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Alzheimer's & Dementia : the Journal of... Sep 2023Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using...
INTRODUCTION
Increased levels of sex hormones have been hypothesized to decrease Alzheimer's disease (AD) risk. We assessed the association between sex steroid hormones with AD using a Mendelian randomization (MR) approach.
METHODS
An inverse-variance weighting (IVW) MR analysis was performed using effect estimates from external genome-wide association study (GWAS) summary statistics. We included independent variants (linkage disequilibrium R < 0.001) and a p-value threshold of 5 × 10 .
RESULTS
An increase in androgens was associated with a decreased AD risk among men: testosterone (odds ratio [OR]: 0.53; 95% confidence interval [CI]: 0.32-0.88; p-value: 0.01; false discovery rate [FDR] p-value: 0.03); dehydroepiandrosterone sulfate (DHEAS; OR: 0.56; 95% CI: 0.38-0.85; p-value: 0.01; FDR p-value: 0.03); and androsterone sulfate (OR: 0.69; 95% CI: 0.46-1.02; p-value: 0.06; FDR p-value: 0.10). There was no association between sex steroid hormones and AD among women, although analysis for estradiol had limited statistical power.
DISCUSSION
A higher concentration of androgens was associated with a decreased risk of AD among men of European ancestry, suggesting that androgens among men might be neuroprotective and could potentially prevent or delay an AD diagnosis.
HIGHLIGHTS
Sex hormones are hypothesized to play a role in developing Alzheimer's disease (AD). The effect of sex hormones on AD was assessed using Mendelian randomization (MR) analysis. Among women, genetically determined effects of sex hormones were limited or null. Among men, a higher concentration of androgens decreased AD risk. This study suggests a causal relationship between androgens and AD among men.
Topics: Male; Humans; Female; Androgens; Alzheimer Disease; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Gonadal Steroid Hormones; Mendelian Randomization Analysis
PubMed: 36938850
DOI: 10.1002/alz.13013 -
EBioMedicine Sep 2023Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of...
BACKGROUND
Autonomous cortisol secretion (ACS), resulting from cortisol-producing adenomas (CPA), causes endogenous steroid-induced osteoporosis (SIOP). However, the risk of endogenous SIOP cannot be explained by cortisol excess alone, and how other steroid metabolites affect bone status is unclear.
METHODS
ACS was diagnosed as serum cortisol ≥1.8 μg/dL after the 1-mg dexamethasone suppression test (DST-cortisol). Using liquid chromatography tandem mass spectrometry, 21 plasma steroid metabolites were measured in 73 patients with ACS and 85 patients with non-functioning adrenal tumors (NFAT). Expression of steroidogenic enzymes and relevant steroid metabolites were analyzed in some of CPA tissues.
FINDINGS
Discriminant and principal component analyses distinguished steroid profiles between the ACS and NFAT groups in premenopausal women. Premenopausal women with ACS exhibited higher levels of a mineralocorticoid metabolite, 11-deoxycorticosterone (11-DOC), and lower levels of androgen metabolites, dehydroepiandrosterone-sulfate, and androsterone-glucuronide. In premenopausal women with ACS, DST-cortisol negatively correlated with trabecular bone score (TBS). Additionally, 11-DOC negatively correlated with lumbar spine-bone mineral density, whereas androsterone-glucuronide positively correlated with TBS. The CPA tissues showed increased 11-DOC levels with increased expression of CYP21A2, essential for 11-DOC synthesis. Adrenal non-tumor tissues were atrophied with reduced expression of CYB5A, required for androgen synthesis.
INTERPRETATION
This study demonstrates that unbalanced production of adrenal steroid metabolites, derived from both adrenal tumor and non-tumor tissues, contributes to the pathogenesis of endogenous SIOP in premenopausal women with ACS.
FUNDING
JSPS KAKENHI, Secom Science and Technology Foundation, Takeda Science Foundation, Japan Foundation for Applied Enzymology, AMED-CREST, JSTA-STEP, JST-Moonshot, and Ono Medical Research Foundation.
Topics: Humans; Female; Adrenal Gland Neoplasms; Hydrocortisone; Androgens; Androsterone; Cushing Syndrome; Glucuronides; Steroids; Osteoporosis; Steroid 21-Hydroxylase
PubMed: 37543511
DOI: 10.1016/j.ebiom.2023.104733 -
Molecular and Cellular Endocrinology Jun 2024Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been...
