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BioRxiv : the Preprint Server For... May 2024The pituitary gland (PG) plays a central role in the production and secretion of pubertal hormones, with documented links to the emergence and increase in mental health...
The pituitary gland (PG) plays a central role in the production and secretion of pubertal hormones, with documented links to the emergence and increase in mental health symptoms known to occur during adolescence. Although much of the literature has focused on examining whole PG volume, recent findings suggest that there are associations among pubertal hormone levels, including dehydroepiandrosterone (DHEA), subregions of the PG, and elevated mental health symptoms (e.g., internalizing symptoms) during adolescence. Surprisingly, studies have not yet examined associations among these factors and increasing transdiagnostic symptomology, despite DHEA being a primary output of the anterior PG. Therefore, the current study sought to fill this gap by examining whether anterior PG volume specifically mediates associations between DHEA levels and changes in dysregulation symptoms in an adolescent sample ( = 114, 9 - 17 years, M = 12.87, SD = 1.88). Following manual tracing of the anterior and posterior PG, structural equation modeling revealed that greater anterior, not posterior, PG volume mediated the association between greater DHEA levels and increasing dysregulation symptoms across time, controlling for baseline dysregulation symptom levels. These results suggest specificity in the role of the anterior PG in adrenarcheal processes that may confer risk for psychopathology during adolescence. This work not only highlights the importance of separately tracing the anterior and posterior PG, but also suggests that transdiagnostic factors like dysregulation are useful in parsing hormone-related increases in mental health symptoms in youth.
PubMed: 38798387
DOI: 10.1101/2024.05.17.594766 -
Discovery Medicine May 202417α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A,...
Revealing a New Homozygous Variant in c.908G>A (p. Gly303Asp) by Genotyping a Chinese Patient with 46, XY 17a-Hydroxylase/17,20-Lyase Deficiency and Adrenal Space-Occupying Lesion.
BACKGROUND
17α-hydroxylase/17,20-lyase deficiency (17OHD) is an autosomal recessive genetic disorder caused by a mutation of the cytochrome P450, family 17, subfamily A, polypeptide 1 (). This study reports the case of a 22-year-old Chinese patient (46, XY) with 17OHD and a unilateral adrenal space-occupying lesion.
METHODS
The patient underwent serological, radiographic, genetic, and molecular analyses including whole-genome exome sequencing through high-throughput sequencing (HTS) technology to analyze the genetic conditions of both the patient and her parents. Additionally, chromosomal karyotype analysis was performed. The impact of the novel mutation on protein conformation was investigated by examining the three-dimensional structure of human using the SWISS-MODEL website tool (PDB code 3RUK).
RESULTS
The patient had a chromosomal karyotype 46, XY, and presented with hypertension, hypokalemia, and male pseudohermaphroditism. Furthermore, decreased levels of testosterone, dehydroepiandrosterone sulfate, and estradiol, along with increased levels of progesterone, luteinizing hormone, and follicle-stimulating hormone (FSH), were observed. DNA sequencing revealed a homozygous mutation (c.908G>A, p.G303A) in the fifth exon of the . Both parents carried a heterozygous c.908G>A mutation in the same exon, confirming the inheritance of the patient's exonic mutation.
CONCLUSION
For the first time, this study reports a novel homozygous mutation (c.908G>A in the fifth exon) in . Modeling analysis of suggested that the substitution of glycine with aspartic acid at position 303 induces alterations in the number, structure, and electrostatic potential of the protein's local binding sites. The p.G303A mutation may possess pathogenic properties. Our study expands the mutation spectrum of .
Topics: Humans; Steroid 17-alpha-Hydroxylase; Female; Adrenal Hyperplasia, Congenital; Homozygote; Young Adult; Asian People; Male; Genotype; Mutation, Missense; East Asian People
PubMed: 38798260
DOI: 10.24976/Discov.Med.202436184.94 -
Discovery Medicine May 2024Polycystic ovary syndrome (PCOS) commonly impacts fertile females with potentially severe effects on fertility and metabolism. Blood ghrelin levels are lower in PCOS...
