Sex Steroids Research Articles

PCSK9 in metabolism and diseases.

PCSK9 is a serine protease that regulates plasma levels of low-density lipoprotein (LDL) and cholesterol by mediating the endolysosomal degradation of LDL receptor (LDLR) in the liver. When PCSK9 functions unchecked, it leads to increased degradation of LDLR, resulting in elevated circulatory levels of LDL and cholesterol. This dysregulation contributes to lipid and cholesterol metabolism abnormalities, foam cell formation, and the development of various diseases, including cardiovascular disease (CVD), viral infections, cancer, and sepsis. Emerging clinical and experimental evidence highlights an imperative role for PCSK9 in metabolic anomalies such as hypercholesterolemia and hyperlipidemia, as well as inflammation, and disturbances in mitochondrial homeostasis. Moreover, metabolic hormones - including insulin, glucagon, adipokines, natriuretic peptides, and sex steroids - regulate the expression and circulatory levels of PCSK9, thus influencing cardiovascular and metabolic functions. In this comprehensive review, we aim to elucidate the regulatory role of PCSK9 in lipid and cholesterol metabolism, pathophysiology of diseases such as CVD, infections, cancer, and sepsis, as well as its pharmaceutical and non-pharmaceutical targeting for therapeutic management of these conditions.

Is Alcohol Consumption Pattern Dependent on Prenatal Sex-Steroids? A Digit Ratio (2D:4D) Study Among University Students.

There is evidence that alcohol consumption is influenced by prenatal sex steroids (as measured by digit ratio [2D:4D]). Here, we clarify the effect size of the relationship in a student (rather than a patient) population. There were 258 (169 women) participants. Digit length was measured directly with calipers. Alcohol use was evaluated by the Polish version of Alcohol Use Disorders Identification Test (AUDIT) and operationalized as total AUDIT scores and grams of alcohol/week. Digit ratios were sexually dimorphic (males < females). There were negative correlations between right 2D:4D and Dr-l (right 2D:4D minus left 2D:4D) and AUDIT scores and grams of alcohol/week in both sexes. Relationships varied from small (r = -0.29) to large (r = -0.69) and they were stronger in males in comparison to females and for right 2D:4D in comparison to Dr-l. In males only, there were small (r = 0.21) to moderate (r = 0.31) positive associations with body size (height, weight, and mean right digit length) and alcohol consumption. Multiple regression analyses showed relationships between digit ratios remained significant but those for body size did not. Alcohol consumption was negatively related to 2D:4D, suggesting high prenatal testosterone and low prenatal estrogen are linked to its consumption. Correlations varied in strength from small to large with the strongest found for right 2D:4D and for males. Positive relationships between body size and alcohol were small to moderate, confined to males, and were not independent of digit ratios. Prenatal androgenization may influence alcohol drinking patterns in non-clinical individuals.

Androgyny and atypical sensory sensitivity associated with savant ability: a comparison between Klinefelter syndrome and sexual minorities assigned male at birth

IntroductionThe extreme male brain (EMB) theory, a major causal hypothesis of autism (ASD: autism spectrum disorder), attributes excess androgens during early development as one of the causes. While studies have generally followed the EMB theory in females at birth, the co-occurrence of ASD in males at birth has been observed in conditions that are assumed to be associated with reduced androgen action during early development, including Klinefelter syndrome (KS) and sexual minorities. ASD is also associated with atypical sensory sensitivity, synesthesia, and savant syndrome.MethodsIn the present study, we examined adult KS individuals (n = 22), sexual minorities assigned male at birth (n = 66), and control males matched for age and educational background to those with KS [Exploratory analysis (control 1st): n = 36; Reanalysis (control 2nd): n = 583]. Participants completed a self-report questionnaire assessing sensory hypersensitivity/hyposensitivity, savant tendency (developed for the present study), synesthesia, and sexual aspects, including gender identity and sexual orientation.ResultsThe results of the exploratory analysis suggested that individuals with KS exhibited a higher tendency toward sensory hypersensitivity/hyposensitivity than the tendency exhibited by the controls. In the Reanalysis, sexual minorities were more likely to be synesthetes, and in both analyses sexual minorities exhibited a higher savant tendency and sensory hypersensitivity/hyposensitivity than the controls. Moreover, the gender dysphoric state was associated with phenotypes observed in individuals with ASD, such as synesthesia, savant tendency, and sensory hypersensitivity/hyposensitivity.DiscussionThese results suggest a common physiological background among gender dysphoria, synesthesia, savant tendency, and atypical sensory sensitivity. Thus, androgynous features (reduced effects of sex steroids during early development) in males at birth may be partially related to the phenotype commonly observed in individuals with ASD. Based on the present results, we propose that the reduction of sex steroids during early development may lead to atypical neurodevelopment and be involved in the atypicality of external and internal sensory perception, and thus in the atypicality of self-concept integration, through the disruption of oxytocin and the gamma-aminobutyric acid system modulating the neural excitation/inhibition balance.