CONTEXT
Adrenarche is a normal developmental event in mid-childhood characterized by increasing adrenal androgen secretion. The role of the classic androgen pathway has been well described in adrenarche, but the role of newer active androgens and additional androgen pathways is less clear.
OBJECTIVE
To study the contribution of novel androgens and related steroid biosynthesis pathways to the development of adrenarche, and to identify additional steroid biomarkers of adrenarche.
DESIGN
A longitudinal study of children aged 6-8 years at baseline, followed up at ages 8-10 and 14-16 years. A total of 34 children (20 girls) with clinical and/or biochemical signs of adrenarche (cases) and 24 children (11 girls) without these signs (controls) at age 8-10 years were included. Serum steroid profiling was performed by liquid chromatography high-resolution mass spectrometry.
MAIN OUTCOME MEASURES
Thirty-two steroids compartmentalized in progestagens, gluco- and mineralocorticoid pathways, and four androgen related pathways, including the classic, backdoor, 11-oxy, and 11-oxy backdoor pathways.
RESULTS
The classic and 11-oxy androgen pathways were more active, and serum concentrations of main androgens in the classic (dehydroepiandrosterone, dehydroepiandrosterone sulfate, androstenedione and androsterone) and 11-oxy (11β-hydroxyandrostenedione, 11β-hydroxytestosterone, 11-ketoandrostenedione, and 11-ketotestosterone) pathways were higher in cases at ages 6-8 and 8-10 years. Pregnenolone concentrations at adrenarchal age (8-10 years) and cortisol concentrations at adolescence (14-16 years) were higher in cases. 11β-hydroxyandrosterone and 11-ketoandrosterone tended to be higher in cases with clinical signs compared to cases who had only biochemical evidence of adrenarche, albeit they were detected at low levels. In biomarker analyses, calculated steroid ratios with cortisol, cortisone, or 11-deoxycortisone as dividers were better classifiers for adrenarche than single steroids. Among these ratios, androstenedione/cortisone was the best.
CONCLUSIONS
The classic and 11-oxy androgen pathways are active in adrenarche. Children with earlier timing of adrenarche have higher serum cortisol levels at late pubertal age, suggesting that early adrenarche might have long-term effects on adrenal steroidogenesis by increasing the activity of the glucocorticoid pathway. Future studies should employ comprehensive steroid profiling to define novel classifiers and biomarkers for adrenarche and premature adrenarche.
PubMed: 38838762
DOI: 10.1016/j.mce.2024.112293 -
Expert Review of Endocrinology &... Mar 2024Hyperandrogenism is a clinical state consequent to excess androgen production by the ovary, adrenals, or increased peripheral conversion of androgens. The varied... (Review)
Review
An updated clinico-investigative approach to diagnosis of cutaneous hyperandrogenism in relation to adult female acne, female pattern alopecia & hirsutism a primer for dermatologists.
INTRODUCTION
Hyperandrogenism is a clinical state consequent to excess androgen production by the ovary, adrenals, or increased peripheral conversion of androgens. The varied manifestations of hyperandrogenism include seborrhea, acne, infertility, hirsutism, or overt virilization of which adult female acne, hirsutism, and female pattern hair loss are of clinical relevance to dermatologists.
AREAS COVERED
We limited our narrative review to literature published during period from 1 January 1985 to Dec 2022 and searched PubMed/MEDLINE, Web of Science (WOS), Scopus, and Embase databases with main search keywords were 'Hyperandrogenism,' 'Female,' 'Biochemical,' 'Dermatological', and 'Dermatology.' We detail the common etiological causes, nuances in interpretation of biochemical tests and imaging tools, followed by an algorithmic approach which can help avoid extensive tests and diagnose the common causes of hyperandrogenism.
EXPERT OPINION
Based on current data, total testosterone, sex hormone binding globulin, DHEAS, prolactin, free androgen index, and peripheral androgenic metabolites like 3-alpha diol and androsterone glucuronide are ideal tests though not all are required in all patients. Abnormalities in these biochemical investigations may require radiological examination for further clarification. Total testosterone levels can help delineate broadly the varied causes of hyperandrogenism. Serum AMH could be used for defining PCOM in adults.