BACKGROUND
Polycystic ovary syndrome (PCOS) commonly impacts fertile females with potentially severe effects on fertility and metabolism. Blood ghrelin levels are lower in PCOS patients, and exogenous supplements have been proposed for their potential to trigger anti-inflammatory effects at the cellular level. This study aimed to investigate whether pretreatment with ghrelin reduced inflammation, insulin resistance, and reproductive abnormalities in PCOS and the underlying mechanism of this disorder.
METHODS
Ghrelin supplementation was first tested in an inflammation model using human ovarian granulosa cells (KGN cells) that were built by treated with Lipolyaccharide. KGN cells were pretreated with ghrelin and exposed to lipopolysaccharide (LPS). Inflammatory gene expression and cytokine production were analyzed by Enzyme-linked immunosorbent assay (ELISA). Based on these results, the PCOS mice model was built with Dehydroepiandrosterone (DHEA) and a high-fat diet. The mRNA and protein expressions of inflammatory factors including Toll-like receptor 4 (TLR4), nuclear factor kappa-B-p65 (NF-κB-p65), Phospho-NF-κB-p65 (p-NF-κB-p65) and myeloid differentiation factor 88 (MYD88) related to the TLR4/NF-κB signaling pathway were evaluated in KGN cells and mouse ovarian tissues using Real-Time Quantitative Polymerase Chain Reaction (RT-qPCR) and western blot, respectively. Lipid metabolism was quantified via an automated biochemical analyzer.
RESULTS
The mRNA and protein expressions of interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α) in ghrelin pretreated KGN cells were lower than the LPS group ( < 0.05). Protein expression was reduced for TLR4, NF-κB-p65, and MYD88 within KGN cells of ghrelin groups compared to the LPS group ( < 0.05). Ghrelin treatment restored the estrous cycle and slowed weight gain and abdominal fat weight of PCOS mice ( < 0.05). Ghrelin treatment decreased the serum concentrations of testosterone, luteinizing hormone, insulin, IL-6, IL-1β, and TNF-α compared to the PCOS group ( < 0.05). Estradiol concentrations of mice treated with ghrelin were higher than the PCOS group ( < 0.05). The concentrations of low and high-density lipoprotein, triglyceride, and cholesterol in mice treated with ghrelin were lower than in the PCOS mice ( < 0.05). Inflammatory gene expression for IL-6, IL-1β, TNF-α, TLR4, NF-κB-p65, and MYD88 decreased in the ovarian tissues of ghrelin-treated mice compared to the PCOS group ( < 0.05), along with reduced protein expression of TLR4, p-NF-κB-p65, and MYD88 ( < 0.05).
CONCLUSIONS
In the present study, ghrelin treatment effectively reduced inflammation , and attenuated insulin resistance and reproductive abnormalities in PCOS mice through the TLR4/NF-κB signaling pathway, highlighting potential therapeutic avenues for future PCOS treatments and research directions.
Topics: Animals; Polycystic Ovary Syndrome; Female; Toll-Like Receptor 4; Mice; Insulin Resistance; Signal Transduction; NF-kappa B; Inflammation; Ghrelin; Humans; Disease Models, Animal; Granulosa Cells
PubMed: 38798254
DOI: 10.24976/Discov.Med.202436184.88 -
Life (Basel, Switzerland) Apr 2024Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR)... (Review)
Review
Pregnane neuroactive steroids, notably allopregnanolone and pregnenolone, exhibit efficacy in mitigating inflammatory signals triggered by toll-like receptor (TLR) activation, thus attenuating the production of inflammatory factors. Clinical studies highlight their therapeutic potential, particularly in conditions like postpartum depression (PPD), where the FDA-approved compound brexanolone, an intravenous formulation of allopregnanolone, effectively suppresses TLR-mediated inflammatory pathways, predicting symptom improvement. Additionally, pregnane neurosteroids exhibit trophic and anti-inflammatory properties, stimulating the production of vital trophic proteins and anti-inflammatory factors. Androstane neuroactive steroids, including estrogens and androgens, along with dehydroepiandrosterone (DHEA), display diverse effects on TLR expression and activation. Notably, androstenediol (ADIOL), an androstane neurosteroid, emerges as a potent anti-inflammatory agent, promising for therapeutic interventions. The dysregulation of immune responses via TLR signaling alongside reduced levels of endogenous neurosteroids significantly contributes to symptom severity across various neuropsychiatric disorders. Neuroactive steroids, such as allopregnanolone, demonstrate efficacy in alleviating symptoms of various neuropsychiatric disorders and modulating neuroimmune responses, offering potential intervention avenues. This review emphasizes the significant therapeutic potential of neuroactive steroids in modulating TLR signaling pathways, particularly in addressing inflammatory processes associated with neuropsychiatric disorders. It advances our understanding of the complex interplay between neuroactive steroids and immune responses, paving the way for personalized treatment strategies tailored to individual needs and providing insights for future research aimed at unraveling the intricacies of neuropsychiatric disorders.