Sex Differences in the Neuroendocrine Stress Response: A View from a CRH-Reporting Mouse Line

Corticotropin-releasing hormone (CRH) neurons within the paraventricular hypothalamic nucleus (PVH) play a crucial role in initiating the neuroendocrine response to stress and are also pivotal in coordination of autonomic, metabolic, and behavioral stress reactions. Although the role of parvocellular CRHPVH neurons in activation of the hypothalamic–pituitary–adrenal (HPA) axis is well established, the distribution and function of CRH-expressing neurons across the whole central nervous system are less understood. Stress responses activate complex neural networks, which differ depending on the type of stressor and on the sex of the individual. Because of the technical difficulties of localizing CRH neurons throughout the rodent brain, several CRH reporter mouse lines have recently been developed. In this study, we used Crh-IRES-Cre;Ai9 reporter mice to examine whether CRH neurons are recruited in a stressor- or sex-specific manner, both within and outside the hypothalamus. In contrast to the clear sexual dimorphism of CRH-mRNA-expressing neurons, quantification of CRH-reporting, tdTomato-positive neurons in different stress-related brain areas revealed only subtle differences between male and female subjects. These results strongly imply that sex differences in CRH mRNA expression occur later in development under the influence of sex steroids and reflects the limitations of using genetic reporter constructs to reveal the current physiological/transcriptional status of a specific neuron population. Next, we compared the recruitment of stress-related, tdTomato-expressing (putative CRH) neurons in male and female Crh-IRES-Cre;Ai9 reporter mice that had been exposed to predator odor. In male mice, fox odor triggered more c-Fos in the CRH neurons of the paraventricular hypothalamic nucleus, central amygdala, and anterolateral bed nucleus of the stria terminalis compared to females. These results indicate that male mice are more sensitive to predator exposure due to a combination of hormonal, environmental, and behavioral factors.

Endocannabinoid System and Metabolism: The Influences of Sex

The endocannabinoid system (ECS) is a lipid signaling system involved in numerous physiological processes, such as endocrine homeostasis, appetite control, energy balance, and metabolism. The ECS comprises endocannabinoids, their cognate receptors, and the enzymatic machinery that tightly regulates their levels within tissues. This system has been identified in various organs, including the brain and liver, in multiple mammalian and non-mammalian species. However, information regarding the sex-specific regulation of the ECS remains limited, even though increasing evidence suggests that interactions between sex steroid hormones and the ECS may ultimately modulate hepatic metabolism and energy homeostasis. Within this framework, we will review the sexual dimorphism of the ECS in various animal models, providing evidence of the crosstalk between endocannabinoids and sex hormones via different metabolic pathways. Additionally, we will underscore the importance of understanding how endocrine-disrupting chemicals and exogenous cannabinoids influence ECS-dependent metabolic pathways in a sex-specific manner.