Topics: Adult; Humans; Female; Hirsutism; Hyperandrogenism; Androgens; Dermatologists; Testosterone; Alopecia; Acne Vulgaris
PubMed: 38205927
DOI: 10.1080/17446651.2023.2299400 -
Environmental Health : a Global Access... Sep 2023Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient...
Knowledge of whether prenatal exposure to ambient air pollution disrupts steroidogenesis is currently lacking. We investigated the association between prenatal ambient air pollution and highly accurate measurements of cord blood steroid hormones from the androgenic pathway.This study included 397 newborns born between the years 2010 and 2015 from the ENVIRONAGE cohort in Belgium of whom six cord blood steroid levels were measured: 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, dehydroepiandrosterone, pregnenolone, androstenedione, and testosterone. Maternal ambient exposure to PM (particles with aerodynamic diameter ≤ 2.5 μm), NO and black carbon (BC) were estimated daily during the entire pregnancy using a high-resolution spatiotemporal model. The associations between the cord blood steroids and the air pollutants were tested and estimated by first fitting linear regression models and followed by fitting weekly prenatal exposures to distributed lag models (DLM). These analyses accounted for possible confounders, coexposures, and an interaction effect between sex and the exposure. We examined mixture effects and critical exposure windows of PM, NO and BC on cord blood steroids via the Bayesian kernel machine regression distributed lag model (BKMR-DLM).An interquartile range (IQR) increment of 7.96 µg/m in PM exposure during pregnancy trimester 3 was associated with an increase of 23.01% (99% confidence interval: 3.26-46.54%) in cord blood levels of 17α-hydroxypregnenolone, and an IQR increment of 0.58 µg/m³ in BC exposure during trimester 1 was associated with a decrease of 11.00% (99% CI: -19.86 to -0.012%) in cord blood levels of androstenedione. For these two models, the DLM statistics identified sensitive gestational time windows for cord blood steroids and ambient air pollution exposures, in particular for 17α-hydroxypregnenolone and PM exposure during trimester 3 (weeks 28-36) and for androsterone and BC exposure during early pregnancy (weeks 2-13) as well as during mid-pregnancy (weeks 18-26). We identified interaction effects between pollutants, which has been suggested especially for NO.Our results suggest that prenatal exposure to ambient air pollutants during pregnancy interferes with steroid levels in cord blood. Further studies should investigate potential early-life action mechanisms and possible later-in-life adverse effects of hormonal disturbances due to air pollution exposure.
Topics: Infant, Newborn; Female; Pregnancy; Humans; 17-alpha-Hydroxypregnenolone; Androstenedione; Bayes Theorem; Birth Cohort; Fetal Blood; Nitrogen Dioxide; Prenatal Exposure Delayed Effects; Air Pollution; Steroids; Air Pollutants; Particulate Matter
PubMed: 37674219
DOI: 10.1186/s12940-023-01010-w -
European Journal of Endocrinology Jul 2023Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
Aldo-keto reductase 1C3 (AKR1C3) has been postulated to be involved in androgen, progesterone, and estrogen metabolism. Aldo-keto reductase 1C3 inhibition has been proposed for treatment of endometriosis and polycystic ovary syndrome. Clinical biomarkers of target engagement, which can greatly facilitate drug development, have not yet been described for AKR1C3 inhibitors. Here, we analyzed pharmacodynamic data from a phase 1 study with a new selective AKR1C3 inhibitor, BAY1128688, to identify response biomarkers and assess effects on ovarian function.
DESIGN
In a multiple-ascending-dose placebo-controlled study, 33 postmenopausal women received BAY1128688 (3, 30, or 90 mg once daily or 60 mg twice daily) or placebo for 14 days. Eighteen premenopausal women received 60 mg BAY1128688 once or twice daily for 28 days.
METHODS
We measured 17 serum steroids by liquid chromatography-tandem mass spectrometry, alongside analysis of pharmacokinetics, menstrual cyclicity, and safety parameters.
