DM patients.

BACKGROUND: We aimed to examine sex-specific associations between sex- and thyroid-related hormones and the risk of metabolic dysfunction-associated fatty liver disease (MAFLD) in patients with type 2 diabetes mellitus (T2DM). METHODS: Cross-sectional analyses of baseline information from an ongoing cohort of 432 T2DM patients (185 women and 247 men) in Xiamen, China were conducted. Plasma sex-related hormones, including estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), progesterone, and total testosterone (TT), and thyroid-related hormones, including free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), and parathyroid hormone (PTH), were measured using chemiluminescent immunoassays. MAFLD was defined as the presence of hepatic steatosis (diagnosed by either hepatic ultrasonography scanning or fatty liver index (FLI) score > 60) since all subjects had T2DM in the present study. RESULTS: Prevalence of MAFLD was 65.6% in men and 61.1% in women with T2DM (P = 0.335). For men, those with MAFLD showed significantly decreased levels of FSH (median (interquartile range (IQR)):7.2 (4.9-11.1) vs. 9.8 (7.1-12.4) mIU/ml) and TT (13.2 (10.4-16.5) vs. 16.7 (12.8-21.6) nmol/L) as well as increased level of FT3 (mean ± standard deviation (SD):4.63 ± 0.68 vs. 4.39 ± 0.85 pmol/L) than those without MAFLD (all p-values < 0.05). After adjusting for potential confounding factors, FSH and LH were negative, while progesterone was positively associated with the risk of MAFLD in men, and the adjusted odds ratios (ORs) (95% confidence intervals (CIs)) were 0.919 (0.856-0.986), 0.888 (0.802-0.983), and 8.069 (2.019-32.258) (all p-values < 0.05), respectively. In women, there was no statistically significant association between sex- or thyroid-related hormones and the risk of MAFLD. CONCLUSION: FSH and LH levels were negative, whereas progesterone was positively associated with the risk of MAFLD in men with T2DM. Screening for MAFLD and monitoring sex-related hormones are important for T2DM patients, especially in men.

Honghua Xiaoyao tablet combined with estradiol improves ovarian function in D-galactose-induced aging mice by reducing apoptosis and affecting the release of reproductive hormones: an in vivo study.

Context: It is very necessary to delay ovarian aging and prevent age-related health problems. The active ingredient in Honghua Xiaoyao tablet (HHXYT) has the effects of anti-oxidation, anti-inflammation, immune regulation and so on. Objective: To explore the effect and mechanism of Honghua Xiaoyao tablet on aging model mice. Materials and methods: The aging model was established by intraperitoneal injection of D-galactose in model mice. The mice in the HHXYT-L,M,H group were given 0.3 g/kg, 0.6 g/kg and 1.2 g/kg Honghua Xiaoyao tablet suspension respectively, and the HHXYT-M + E2 group was given 0.6 g/kg HHXYT +0.13 mg/kg estradiol valerate for 30 days. In this study, ELISA, HE, Western blot, IH and TUNEL were used. Results: HHXYT + E2 can improve the gonadal index, estrous cycle of aging mice. In HHXYT-M + E2 group, the level of FSH and LH decreased, while E2 and AMH increased significantly. The number of growing follicles in HHXYT-M + E2 group increased, which was better than that of HHXYT alone. Western blot results showed that HHXYT-M + E2 group decreased the expression of Bax, cleaved-Parp, cleaved-Casp-3 and CytC molecules and increased the expression of Bcl-2 in ovarian tissue. FSHR expression decreased in model group and increased in HHXYT group. TUNEL staining showed that the number of apoptotic cells in HHXYT group was reduced, and the HHXYT-M + E2 group was the most significantly. Discussion and conclusion: HHXYT can improve the level of sex hormones and increase the number of growing follicles in aging mice. HHXYT-M + E2 group has the best effect, and its mechanism may be related to reducing ovarian granulosa cell apoptosis.

Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome.

BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS. METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association. RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings. CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

Serum anti-mullerian hormone, sex hormone, and nutrient levels in reproductive age women with celiac disease.