Sex Differences in Blood Accumulation of Neurodegenerative-Related Proteins and Antioxidant Responses to Regular Physical Exercise

Physical activity has been demonstrated to improve cognitive function, thereby preventing/slowing neurodegenerative diseases (NDs). Biological responses to physical activity and vulnerabilities to NDs are emerging to be gender-related. Herein, known ND-associated markers (β-amyloid, tau, α-synuclein), main sex steroid hormones, antioxidant responses, and key gene transcription modulators were evaluated in the blood of physically active and sedentary women and men. In our hands, females presented higher basal erythrocytes β-amyloid and α-synuclein amounts than males. Regular physical activity was able to significantly reduce the erythrocyte content of β-amyloid in females and the tau levels in males, suggesting that these differences may be mediated by organizational actions of sex steroid hormones during development. Furthermore, despite a comparable plasma antioxidant capability (AOC) between males and females, in the latter group, physical activity significantly enhances AOC versus peroxynitrite radicals only. Finally, regular physical activity modulated the levels of transcription factor Nrf2 in erythrocytes, as well as the plasma concentration of the microRNA miR-195 and miR-153, suggesting the promotion of antioxidant/autophagic processes associated with ND-related proteins. Overall, these results could shed light on how cerebral adaptations to physical activity differ between males and females, especially with regard to blood accumulation of ND proteins and mechanisms of antioxidant responses to regular exercise.

The associations between exposure to mixed environmental endocrine disruptors and sex steroid hormones in men: a comparison of different statistical models

In recent years, worldwide fertility rates have continued to decrease. Humans are frequently exposed to a combination of environmental endocrine disruptors, which can cause male reproductive disorders. The study employed three distinct analytical models to examine the correlation between exposure to a combination of 25 chemicals and sex steroid hormone levels in adult males. This involved evaluating 12 chemicals and their metabolites from personal care and consumer products, as well as 13 metabolites linked to phthalates and plasticisers. The study analysed 25 chemicals and 3 measured sex steroid hormone outcomes, as well as two calculated hormonal outcomes (free androgen index, TT/E2 ratio) in 1262 adult men who participated in the National Health and Nutrition Examination Survey (NHANES) 2013–2016 in the United States. The study employed several statistical methods to estimate the relationships between single chemicals or chemical blends and sex hormones. These methods included linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine (BKMR) regression. The results of the linear regression analysis indicate that chemical exposure has a negative correlation with E2, TT, and FAI, and a positive correlation with SHBG and TT/E2. The mixture effect analyses using the WQS and BKMR models further confirmed that BP3, MECPP, and MECOP were the most highly weighted chemical mixtures. The analyses also suggested that there were differences in the effects of different concentrations of EDCs on sex steroid hormones. Exposure to environmental endocrine-disrupting chemicals (EDCs) has been found to have a negative correlation with estradiol and total testosterone, as well as FAI. Conversely, this exposure has been found to have a positive correlation with sex hormone binding globulin and the TT/E2 ratio. The study also revealed differences in the effects of different concentrations of EDCs.

Revisiting the specific and potentially independent role of the gonad in hormone regulation and reproductive behavior.

Gonadal sex steroid hormones are well-studied modulators of reproductive physiology and behavior. Recent behavioral endocrinology research has focused on how the brain dynamically responds to - and may even produce - sex steroids, but the gonadal tissues that primarily release these hormones receive much less attention as a potential mediator of behavioral variation. This Commentary revisits mechanisms by which the reproductive hypothalamic-pituitary-gonadal (HPG) axis can be modulated specifically at the gonadal level. These mechanisms include those that may allow the gonad to be regulated independently of the HPG axis, such as receptors for non-HPG hormones, neural inputs and local production of conventional 'neuropeptides'. Here, I highlight studies that examine variation in these gonadal mechanisms in diverse taxa, with an emphasis on recent transcriptomic work. I then outline how future work can establish functional roles of gonadal mechanisms in reproductive behavior and evaluate gonad responsiveness to environmental cues. When integrated with neural mechanisms, further investigation of gonadal hormone regulation can yield new insight into the control and evolution of steroid-mediated traits, including behavior.

Pyrethroids and reproductive function: some endocrine disrupting perspectives from molecular simulations.

