Premenopausal women generally exhibit lower blood pressure and a lower prevalence of hypertension than men of the same age, but these differences reverse postmenopause due to estrogen withdrawal. Sexual dimorphism has been described in different components of kidney physiology and pathophysiology, including the renin-angiotensin-aldosterone system, endothelin system, and tubular transporters. This review explores the sex-specific differences in kidney function and blood pressure regulation. Understanding these differences provides insights into potential therapeutic targets for managing hypertension and kidney diseases, considering the patient\'s sex and hormonal status.

Seahorses exhibit the unique characteristic of male pregnancy, which incubates numerous embryos in a brood pouch that plays an essential role in enhancing offspring survivability. The pot-belly seahorse (Hippocampus abdominalis) possesses the largest body size among seahorses and is a significant species in Chinese aquaculture. In this study, we revealed the cytological and morphological characteristics, as well as regulatory mechanisms, throughout the entire brood pouch development in H. abdominalis. The brood pouch originated from the abdominal dermis, extending towards the ventral midline. As the dermal layers thicken, the inner epithelium folds, the stroma loosens, and vascularization occurs, culminating in the formation of the brood pouch. Furthermore, through transcriptomic analysis of brood pouches at various developmental stages, 8 key genes (tgfb3, fgf2, wnt7a, pgf, mycn, tln2, jund, ccn4) closely related to the development of brood pouch were identified in the MAPK, Rap1, TGF-β, and Wnt signaling pathways. These genes were highly expressed in the pseudoplacenta and dermal layers at the newly formed stage as examined by in situ hybridization (ISH). The angiogenesis, densification of collagen fibers, and proliferation of fibroblasts and endothelial cells in seahorse brood pouch formation may be regulated by these genes and pathways. Additionally, the expression of the androgen receptor gene (ar) was significantly upregulated during the formation of the brood pouch, and ISH confirmed the expression of the ar gene in the dermis and pseudoplacenta of the brood pouch, highlighting its role in the developmental process. Androgen and flutamide (androgen receptor antagonist) treatments significantly accelerated the formation of the brood pouch and completely inhibited its occurrence respectively, concomitant to the upregulated expression of differentially expressed genes involved above signaling pathways. These findings demonstrated that formation of the brood pouch is determined by androgen and the androgen receptor activates the above signaling pathways in the brood pouch through the regulation of fgf2, tgfb3, pgf, and wnt7a. Interestingly, androgen even induced the formation of the brood pouch in females. We firstly elucidated the formation of the seahorse brood pouch, demonstrating that androgens and their receptors directly induce the thickening, folding, and vascularization of the abdominal dermal layer into a placenta-like structure through multiple signaling pathways. These findings provide foundational insights to further exploring the evolution of male pregnancy and adaptive convergence in viviparity across vertebrates.

Endocrine-disrupting chemicals (EDCs) are chemicals that can interfere with homeostatic processes. They are a major concern for public health, and they can cause adverse long-term effects such as cancer, intellectual impairment, obesity, diabetes, and male infertility. The endocrine system is a complex machinery, with the estrogen (E), androgen (A), and thyroid hormone (T) modes of action being of major importance. In this context, the availability of in silico models for the rapid detection of hazardous chemicals is an effective contribution to toxicological assessments. We developed Qualitative Gene expression Activity Relationship (QGexAR) models to predict the propensities of chemically induced disruption of EAT modalities. We gathered gene expression profiles from the LINCS database tested on two cell lines, i.e., MCF7 (breast cancer) and A549 (adenocarcinomic human alveolar basal epithelial). We optimized our prediction protocol by testing different feature selection methods and classification algorithms, including CATBoost, XGBoost, Random Forest, SVM, Logistic regression, AutoKeras, TPOT, and deep learning models. For each EAT endpoint, the final prediction was made according to a consensus prediction as a function of the best model obtained for each cell line. With the available data, we were able to develop a predictive model for estrogen receptor and androgen receptor binding and thyroid hormone receptor antagonistic effects with a consensus balanced accuracy on a validation set ranging from 0.725 to 0.840. The importance of each predictive feature was further assessed to identify known genes and suggest new genes potentially involved in the mechanisms of action of EAT perturbation.