PubMed: 38792602
DOI: 10.3390/life14050582 -
Frontiers in Endocrinology 2024Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Accumulating evidence suggests that the autism spectrum disorder (ASD) population exhibits altered hormone levels, including androgens. However, studies on the regulation of androgens, such as testosterone and dehydroepiandrosterone (DHEA), in relation to sex differences in individuals with ASD are limited and inconsistent. We conducted the systematic review with meta-analysis to quantitatively summarise the blood, urine, or saliva androgen data between individuals with ASD and controls.
METHODS
A systematic search was conducted for eligible studies published before 16 January 2023 in six international and two Chinese databases. We computed summary statistics with a random-effects model. Publication bias was assessed using funnel plots and heterogeneity using I statistics. Subgroup analysis was performed by age, sex, sample source, and measurement method to explain the heterogeneity.
RESULTS
17 case-control studies (individuals with ASD, 825; controls, 669) were assessed. Androgen levels were significantly higher in individuals with ASD than that in controls (SMD: 0.27, 95% CI: 0.06-0.48, =0.01). Subgroup analysis showed significantly elevated levels of urinary total testosterone, urinary DHEA, and free testosterone in individuals with ASD. DHEA level was also significantly elevated in males with ASD.
CONCLUSION
Androgen levels, especially free testosterone, may be elevated in individuals with ASD and DHEA levels may be specifically elevated in males.
Topics: Humans; Male; Androgens; Autism Spectrum Disorder; Case-Control Studies; Dehydroepiandrosterone; Testosterone; Female
PubMed: 38779452
DOI: 10.3389/fendo.2024.1371148 -
Reproductive Biology and Endocrinology... May 2024Reproduction in women is at risk due to exposure to chemicals that can disrupt the endocrine system during different windows of sensitivity throughout life. Steroid...
BACKGROUND
Reproduction in women is at risk due to exposure to chemicals that can disrupt the endocrine system during different windows of sensitivity throughout life. Steroid hormone levels are fundamental for the normal development and function of the human reproductive system, including the ovary. This study aims to elucidate steroidogenesis at different life-stages in human ovaries.
METHODS
We have developed a sensitive and specific LC-MS/MS method for 21 important steroid hormones and measured them at different life stages: in media from cultures of human fetal ovaries collected from elective terminations of normally progressing pregnancy and in media from adult ovaries from Caesarean section patients, and follicular fluid from women undergoing infertility treatment. Statistically significant differences in steroid hormone levels and their ratios were calculated with parametric tests. Principal component analysis (PCA) was applied to explore clustering of the ovarian-derived steroidogenic profiles.
RESULTS
Comparison of the 21 steroid hormones revealed clear differences between the various ovarian-derived steroid profiles. Interestingly, we found biosynthesis of both canonical and "backdoor" pathway steroid hormones and corticosteroids in first and second trimester fetal and adult ovarian tissue cultures. 17α-estradiol, a less potent naturally occurring isomer of 17β-estradiol, was detected only in follicular fluid. PCA of the ovarian-derived profiles revealed clusters from: adult ovarian tissue cultures with relatively high levels of androgens; first trimester and second trimester fetal ovarian tissue cultures with relatively low estrogen levels; follicular fluid with the lowest androgens, but highest corticosteroid, progestogen and estradiol levels. Furthermore, ratios of specific steroid hormones showed higher estradiol/ testosterone and estrone/androstenedione (indicating higher CYP19A1 activity, p < 0.01) and higher 17-hydroxyprogesterone/progesterone and dehydroepiandrosterone /androstenedione (indicating higher CYP17A1 activity, p < 0.01) in fetal compared to adult ovarian tissue cultures.