Pyrethroids are widely used insecticides with huge applications for household as well as agricultural purposes and contribute to improved product quality and higher yields. In recent decades, the demand for pyrethroids has increased significantly due to advantages such as broad-spectrum efficacy, high insecticidal potential, and lower pest resistance. However, several studies have suggested that human exposure to pyrethroids leads to reproductive problems. Sex hormone-binding globulin (SHBG) is an important hormone transport protein regulating the availability of steroids at their target site. The aim of our study was to investigate the structural interactions of commonly used pyrethroids, cypermethrin and deltamethrin, with ligand binding pocket of SHBG. Cypermethrin and deltamethrin were docked into the steroid binding pocket of SHBG using Schrodinger's induced fit docking (IFD) followed by molecular dynamics (MD) simulation studies. The resultant SHBG-pyrethroid complexes from IFD experiments were subjected to structural analysis including the molecular interactions followed by binding energy estimation. The analysis revealed that both the ligands were tightly bound in the SHBG pocket with high percentage of commonality among the SHBG residues between the indicated pyrethroid ligands and the SHBG native ligand, dihydrotestosterone (DHT). The estimated binding energy values for cypermethrin were less but close to the values calculated for the SHBG native ligand, DHT. However, the estimated binding energy values for deltamethrin were higher compared to the values calculated for SHBG native ligand, DHT. Furthermore, the MD simulation results also revealed the higher stability of SHBG-deltamethrin than SHBG-cypermethrin complex. To sum up, the results suggested that deltamethrin has a greater capability than cypermethrin to prevent sex steroid hormone from binding to SHBG, even though both pyrethroids have this ability. Consequently, this might hamper the circulatory transport of sex steroid hormones and their availability at the target site, subsequently interfering with reproductive function.

Antibody Preparation, Protein Expression, and Function Analysis of Cyp19a1b in Ovarian Differentiation in a Natural Triploid Teleost Qi River Crucian Carp (Carassius auratus)

Estrogen is an essential sex steroid that functions in numerous biological systems including female reproduction, neuroendocrine, vascular, skeletal, and immune systems. The synthesis of estrogen is controlled by the rate-limiting enzyme, which has been confirmed to exist in two different forms, named brain aromatase and ovary aromatase, and encoded by cyp19a1a and cyp19a1b respectively in teleosts. However, existing studies have primarily focused on the expression and function of cyp19a1b in the brain and cyp19a1a in the gonad, the roles of cyp19a1b in the female gonad of teleosts are largely unknown. In our previous study, we cloned the full length of the cyp19a1b gene from a natural triploid teleost Qi River crucian carp (Carassius auratus), andthe spatial and temporal expression patterns of cyp19a1b mRNA were detected. To further clarify the roles of cyp19a1b in the ovarian differentiation of Qi River crucian carp, we produced a polyclonal antibody of Cyp19a1b in this study. Western blotting results showed that Cyp19a1b was mainly expressed in the brain and then in the ovary, heart, liver, and muscle. During embryogenesis, Cyp19a1b was abundantly expressed in the neurula stage. Immunohistochemistry demonstrated that Cyp19a1b was expressed in the radioactive glial cells (RGCs) of the brain from 20 days after hatching (dah) and the somatic cells of the ovaries from 30 dah, the critical period of ovarian differentiation in Qi River crucian carp. With the treatment of letrozole, an inhibitor of the aromatase, the expression of Cyp19a1b was downregulated both in the brain and gonad. Our results suggested that Cyp19a1b might be involved in the development of the nervous system and also participate in the ovarian differentiation of Qi River crucian carp.

Neurotensin and Its Involvement in Female Hormone-Sensitive Cancers.

Neurotensin (NT) is a peptide involved in digestion, neuromodulation, and cancer progression. NT and its receptors (NTR1 and SORT1 mainly) have been widely studied in oncology. Data show that NT expression is under the control of sex steroid hormones, in particular estradiol. We focused on its involvement in three main female hormone-sensitive cancers, breast, ovarian, and endometrial cancer, in a narrative review. NT, NTR1, and SORT1 are mostly expressed in these three cancers, and their involvement in oncologic processes such as proliferation and invasion seems to match, as does their impact on prognosis for most. The development of NT receptor-targeted therapies, including theranostics and radioligand treatments, presents a promising avenue for personalized cancer treatment.