PURPOSE: This study aimed to investigate the changes in serum Anti-Müllerian Hormone (AMH) levels, sex hormone levels, follicle-stimulating hormone (FSH)/luteinizing hormone (LH) ratio in patients with celiac disease (CeD), and their correlation with clinical characteristics and nutrient levels. METHODS: This cross-sectional study collected clinical and biochemical data from a total of 67 females diagnosed with CeD and 67 healthy females within the reproductive age range of 18-44 years. The study was conducted at a tertiary hospital between September 2016 and January 2024. Both groups underwent comprehensive clinical and laboratory assessments. Serum levels of AMH and sex hormones were quantified using chemiluminescence immunoassay, and their associations with CeD clinical features and nutrient levels were thoroughly analyzed. RESULTS: The study included 67 patients and 67 controls with a mean age of 36.7±7.6 years. No statistically significant differences were found between the two groups in mean age, BMI, FSH, LH, E2, P levels, FSH/LH, menstrual irregularities, abortions history, parity, and gravidity (all P>0.05). However, AMH, T, FER, FA, Zn, and Se levels were significantly lower, and PRL levels were higher in the CeD group (all P<0.05). Spearman's correlation analysis showed that AMH levels were negatively correlated with age, tTG level, disease duration, and Marsh grading (P<0.05). CONCLUSIONS: This study highlights the association between impaired ovarian function in CeD patients and disease severity and nutrient levels. Early detection and intervention for ovarian function abnormalities are imperative to enhance fertility potential in CeD patients.

Recent Advances on Sex Hormone-Binding Globulin Regulation by Nutritional Factors: Clinical Implications.

Sex hormone-binding globulin (SHBG) is a homodimeric glycoprotein produced by the human liver and secreted into the systemic circulation where it binds with high affinity sex steroids regulating their availability in blood and accessibility to target tissues. Plasma SHBG levels are altered in metabolic disorders such as obesity, anorexia, and insulin resistance. Several reports have shown that diets in terms of total calories or fat, fiber, or protein content can alter plasma SHBG levels. However, there are many components in a diet that can affect SHBG gene expression in the liver. In order to unravel the molecular mechanisms by which diets regulate SHBG production, it would be necessary to analyze single diet components and/or nutritional factors. This review summarizes the recent advances in identifying different nutritional factors regulating SHBG production and the related molecular mechanism, as well as the clinical implications.

Molecular and Physiological Effects of 17α-methyltestosterone on Sex Differentiation of Black Rockfish, Sebastes schlegelii.

It is widely known that all-female fish production holds economic value for aquaculture. Sebastes schlegelii, a preeminent economic species, exhibits a sex dimorphism, with females surpassing males in growth. In this regard, achieving all-female black rockfish production could significantly enhance breeding profitability. In this study, we utilized the widely used male sex-regulating hormone, 17α-methyltestosterone (MT) at three different concentrations (20, 40, and 60 ppm), to produce pseudomales of S. schlegelii for subsequent all-female offspring breeding. Long-term MT administration severely inhibits the growth of S. schlegelii, while short term had no significant impact. Histological analysis confirmed sex reversal at all MT concentrations; however, both medium and higher MT concentrations impaired testis development. MT also influenced sex steroid hormone levels in pseudomales, suppressing E2 while increasing T and 11-KT levels. In addition, a transcriptome analysis revealed that MT down-regulated ovarian-related genes (cyp19a1a and foxl2) while up-regulating male-related genes (amh) in pseudomales. Furthermore, MT modulated the TGF-ß signaling and steroid hormone biosynthesis pathways, indicating its crucial role in S. schlegelii sex differentiation. Therefore, the current study provides a method for achieving sexual reversal using MT in S. schlegelii and offers an initial insight into the underlying mechanism of sexual reversal in this species.

Immunophenotypic analysis of angiomyolipoma with epithelial cysts, comparison to mixed epithelial and stromal tumors and epithelial and stromal elements of normal kidney and ovaries.

Angiomyolipoma with epithelial cysts (AMLEC) is a rare variant of renal angiomyolipoma (AML). It is characterized by a conventional AML component admixed with epithelial cysts within an "ovarian-like" stroma. Mixed epithelial and stromal tumor (MEST) is another renal neoplasm featuring epithelial cysts and "ovarian-like" stroma. While there is consensus that in MEST the epithelial and stromal components are neoplastic, in AMLEC it has been hypothesized that the epithelial component may represent renal tubular entrapment or ovarian-like transdifferentiation of tumor cells. The aim of this study was to compare the immunophenotypes of the epithelial-stromal components of AMLEC and MEST, with normal kidney and ovary to provide additional insights into the pathogenesis and relationships of these entities. In this study, we analyzed eight cases of AMLEC and 14 cases of MEST from 2003 to 2023. We used tissue microarrays, full sections, or unstained slides with an immunohistochemical panel including renal and ovarian markers: SF1, ER, PR, AR, PAX8, WT1, GATA3, CA-IX, p16, inhibin A, and BCL2. We compared these cases with ten non-neoplastic ovary and kidney samples. Our findings indicate that the epithelial component of AMLEC and MEST resembles hormone receptor positive renal tubular epithelium (AR + /ER - /PR -). AMLEC's stromal component resembled hormone receptor positive renal stroma, while MEST's resembled ovarian stroma, supporting mullerian transdifferentiation. Our study showed that the epithelial and stromal components of AMLEC and MEST are immunophenotypically different and also differ from normal tissues. Our findings suggest that in AMLEC, the epithelial-stromal component represents a hormonally driven proliferation of non-neoplastic renal elements within a dysregulated tumor microenvironment.