RESULTS
In both study populations, we observed substantial, dose-dependent increases in circulating concentrations of the inactive androgen metabolite androsterone and minor increases in circulating etiocholanolone and dihydrotestosterone concentrations. In premenopausal women, androsterone concentrations increased 2.95-fold on average (95% confidence interval: 0.35-3.55) during once- or twice-daily treatment. Note, no concomitant changes in serum 17β-estradiol and progesterone were observed, and menstrual cyclicity and ovarian function were not altered by the treatment.
CONCLUSIONS
Serum androsterone was identified as a robust response biomarker for AKR1C3 inhibitor treatment in women. Aldo-keto reductase 1C3 inhibitor administration for 4 weeks did not affect ovarian function.ClinicalTrials.gov Identifier: NCT02434640; EudraCT Number: 2014-005298-36.
Topics: Female; Humans; Aldo-Keto Reductase Family 1 Member C3; Androgens; Androsterone; Dihydrotestosterone; Hydroxyprostaglandin Dehydrogenases; Progesterone; Steroids
PubMed: 37306288
DOI: 10.1093/ejendo/lvad063 -
BMC Geriatrics Apr 2024Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood...
BACKGROUND
Sarcopenia is a progressive loss of muscle mass and function. Since skeletal muscle plays a critical role in metabolic homeostasis, identifying the relationship of blood metabolites with sarcopenia components would help understand the etiology of sarcopenia.
METHODS
A two-sample Mendelian randomization study was conducted to examine the causal relationship of blood metabolites with the components of sarcopenia. Summary genetic association data for 309 known metabolites were obtained from the Twins UK cohort and KORA F4 study (7824 participants). The summary statistics for sarcopenia components [hand grip strength (HGS), walking pace (WP), and appendicular lean mass (ALM)] were obtained from the IEU Open GWAS project (461,089 participants). The inverse variance weighted method was used, and the MR-Egger, weighted median, and MR-PRESSO were used for the sensitivity analyses. Metabolic pathways analysis was further performed.
RESULTS
Fifty-four metabolites associated with sarcopenia components were selected from 275 known metabolites pool. Metabolites that are causally linked to the sarcopenia components were mainly enriched in amino sugar and nucleotide sugar metabolism, galactose metabolism, fructose and mannose metabolism, carnitine synthesis, and biotin metabolism. The associations of pentadecanoate (15:0) with ALM, and 3-dehydrocarnitine and isovalerylcarnitine with HGS were significant after Bonferroni correction with a threshold of P < 1.82 × 10 (0.05/275). Meanwhile, the association of hyodeoxycholate and glycine with the right HGS, and androsterone sulfate with ALM were significant in the sensitivity analyses.
CONCLUSION
Blood metabolites from different metabolism pathways were causally related to the components of sarcopenia. These findings might benefit the understanding of the biological mechanisms of sarcopenia and targeted drugs development for muscle health.
Topics: Humans; Sarcopenia; Hand Strength; Mendelian Randomization Analysis; Muscle, Skeletal; Causality
PubMed: 38622574
DOI: 10.1186/s12877-024-04938-x -
Frontiers in Genetics 2024Ischemic stroke (IS) is a major cause of death and disability worldwide. Previous studies have reported associations between metabolic disorders and IS. However,...
Ischemic stroke (IS) is a major cause of death and disability worldwide. Previous studies have reported associations between metabolic disorders and IS. However, evidence regarding the causal relationship between blood metabolites and IS lacking. A two-sample Mendelian randomization analysis (MR) was used to assess the causal relationship between 1,400 serum metabolites and IS. The inverse variance-weighted (IVW) method was employed to estimate the causal effect between exposure and outcome. Additionally, MR-Egger regression, weighted median, simple mode, and weighted mode approaches were employed as supplementary comprehensive evaluations of the causal effects between blood metabolites and IS. Tests for pleiotropy and heterogeneity were conducted. After rigorous selection, 23 known and 5 unknown metabolites were identified to be associated with IS. Among the 23 known metabolites, 13 showed significant causal effects with IS based on 2 MR methods, including 5-acetylamino-6-formylamino-3-methyluracil, 1-ribosyl-imidazoleacetate, Behenoylcarnitine (C22), N-acetyltyrosine, and N-acetylputrescine to (N (1) + N (8))-acetate,these five metabolites were positively associated with increased IS risk. Xanthurenate, Glycosyl-N-tricosanoyl-sphingadienine, Orotate, Bilirubin (E,E), Bilirubin degradation product, CHNO, Bilirubin (Z,Z) to androsterone glucuronide, Bilirubin (Z,Z) to etiocholanolone glucuronide, Biliverdin, and Uridine to pseudouridine ratio were associated with decreased IS risk. Among 1,400 blood metabolites, this study identified 23 known metabolites that are significantly associated with IS risk, with 13 being more prominent. The integration of genomics and metabolomics provides important insights for the screening and prevention of IS.