Alteration of the metabolite interconversion enzyme in sperm and Sertoli cell of non-obstructive azoospermia: a microarray data and in-silico analysis

Numerous variables that regulate the metabolism of Sertoli cells and sperm have been identified, one of which is sex steroid hormones. These hormones play a vital role in maintaining energy homeostasis, influencing the overall metabolic balance of the human body. The proper functioning of the reproductive system is closely linked to energy status, as the reproductive axis responds to metabolic signals. The aim of this study was to investigate the gene expression patterns of metabolite interconversion enzymes in testicular cells (Sertoli cells and spermatogonia) of non-obstructive azoospermia (NOA) patients, as compared to normal controls, to understand the molecular mechanisms contributing to NOA. We used microarray and bioinformatics techniques to analyze 2912 genes encoding metabolite interconversion enzymes, including methyltransferase, monooxygenase, transmembrane reductase, and phosphohydrolase, in both testicular cells and normal samples. In sperm, the upregulation of MOXD1, ACAD10, PCYT1A, ARG1, METTL6, GPLD1, MAOA, and CYP46A1 was observed, while ENTPD2, CPT1C, ADC, and CYB5B were downregulated. Similarly, in the Sertoli cells of three NOA patients, RPIA, PIK3C3, LYPLA2, CA11, MBOAT7, and HDHD2 were upregulated, while NAA25, MAN2A1, CYB561, PNPLA5, RRM2, and other genes were downregulated. Using STRING and Cytoscape, we predicted the functional and molecular interactions of these proteins and identified key hub genes. Pathway enrichment analysis highlighted significant roles for G1/S-specific transcription, pyruvate metabolism, and citric acid metabolism in sperm, and the p53 signaling pathway and folate metabolism in Sertoli cells. Additionally, Weighted Gene Co-expression Network Analysis (WGCNA) and single-cell RNA sequencing (scRNA-seq) were performed to validate these findings, revealing significant alterations in gene expression and cellular distribution in NOA patients. Together, these results provide new insights into the molecular mechanisms underlying NOA and identify potential therapeutic targets.

Disorders in cytokine synthesis in women with uterine fibroids

In the structure of gynecological diseases, uterine fibroids occupy an “honorable” second place after inflammatory processes of the genital organs, and its share reaches 40%. Uterine fibroids are a benign monoclonal tumor that develops from one abnormal smooth muscle cell of the myometrium, which, as a result of mutation, has the ability to grow unregulated. Common symptoms of the disease include pelvic discomfort or pain, excessive uterine bleeding, secondary anemia, infertility, and bowel and bladder dysfunction. Uterine fibroids can negatively affect the general condition of a woman, causing hormonal, vegetative-vascular and psycho-emotional disorders. Moreover, about 80% of patients with uterine fibroids undergo radical surgical treatment. The mechanisms of development and growth of this benign tumor have not been fully established and remain controversial. The role of immune disorders in the pathogenesis of fibroids is currently being discussed. It has been proven that the growth of fibroids is accompanied by a weakening of immune defense against the background of an increase in the level of proinflammatory cytokines, which are regulators of the processes of proliferation and apoptosis, mediators of the action of sex steroids. The aim of the study was to study the level of some pro-inflammatory cytokines (IL-1β, IL-2, TGF-β2 and MCP-1) in the blood serum of women of reproductive age with uterine fibroids, depending on the size and nature of tumor growth. A comparative analysis of the results of examination of 123 women with uterine fibroids, who made up 2 groups: 1st group of 65 women with simple uterine fibroids and 2nd group of 58 women with rapidly growing uterine fibroids, is presented. The examination included a comprehensive clinical and laboratory study. The level of cytokines (IL-1β, IL- 2, TGF-β2, MCP-1) in the blood serum was assessed by ELISA. It was found that in patients of reproductive age with uterine fibroids, there is an increase in the levels of IL-1β, TGF-β2 and MCP-1. In women with rapidly growing uterine fibroids, these changes are more pronounced. The concentration of IL-2 is reduced in all women with uterine fibroids, regardless of the size and nature of tumor growth. It has been established that an increase in the size of myomatous nodes is accompanied by an increase in immune imbalance: there is an increase in the levels of pro-inflammatory cytokines (IL-1β, TGF-β2, MCP-1) against the background of a reduced content of the lymphokine IL-2, which we regard as possible links in the pathogenesis of uterine fibroids. A pronounced deficiency of IL-2 in the blood serum against the background of a sharp increase in the concentration of TGF-β2 and MCP-1 in the blood of women with uterine fibroids can be considered as a negative criterion for predicting disease progression and used as an additional prognostic marker of tumor growth

