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Discovery Medicine 2020The new immunosenescence paradigm (2015) was an attempt to explain a mechanism by which macrophages could be immunosuppressed and dysfunctional, yet paradoxically... (Review)
Review
The new immunosenescence paradigm (2015) was an attempt to explain a mechanism by which macrophages could be immunosuppressed and dysfunctional, yet paradoxically release proinflammatory factors in an unregulated manner. This mechanism was linked to the loss of dehydroepiandrosterone (DHEA) with aging and thus explained how immunosenescence could be causally related to the risk of stress and/or age-associated chronic diseases. At the center of this paradigm was lipid body negative (LB-) foamy macrophage (CD14+CD16+) which produced human endogenous retrovirus K102 (HERV-K102) particles. HERV-K102 may be a protector foamy virus of humans, and its induction may generate trained innate immunity, a special type of autoimmunity, in response to intracellular pathogens, their constituents, toxins, and/or tumors. Overwhelming evidence now suggests that the proinflammatory foamy macrophages driving ASCVD are LB-. Moreover, the monocyte/macrophage phenotype implicated in atherosclerosis-cardiovascular disease (ASCVD) appears to be the CD14+CD16+ intermediate phenotype. These and other observations directly challenge the cholesterol hypothesis. For the prevention and treatment of ASCVD, it is important to address the putative cause of ASCVD -- immunosenescence, rather than the signs or symptoms such as inflammation or elevated cholesterol. Therefore, strategies to reverse or prevent immunosenescence, which improve or maintain an optimal cortisol/DHEA ratio such as isoflavonoids, would be expected to alleviate not only ASCVD but the risk of many other age-associated chronic diseases. Here, the new immunosenescence paradigm will be appraised for its suitability to explain ASCVD risks.
Topics: Atherosclerosis; Autoantigens; Chronic Disease; Dehydroepiandrosterone; Endogenous Retroviruses; Humans; Hydrocortisone; Immunity, Innate; Immunologic Factors; Immunosenescence; Isoflavones; Macrophages; Plant Extracts; Randomized Controlled Trials as Topic; Risk Factors; Simian foamy virus; Treatment Outcome
PubMed: 32598862
DOI: No ID Found -
Trends in Endocrinology and Metabolism:... Sep 2020Dehydroepiandrosterone (DHEA) and DHEA sulfate together are abundant adrenal steroids whose physiological effects are mediated through their conversion to potent... (Review)
Review
Dehydroepiandrosterone (DHEA) and DHEA sulfate together are abundant adrenal steroids whose physiological effects are mediated through their conversion to potent downstream androgens. 3β-Hydroxysteroid dehydrogenase isotype 1 (3βHSD1) facilitates the rate-limiting step of DHEA metabolism and gates the flux of substrate into the distal portion of the androgen synthesis pathway. Notably, a germline, missense-encoding change, HSD3B1(1245C), results in expression of 3βHSD1 protein that is resistant to degradation, yielding greater potent androgen production in the periphery. In contrast, HSD3B1(1245A) encodes 3βHSD1 protein that is easily degraded, limiting peripheral androgen synthesis. These adrenal-permissive (AP) and adrenal-restrictive (AR) alleles have recently been associated with divergent outcomes in androgen-sensitive disease states, underscoring the need to reevaluate DHEA metabolism using HSD3B1 genetics.
Topics: 3-Hydroxysteroid Dehydrogenases; Androgens; Animals; Dehydroepiandrosterone; Humans; Male; Progesterone Reductase
PubMed: 32565196
DOI: 10.1016/j.tem.2020.05.006 -
Frontiers in Endocrinology 2022Sex hormones play an important role in the pathogenesis of cardiovascular disease (CVD). This cross-sectional study aimed to explore the associations of...
AIMS
Sex hormones play an important role in the pathogenesis of cardiovascular disease (CVD). This cross-sectional study aimed to explore the associations of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) with coronary heart disease (CHD) and stroke in middle-aged and elderly patients with type 2 diabetes mellitus (T2DM).