PubMed: 38313676
DOI: 10.3389/fgene.2024.1333454 -
Frontiers in Genetics 2024Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal...
Physical weakness and cardiovascular risk increase significantly with age, but the underlying biological mechanisms remain largely unknown. This study aims to reveal the causal effect of circulating metabolites on frailty, sarcopenia and vascular aging related traits and diseases through a two-sample Mendelian Randomization (MR) analysis. Exposures were 486 metabolites analyzed in a genome-wide association study (GWAS), while outcomes included frailty, sarcopenia, arterial stiffness, atherosclerosis, peripheral vascular disease (PAD) and aortic aneurysm. Primary causal estimates were calculated using the inverse-variance weighted (IVW) method. Methods including MR Egger, weighted median, Q-test, and leave-one-out analysis were used for the sensitive analysis. A total of 125 suggestive causative associations between metabolites and outcomes were identified. Seven strong causal links were ultimately identified between six metabolites (kynurenine, pentadecanoate (15:0), 1-arachidonoylglycerophosphocholine, androsterone sulfate, glycine and mannose) and three diseases (sarcopenia, PAD and atherosclerosis). Besides, metabolic pathway analysis identified 13 significant metabolic pathways in 6 age-related diseases. Furthermore, the metabolite-gene interaction networks were constructed. Our research suggested new evidence of the relationship between identified metabolites and 6 age-related diseases, which may hold promise as valuable biomarkers.
PubMed: 38415056
DOI: 10.3389/fgene.2024.1353908 -
BMC Genomics Jan 2024Current evidence suggests a significant association between metabolites and ovarian cancer (OC); however, the causal relationship between the two remains unclear. This...
BACKGROUND
Current evidence suggests a significant association between metabolites and ovarian cancer (OC); however, the causal relationship between the two remains unclear. This study employs Mendelian randomization (MR) to investigate the causal effects between different metabolites and OC.
METHODS
In this study, a total of 637 metabolites were selected as the exposure variables from the Genome-wide Association Study (GWAS) database ( http://gwas.mrcieu.ac.uk/datasets/ ). The OC related GWAS dataset (ieu-b-4963) was chosen as the outcome variable. R software and the TwoSampleMR package were utilized for the analysis in this study. MR analysis employed the inverse variance-weighted method (IVW), MR-Egger and weighted median (WM) for regression fitting, taking into consideration potential biases caused by linkage disequilibrium and weak instrument variables. Metabolites that did not pass the tests for heterogeneity and horizontal pleiotropy were considered to have no significant causal effect on the outcome. Steiger's upstream test was used to determine the causal direction between the exposure and outcome variables.
RESULTS
The results from IVW analysis revealed that a total of 31 human metabolites showed a significant causal effect on OC (P < 0.05). Among them, 9 metabolites exhibited consistent and stable causal effects, which were confirmed by Steiger's upstream test (P < 0.05). Among these 9 metabolites, Androsterone sulfate, Propionylcarnitine, 5alpha-androstan-3beta,17beta-diol disulfate, Total lipids in medium VLDL and Concentration of medium VLDL particles demonstrated a significant positive causal effect on OC, indicating that these metabolites promote the occurrence of OC. On the other hand, X-12,093, Octanoylcarnitine, N2,N2-dimethylguanosine, and Cis-4-decenoyl carnitine showed a significant negative causal association with OC, suggesting that these metabolites can inhibit the occurrence of OC.
CONCLUSIONS
The study revealed the complex effect of metabolites on OC through Mendelian randomization. As promising biomarkers, these metabolites are worthy of further clinical validation.
Topics: Humans; Female; Genome-Wide Association Study; Mendelian Randomization Analysis; Ovarian Neoplasms; Analysis of Variance; Databases, Factual
PubMed: 38262941
DOI: 10.1186/s12864-024-09997-3