Nesfatin-1 expressed in human endometrial stromal cell line (THESC) stimulates decidualization through FAK/PI3K/AKT signaling pathway

This study aimed to investigate the expression and functional role of nesfatin-1, a peptide hormone traditionally associated with appetite regulation, in the human endometrium. Specifically, we examined its presence and regulatory potential in the human endometrial stromal cell line, THESC cells, focusing on the process of endometrial decidualization, which is critical for implantation and pregnancy maintenance. We found that nesfatin-1 and its binding sites were expressed in THESC cells. Furthermore, nesfatin-1 protein expression decreased after treatment with 17β- estradiol but increased upon exposure to progesterone, indicating an influence of sexsteroid hormones on nesfatin-1 expression. Notably, administration of nesfatin-1 protein to THESC cells resulted in significant upregulation of genes associated with decidualization, such as insulin-like growth factor binding protein 1 (IGFBP1) and prolactin. In addition, our research showed that nesfatin-1 promotes decidualization through the activation of the FAK/PI3K/AKT signaling pathway. These findings underscore the central role of nesfatin-1 in endometrial decidualization, and suggest its potential utility in the development of new treatments to improve fertility and pregnancy outcomes.

Activation of ionotropic and group I metabotropic glutamate receptors stimulates kisspeptin neuron activity in mice.

Different populations of hypothalamic kisspeptin (KISS1) neurons located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARC) are thought to generate the sex-specific patterns of gonadotropin secretion. These neuronal populations integrate gonadal sex steroid feedback with internal and external cues relayed via the actions of neurotransmitters and neuropeptides. The excitatory amino acid neurotransmitter glutamate, the main excitatory neurotransmitter in the brain, plays a role in regulating gonadotropin secretion, at least partially through engaging KISS1 signaling. The expression and function of individual glutamate receptor subtypes in KISS1 neurons, however, are not well characterized. Here, we used GCaMP-based calcium imaging and patch-clamp electrophysiology to assess the impact of activating individual ionotropic (iGluR) and group I metabotropic (mGluR) glutamate receptors on KISS1 neuron activity in the mouse RP3V and ARC. Our results indicate that activation of all iGluR subtypes and of group I mGluRs, likely mGluR1, consistently drives activity in the majority of KISS1 neurons within the RP3V and ARC of males and females. Our results also revealed, somewhat unexpectedly, sex- and region-specific differences. Indeed, activating (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) type iGluRs evoked larger responses in female ARCKISS1 neurons than in their male counterparts whereas activating group I mGluRs induced larger responses in RP3VKISS1 neurons than in ARCKISS1 neurons in females. Together, our findings suggest that glutamatergic neurotransmission in KISS1 neurons, and its impact on the activity of these cells, might be sex- and region-dependent in mice.