CONCLUSIONS
Human ovaries demonstrate de novo synthesis of non-canonical and "backdoor" pathway steroid hormones and corticosteroids. Elucidating the steroid profiles in human ovaries improves our understanding of physiological, life-stage dependent, steroidogenic capacity of ovaries and will inform mechanistic studies to identify endocrine disrupting chemicals that affect female reproduction.
Topics: Humans; Female; Ovary; Adult; Pregnancy; Fetus; Gonadal Steroid Hormones; Tandem Mass Spectrometry; Follicular Fluid; Estradiol; Chromatography, Liquid
PubMed: 38778396
DOI: 10.1186/s12958-024-01233-7 -
Stem Cells and Development Jun 2024With the postponement of the reproductive age of women, the difficulty of embryo implantation caused by uterine aging has become a key factor restricting fertility....
With the postponement of the reproductive age of women, the difficulty of embryo implantation caused by uterine aging has become a key factor restricting fertility. However, there are few studies on protective interventions for naturally aging uteri. Although many factors cause uterine aging, such as oxidative stress (OS), inflammation, and fibrosis, their impact on uterine function manifests as reduced endometrial receptivity. This study aimed to use a combination of human umbilical cord mesenchymal stem cells (hUC-MSCs) and dehydroepiandrosterone (DHEA) to delay uterine aging. The results showed that the combined treatment of hUC-MSCs + DHEA increased the number of uterine glandular bodies and the thickness of the endometrium while inhibiting the senescence of endometrial epithelial cells. This combined treatment alleviates the expression of OS (reactive oxygen species, superoxide dismutase, and GSH-PX) and proinflammatory factors (interleukin [IL]-1, IL6, IL-18, and tumor necrosis factor-α) in the uterus, delaying the aging process. The combined treatment of hUC-MSCs + DHEA alleviated the abnormal hormone response of the endometrium, inhibited excessive accumulation and fibrosis of uterine collagen, and upregulated uterine estrogen and progesterone receptors through the PI3K/AKT/mTOR pathway. This study suggests that uterine aging can be delayed through hUC-MSCs + DHEA combination therapy, providing a new treatment method for uterine aging.
PubMed: 38770820
DOI: 10.1089/scd.2023.0290 -
Journal of Bone and Mineral Metabolism May 2024This study is to investigate the relation between serum dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) levels and the risk of osteoporosis in patients with T2DM.
INTRODUCTION
This study is to investigate the relation between serum dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) levels and the risk of osteoporosis in patients with T2DM.
MATERIALS AND METHODS
This cross-sectional study involved 938 hospitalized patients with T2DM. Linear regression models were used to explore the relationship between DHEA and DHEAS and the BMD at different skeletal sites. Multinominal logistic regression models and the restricted cubic spline (RCS) were used to evaluate the associations of DHEA and DHEAS with the risks of osteopenia and/or osteoporosis.
RESULTS
In postmenopausal women with T2DM, after adjustment for confounders including testosterone and estradiol, DHEA showed a significant positive correlation with lumbar spine BMD (P = 0.013). Moreover, DHEAS exhibited significant positive correlations with BMD at three skeletal sites: including femoral neck, total hip, and lumbar spine (all P < 0.05). Low DHEA and DHEAS levels were associated with increased risk of osteopenia and/or osteoporosis (all P < 0.05) and the risk of osteoporosis gradually decreased with increasing DHEAS levels (P overall = 0.018, P-nonlinear = 0.559). However, DHEA and DHEAS levels in men over the age of 50 with T2DM were not associated with any of above outcomes.
CONCLUSION
In patients with T2DM, independent of testosterone and estradiol, higher DHEA and DHEAS levels are associated with higher BMD and lower risk of osteopenia/osteoporosis in postmenopausal women but not men over the age of 50.