Causal associations of cognition, intelligence, education, health and lifestyle factors with cervical spondylosis: a mendelian randomization study.

Background: Education, cognition, and intelligence are phenotypically and genetically related. Education has been shown to have a protective effect on the risk of developing cervical spondylosis. However, it is unclear whether cognition and intelligence have independent causal effects on cervical spondylosis, and whether health and lifestyle factors influence this association. Methods: We first assessed the independent effects of education, cognition, and intelligence on cervical spondylosis by two-sample Mendelian randomization and multivariable Mendelian randomization analysis, and evaluated 26 potential association mediators using two-step Mendelian randomization, and calculated the median proportion. Results: The results showed that only education had an independent causal effect on cervical spondylosis, and had a protective effect on the risk of cervical spondylosis (ß: 0.3395; se: 0.166; p < 0.05; OR:0.71; [95%CI: 0.481-0.943]. Of the 26 potential associated mediators, a factor was identified: SHBG (mediated proportion: 2.5%). Univariable Mendelian randomization results showed that the risk factors for cervical spondylosis were time spent watching TV (OR:1.96; [95%CI: 1.39-2.76]), smoking (OR:2.56; [95%CI: 1.061-1.486]), body mass index (OR:1.26; [95%CI: 1.124-1.418]), percentage of body fat (OR:1.32; [95%CI: 1.097-1.593]), major depression (OR:1.27; [95%CI: 1.017-1.587]) and sitting height (OR:1.15; [95%CI: 1.025-1.291]). Protective factors include computer using (OR:0.65; [95%CI: 0.418-0.995]), sex hormone binding globulin (OR:0.87; [95%CI: 0.7955-0.951]) and high-density lipoprotein (OR:0.90; [95%CI: 0.826-0.990]). Conclusion: Our findings demonstrate the causal and independent effects of education on cervical spondylosis and suggest that lifestyle media may be a priority target for the prevention of cervical spondylosis due to low educational attainment.

Blood lipid levels mediating the effects of sex hormone-binding globulin on coronary heart disease: Mendelian randomization and mediation analysis.

Observational studies indicate that serum sex hormone-binding globulin (SHBG) levels are inversely correlated with blood lipid levels and coronary heart disease (CHD) risk. Given that dyslipidemia is an established risk factor for CHD, we aim to employ Mendelian randomization (MR) in conjunction with mediation analysis to confirm the mediating role of blood lipid levels in the association between SHBG and CHD. First, we assessed the causality between serum SHBG levels and five cardiovascular diseases using univariable MR. The results revealed causality between SHBG levels and reduced risk of CHD, myocardial infarction, as well as hypertension. Specifically, the most significant reduction was observed in CHD risk, with an odds ratio of 0.73 (95% CI 0.63-0.86) for each one-standard-deviation increase in SHBG. The summary-level data of serum SHBG levels and CHD are derived from a sex-specific genome-wide association study (GWAS) conducted by UK Biobank (sample size = 368,929) and a large-scale GWAS meta-analysis (60,801 cases and 123,504 controls), respectively. Subsequently, we further investigated the mediating role of blood lipid level in the association between SHBG and CHD. Mediation analysis clarified the mediation proportions for four mediators: high cholesterol (48%), very low-density lipoprotein cholesterol (25.1%), low-density lipoprotein cholesterol (18.5%), and triglycerides (44.3%). Summary-level data for each mediator were sourced from the UK Biobank and publicly available GWAS. The above results confirm negative causality between serum SHBG levels and the risk of CHD, myocardial infarction, and hypertension, with the causal effect on reducing CHD risk largely mediated by the improvement of blood lipid profiles.