Rat Model of Menopausal/Andropausal Hypertension with Different Sensitivities to Non-Genomic Antihypertensive Responses of Female and Male Sex Steroids

Introduction: Hypertension is prevalent in older women and men, but the impact of sex differences is unclear. Methods: Blood pressure (BP) was evaluated weekly for 15 weeks using tail-cuff plethysmography in intact or gonadectomized female and male rats. Similarly, gonadectomized rats were subcutaneously treated daily for 15 weeks with estradiol in females or testosterone in males. Treatment with estrogen in males and androgen in females for BP was also examined. The non-genomic antihypertensive potency and efficacy of different sex steroids were determined; catheters were implanted in the carotid artery of hypertensive rats for BP recording with bolus injections in the jugular vein at cumulative doses (1 × 10−7−1 × 10−4M kg−1 min−1) of dehydroepiandrosterone (DHEA), estradiol, testosterone, or 5β-dihydrotestosterone (5β-DHT). Results: Data showed a time-dependent increase in BP after gonadectomy in female and male rats until hypertension values were reached. Males are more sensitive to the development of hypertension than females. The increases in BP in females and males were completely prevented by estradiol or testosterone, respectively. Testosterone completely prevented hypertension in females, whereas estradiol only partially in males. Antihypertensive potencies in conscious hypertensive rats were DHEA = 5β-DHT = testosterone >> estradiol, in females and DHEA = 5β-DHT >> testosterone >> estradiol in males. The efficacy was DHEA = 5β-DHT = testosterone >> estradiol in females and 5β-DHT = DHEA >> testosterone >> estradiol in males. Conclusion: Gonadectomized males developed hypertension faster than females, suggesting that androgen deficiency plays an important role in BP reduction. Antihypertensive responses of steroids are structure-dependent; estradiol demonstrated the lowest potency, whereas 5β-DHT was a potent antihypertensive without estrogenic and androgenic actions, suggesting it is as a therapeutic candidate for controlling hypertension in both sexes.

Targeted long-read sequencing identifies missing pathogenic variant in unsolved 11β-hydroxylase deficiency

Background11β-hydroxylase deficiency (11β-OHD), caused by homozygosity or compound heterozygosity CYP11B1 variants, is the second most common cause of congenital adrenal hyperplasia (CAH). Due to the high degree of sequence identity between CYP11B1 and CYP11B2, chimeric genes, and complex structural variants (SVs), the conventional approach to gene testing for 11β-OHD is facing challenges. The study aimed to clarify the underlying genetic causes of two siblings of a Chinese family with 11β-OHD.MethodsPeripheral blood samples and clinical information were collected from subjects and their family members. Sex steroid concentrations were measured using LC-MS/MS. Long-range PCR-based next-generation sequencing (NGS), PCR assay and target long-read sequencing were used to detect the pathogenic variants.ResultsEarly onset hypertension, increased serum levels of adrenocorticotropin (ACTH), progesterone, testosterone, and decreased cortisol and potassium were detected in both affected siblings. Long-range PCR-based NGS identified a heterozygous missense variant (NM_000497.4:c.281 C > T, p.P94> L) in CYP11B1 gene in the two siblings. PCR detected no chimeric CYP11B2/CYP11B1 gene. We finally identified a second pathogenic variant in CYP11B1 gene via target long-read sequencing (T-LRS). This novel variant was a deletion-insertion variant and located chr8:143957269–143,957,579 (hg19) with the insertion of ‘ACAG’ (NM_000497.4:c.954 + 78_980delinsACAG), which was in trans with CYP11B1: c.281 C > T.ConclusionsOur study suggests that the integrated long-range PCR-based NGS and T-LRS seem to be the most reliable and accurate method for 11β-OHD genetic diagnosis and carrier sequencing.

Associations of Co-Exposure to Polycyclic Aromatic Hydrocarbons and Heavy Metals with Sex Steroid Hormones among Children Aged 6–19 Years

Plain Language SummaryPolycyclic aromatic hydrocarbons (PAHs) and HMs are two classic groups of environmental endocrine-disrupting chemicals (EDCs). PAHs usually coexist with HMs and they may have a combined effect in affecting sex hormone levels in children. Sex steroid hormones have an important role in children’s growth and development which affects growth rate, central nervous system function, normal skeletal mineralization, and reproductive health. This study investigated the correlations between co-exposure to PAHs and HMs and levels of sex steroid hormones in children. Weighted multivariate linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were used to analyze the associations between co-exposure to PAHs and HMs and sex steroid hormone levels. We found that co-exposure to PAHs and HMs was associated with the levels of estradiol (E2), the testosterone (TT)/E2 ratio, free androgen index (FAI), and sex hormone-binding globulin (SHBG). Our analysis reveals that co-exposure to PAHs and HMs is hazardous to the reproductive health of children, and further mechanism and prospective studies are needed to provide additional substantial evidence.