Topics: Humans; Female; Diabetes Mellitus, Type 2; Osteoporosis; Middle Aged; Male; Dehydroepiandrosterone; Bone Density; Aged; Dehydroepiandrosterone Sulfate; Cross-Sectional Studies; Sex Characteristics; Sulfates
PubMed: 38769209
DOI: 10.1007/s00774-024-01511-9 -
Zoological Research May 2024The Chinese tree shrew ( ) has emerged as a promising model for investigating adrenal steroid synthesis, but it is unclear whether the same cells produce steroid...
The Chinese tree shrew ( ) has emerged as a promising model for investigating adrenal steroid synthesis, but it is unclear whether the same cells produce steroid hormones and whether their production is regulated in the same way as in humans. Here, we comprehensively mapped the cell types and pathways of steroid metabolism in the adrenal gland of Chinese tree shrews using single-cell RNA sequencing, spatial transcriptome analysis, mass spectrometry, and immunohistochemistry. We compared the transcriptomes of various adrenal cell types across tree shrews, humans, macaques, and mice. Results showed that tree shrew adrenal glands expressed many of the same key enzymes for steroid synthesis as humans, including , , , and . Biochemical analysis confirmed the production of aldosterone, cortisol, and dehydroepiandrosterone but not dehydroepiandrosterone sulfate in the tree shrew adrenal glands. Furthermore, genes in adrenal cell types in tree shrews were correlated with genetic risk factors for polycystic ovary syndrome, primary aldosteronism, hypertension, and related disorders in humans based on genome-wide association studies. Overall, this study suggests that the adrenal glands of Chinese tree shrews may consist of closely related cell populations with functional similarity to those of the human adrenal gland. Our comprehensive results (publicly available at http://gxmujyzmolab.cn:16245/scAGMap/) should facilitate the advancement of this animal model for the investigation of adrenal gland disorders.
Topics: Animals; Adrenal Glands; Humans; Steroids; Transcriptome; Mice; Tupaiidae; Female; Multiomics
PubMed: 38766745
DOI: 10.24272/j.issn.2095-8137.2023.280 -
Behavioural Brain Research Jul 2024This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived...
BACKGROUND
This systematic review aims to comprehensively explore the impact of psychostimulant substances on neurotrophic and inflammatory pathways, including brain-derived neurotrophic factor (BDNF), pro-BDNF, cortisol, dehydroepiandrosterone sulfate (DHEAS), thiobarbituric acid reactive substances (TBARS), interleukins, and the role of genetic factors. The study seeks to address existing gaps in the literature by providing a thorough evaluation of neurotrophic and inflammatory system alterations associated with different stages of psychostimulant dependence for a more nuanced understanding of substance use disorder (SUD) neurobiology.
METHODS
A systematic review was conducted in PubMed, Scopus, and Web of Science databases following the PRISMA guidelines. The research encompasses 50 studies with a participant pool totaling 6792 individuals using psychostimulant substances.
RESULTS
Key findings include diverse impacts of cocaine on BDNF levels, mainly consisting of their significant increase during withdrawal. In contrast, NGF showed an opposite behavior, reducing during withdrawal. Cortisol and DHEAS levels exhibited relevant increases after psychostimulant use, while TBARS showed conflicting results. Genetic investigations predominantly focused on the Val66Met polymorphism of the BDNF gene, revealing associations with susceptibility to stimulant addiction.
CONCLUSIONS
Neurotrophins and inflammatory molecules play a significant role in the pathophysiological mechanisms following psychostimulant use. A better understanding of their complex interplay could aid clinicians in identifying biomarkers of different disease stages. Moreover, clinical interventions designed to interfere with neurotrophic and inflammatory pathways could possibly lead to craving-modulatory strategies and reduce pathological neuronal and systemic consequences of psychostimulant use.
Topics: Humans; Biomarkers; Brain-Derived Neurotrophic Factor; Central Nervous System Stimulants; Hydrocortisone; Nerve Growth Factors; Oxidative Stress; Substance-Related Disorders
PubMed: 38761859
DOI: 10.1016/j.bbr.2024.115046