UNASSIGNED: This study aimed to translate and validate the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese language, as we hypothesized that this tool would be consistent for addressing the specific context of hormonal symptoms in menopause.
UNASSIGNED: In a cross-sectional study, a total of 119 women with Genitourinary Syndrome of Menopause (GSM) and 119 climacteric women without GSM were included. The EASQ-W was translated, and its psychometric properties were rigorously examined. Participants completed questionnaires covering sociodemographic details, the EASQ-W, and the Menopause Rating Scale (MRS). A subgroup of 173 women was re-invited after 4 weeks for test-retest analysis of the EASQ-W. Additionally, the responsiveness of the questionnaire was evaluated in 30 women who underwent oral hormonal treatment.
UNASSIGNED: The internal consistency of the EASQ-W was found to be satisfactory in both GSM and control groups (Cronbach\'s alpha ≥ 0.70). Notably, a floor effect was observed in both groups; however, a ceiling effect was only evident in the sexual domain of the GSM group. Construct validity was established by comparing the EASQ-W with the MRS, yielding statistically significant correlations (0.33831-0.64580, p < 0.001). The test-retest reliability over a 4-week period was demonstrated to be satisfactory in both the GSM and control groups (ICC 0.787-0.977). Furthermore, the EASQ-W exhibited appropriate responsiveness to oral hormonal treatment (p < 0.001).
UNASSIGNED: This study successfully translated and validated the Estro-Androgenic-Symptom Questionnaire in Women (EASQ-W) into Brazilian Portuguese, with satisfactory internal consistency, test-retest reliability, and construct validity.

Kidney cancer is a common malignancy that constitutes around 5% of all cancer cases. Males are twice as likely to acquire renal cell carcinoma (RCC) compared to females and experience a higher rate of mortality. These disparities indicate that sex hormone (SH)-dependent pathways may have an impact on the aetiology and pathophysiology of RCC. Examination of SH involvement in conventional signalling pathways, as well as genetics and genomics, especially the involvement of ribonucleic acid, reveal further insights into sex-related differences. An understanding of SHs and their influence on kidney cancer is essential to offer patients individualized medicine that would better meet their needs in terms of prevention, diagnosis and treatment. This review presents the understanding of sex-related differences in the clinical manifestation of kidney cancer patients and the underlying biological processes.

UNASSIGNED: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) or 11-hydroxylase deficiency (11OHD) is characterized by underproduction of cortisol and overproduction of adrenal androgens. These androgens lead to a variable degree of virilization of the female external genitalia in 46,XX individuals. Especially in developing countries, diagnosis is often delayed and 46,XX patients might be assigned as males. This study aims to describe the clinical and biochemical characteristics of a unique cohort of untreated male-reared 46,XX classic CAH patients from Indonesia and discusses treatment challenges.
UNASSIGNED: Nine untreated classic CAH patients with 46,XX genotype and 21OHD (n=6) or 11OHD (n=3), aged 3-46 years old, were included. Biometrical parameters, clinical characteristics, and biochemical measurements including glucocorticoids, renin, androgens, and the pituitary-gonadal axis were evaluated.
UNASSIGNED: All patients had low early morning serum cortisol concentrations (median 89 nmol/L) without significant increase after ACTH stimulation. Three patients with salt wasting 21OHD reported one or more periods with seizures and/or vomiting in their past until the age of 6, but not thereafter. The remaining patients reported no severe illness or hospitalization episodes, despite their decreased capacity to produce cortisol. In the 21OHD patients, plasma renin levels were elevated compared to the reference range, and in 11OHD patients renin levels were in the low-normal range. All adult patients had serum testosterone concentrations within the normal male reference range. In 21OHD patients, serum 11-oxygenated androgens comprised 41-60% of the total serum androgen concentrations. Glucocorticoid treatment was offered to all patients, but they refused after counseling as this would reduce their endogenous androgen production and they did not report complaints of their low cortisol levels.
UNASSIGNED: We describe a unique cohort of untreated classic 46,XX male CAH patients without overt clinical signs of cortisol deficiency despite their cortisol underproduction and incapacity to increase cortisol levels after ACTH stimulation. The described adolescent and adult patients produce androgen levels within or above the normal male reference range. Glucocorticoid treatment will lower these adrenal androgen concentrations. Therefore, in 46,XX CAH patients reared as males an individual treatment approach with careful counseling and clear instructions is needed.