Physiological influences on neurovascular coupling: A systematic review of multimodal imaging approaches and recommendations for future study designs.

In this review, we have amalgamated the literature, taking a multimodal neuroimaging approach to quantify the relationship between neuronal firing and haemodynamics during a task paradigm (i.e., neurovascular coupling response), while considering confounding physiological influences. Original research articles that used concurrent neuronal and haemodynamic quantification in humans (n ≥ 10) during a task paradigm were included from PubMed, Scopus, Web of Science, EMBASE and PsychINFO. Articles published before 31 July 2023 were considered for eligibility. Rapid screening was completed by the first author. Two authors completed the title/abstract and full-text screening. Article quality was assessed using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A total of 364 articles were included following title/abstract and full-text screening. The most common combination was EEG/functional MRI (68.7%), with cognitive (48.1%) and visual (27.5%) tasks being the most common. The majority of studies displayed an absence/minimal control of blood pressure, arterial gas concentrations and/or heart rate (92.9%), and only 1.3% monitored these factors. A minority of studies restricted or collected data pertaining to caffeine (7.4%), exercise (0.8%), food (0.5%), nicotine (2.7%), the menstrual cycle (0.3%) or cardiorespiratory fitness levels (0.5%). The cerebrovasculature is sensitive to numerous factors; thus, to understand the neurovascular coupling response fully, better control for confounding physiological influences of blood pressure and respiratory metrics is imperative during study-design formulation. Moreover, further work should continue to examine sex-based differences, the influence of sex steroid hormone concentrations and cardiorespiratory fitness.

Estradiol and progesterone from pregnancy to postpartum: a longitudinal latent class analysis.

During the peripartum, women undergo significant hormonal changes that are crucial for fetal development and a healthy pregnancy and postpartum period for mother and infant. Although several studies have determined healthy norm ranges of estradiol and progesterone, there are discrepancies among the reports, rendering it unclear which hormone levels are linked to adverse health outcomes. To account for the impact of sex steroid patterns on health outcomes in mothers and children, a longitudinal assessment of different parameters is needed. We longitudinally assessed a cohort of 130 women over five months during pregnancy and postpartum. The women provided saliva samples and completed psychosocial questionnaires. Hormone analyses were conducted using enzyme-linked immunosorbent assay (ELISA). Different parameters of estradiol and progesterone were analyzed and evaluated in relation to psychometric variables. To examine the presence of heterogenous hormonal trajectories in the peripartum, we applied group-based trajectory modelling as a special case of latent-class group analysis. Estradiol and progesterone levels rose towards the end of pregnancy and dropped sharply after birth, with considerable individual variation, particularly during pregnancy. However, their ratio remained stable. We identified three estradiol trajectory subgroups and two progesterone subgroups. Age influenced progesterone levels, with older pregnant women having higher levels than younger women. Anxiety and depressive symptoms had a predictive value for trajectories of specific subgroups of women. The study also revealed two distinct subgroups regarding the course of estradiol and progesterone fluctuations as well as their ratio. This study provides insights into the course and fluctuation of salivary estradiol and progesterone levels among healthy women during the peripartum period, highlighting significant variations in hormone levels but stability in their ratio during this time. The finding of distinct sex steroid courses in the peripartum is new and suggests the need for further research to explore their impact on health outcomes. Our preliminary results suggest that hormonal fluctuations at the end of pregnancy appear to be a normal occurrence and might even be a protective factor for associated psychological symptoms and sleep disturbances in women.