Dysfunctional RNA-binding proteins (RBPs) have been implicated in several geriatric diseases, including Alzheimer\'s disease (AD). However, little is known about the nuclear molecular actions and cooperative functions mediated by RBPs that affect gene regulation in sporadic AD or aging. In the present study, we investigated aging- and AD-associated changes in the expression of PSF and G3BP2, which are representative RBPs associated with sex hormone activity. We determined that both PSF and G3BP2 levels were decreased in aged brains compared to young brains of mice. RNA sequencing (RNA-seq) analysis of human neuronal cells has shown that PSF is responsible for neuron-specific functions and sustains cell viability. In addition, we showed that PSF interacted with G3BP2 in the nucleus and stress granules (SGs) at the protein level. Moreover, PSF-mediated gene regulation at the RNA level correlated with G3BP2. Interestingly, PSF and G3BP2 target genes are associated with AD development. Mechanistically, quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis demonstrated that the interaction of RBPs with the pre-mRNA of target genes enhanced post-transcriptional mRNA stability, suggesting a possible role for these RBPs in preserving neuronal cell viability. Notably, in the brains of patients with sporadic AD, decreased expression of PSF and G3BP2 in neurons was observed compared to non-AD patients. Overall, our findings suggest that the cooperative action of PSF and G3BP2 in the nucleus is important for preventing aging and AD development.

BACKGROUND: Prostate cancer (PCa) patients with elevated level of androgen receptor (AR) correlate with higher metastatic incidence. Protein expression of AR and its target gene prostate-specific antigen (PSA) are elevated in metastatic prostate tumors as compared to organ-confined tumors. Androgen treatment or elevation of AR promotes metastasis of PCa in cell culture and murine model. However, under androgen depleted condition, AR suppressed cell mobility and invasiveness of PCa cells. Androgen deprivation therapy in PCa patients is associated with higher risk of cancer metastasis. We therefore investigated the dual roles of AR and miRNAs on PCa metastasis.
METHODS: The PC-3AR (PC-3 cells re-expressing AR) and LNCaP cells were used as PCa cell model. Transwell migration and invasion assay, wound-healing assay, zebrafish xenotransplantation assay, and zebrafish vascular exit assay were used to investigate the role of AR and androgen on PCa metastasis. Micro-Western Array, co-immunoprecipitation and Immunofluorescence were applied to dissect the molecular mechanism lying underneath. The miRNA array, miRNA inhibitors or plasmid, and chromatin immunoprecipitation assay were used to study the role of miRNAs on PCa metastasis.
RESULTS: In the absence of androgen, AR repressed the migration and invasion of PCa cells. When androgen was present, AR stimulated the migration and invasion of PCa cells both in vitro and in zebrafish xenotransplantation model. Androgen increased phospho-AR Ser81 and yes-associated protein 1 (YAP), decreased phospho-YAP Ser217, and altered epithelial-mesenchymal transition (EMT) proteins in PCa cells. Co-IP assay demonstrated that androgen augmented the interaction between YAP and AR in nucleus. Knockdown of YAP or treatment with YAP inhibitor abolished the androgen-induced migration and invasion of PCa cells, while overexpression of YAP showed opposite effects. The miRNA array revealed that androgen decreased hsa-miR-5001-5p but increased hsa-miR-203a and hsa-miR-210-3p in PC-3AR cells but not PC-3 cells. Treatment with inhibitors targeting hsa-miR-203a/hsa-miR-210-3p, or overexpression of hsa-miR-5001-5p decreased YAP expression as well as suppressed the androgen-induced migration and invasion of PCa cells. Chromatin immunoprecipitation (ChIP) assay demonstrated that AR binds with promoter region of has-miR-210-3p in the presence of androgen.
CONCLUSIONS: Our observations indicated that miRNAs 203a/210-3p/5001-5p regulate the androgen/AR/YAP-induced PCa metastasis.

OBJECTIVE: Microglial cells are integral to the pathogenesis of Alzheimer\'s disease (AD). The observed sex disparity in AD prevalence, with a notable predominance in women, implies a potential influence of sex hormones, such as androgens, on disease mechanisms. Despite this, the specific effects of androgens on microglia remain unclear. This study is designed to delineate the interplay between androgens and the survival and inflammatory profile of microglial cells, as well as to explore their contribution to the progression of AD.
RESULTS: To create a chronic androgen deficiency model, 3-month-old wild-type (WT) mice and APP/PS1 mice underwent bilateral orchiectomy (ORX), with age-matched sham-operated controls. Cognitive and memory were evaluated at 5 and 12 months, paralleled by assessments of amyloid-beta (Aβ) and microglial morphology in hippocampal and cortical areas. The ORX treatment in mice resulted in diminished microglial populations and morphological alterations, alongside an increase in Aβ plaques and a concomitant decline in cognitive performance that exacerbated over time. In vitro, dihydrotestosterone (DHT) was found to stimulate microglial proliferation and ameliorate Aβ1-42-induced apoptosis.
CONCLUSIONS: These findings suggested that androgens may exert a protective role, maintaining the normal proliferation and functionality of microglial cells. This preservation could potentially slow the progression of AD. As a result, our study provided a conceptual framework for the development of novel therapeutic strategies for AD.

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