MATERIALS AND METHODS
A total of 995 patients with T2DM were included in the study analysis. Serum levels of DHEA and DHEAS were quantified using liquid chromatography-tandem mass spectrometry. Binary logistic regression analyses were performed to assess the associations of DHEA and DHEAS with CHD and stroke. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal DHEA and DHEAS cutoff values for the detection of CHD in men with T2DM.
RESULTS
In men with T2DM, after adjustment for potential confounders in model 3, the risk of CHD decreased with an increasing serum DHEA level [odds ratio (OR) = 0.38, quartile 4 . quartile 1; 95% confidence interval (CI) = 0.16-0.90; = 0.037 for trend). Consistently, when considered as a continuous variable, this association remained significant in the fully adjusted model (OR = 0.59, 95% CI = 0.40-0.87, < 0.05). When taken as a continuous variable in model 3, serum DHEAS level was also inversely related to the risk of CHD among men (OR = 0.56, 95% CI = 0.38-0.82, < 0.05). Similarly, this relationship remained statistically significant when DHEAS was categorized into quartiles (OR = 0.27, quartile 4 . quartile 1; 95% CI = 0.11-0.67; = 0.018 for trend). ROC curve analyses revealed that the optimal cutoff values to detect CHD in men with T2DM were 6.43 nmol/L for DHEA and 3.54 μmol/L for DHEAS. In contrast, no significant associations were found between DHEA and DHEAS on the one hand and stroke on the other in men and women with T2DM (all > 0.05).
CONCLUSIONS
Serum DHEA and DHEAS were significantly and negatively associated with CHD in middle-aged and elderly men with T2DM. This study suggests potential roles of DHEA and DHEAS in CHD pathogenesis.
Topics: Aged; Coronary Disease; Cross-Sectional Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Diabetes Mellitus, Type 2; Female; Humans; Male; Middle Aged; Risk Factors; Stroke
PubMed: 35832423
DOI: 10.3389/fendo.2022.890029 -
Hormones (Athens, Greece) Mar 2023
Topics: Humans; Hydrocortisone; COVID-19; Dehydroepiandrosterone Sulfate; Dehydroepiandrosterone
PubMed: 36374475
DOI: 10.1007/s42000-022-00417-3 -
Physiological Research Dec 2022Pulmonary hypertension is a group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance. To test our hypothesis...
Pulmonary hypertension is a group of disorders characterized by elevated mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance. To test our hypothesis that combining two drugs useful in experimental pulmonary hypertension, statins and dehydroepiandrosterone sulfate (DHEA S), is more effective than either agent alone, we induced pulmonary hypertension in adult male rats by exposing them to hypoxia (10%O2) for 3 weeks. We treated them with simvastatin (60 mg/l) and DHEA S (100 mg/l) in drinking water, either alone or in combination. Both simvastatin and DHEA S reduced mPAP (froma mean±s.d. of 34.4±4.4 to 27.6±5.9 and 26.7±4.8 mmHg, respectively), yet their combination was not more effective (26.7±7.9 mmHg). Differences in the degree of oxidative stress (indicated by malondialdehydeplasma concentration),the rate of superoxide production (electron paramagnetic resonance), or blood nitric oxide levels (chemiluminescence) did not explain the lack of additivity of the effect of DHEA S and simvastatin on pulmonary hypertension. We propose that the main mechanism of both drugs on pulmonary hypertension could be their inhibitory effect on 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which could explain their lack of additivity.
Topics: Rats; Male; Animals; Hypertension, Pulmonary; Simvastatin; Dehydroepiandrosterone Sulfate; Pulmonary Artery; Hypoxia; Dehydroepiandrosterone
PubMed: 36426885
DOI: 10.33549/physiolres.934913 -
Drug Discoveries & Therapeutics May 2023Diminished ovarian reserve (DOR) refers to the decline in fertility caused by the loss of normal ovarian function. DOR is associated with adverse reactions to ovarian... (Review)
Review
Diminished ovarian reserve (DOR) refers to the decline in fertility caused by the loss of normal ovarian function. DOR is associated with adverse reactions to ovarian stimulation during in vitro fertilization and embryo transfer (IVF-ET), increasing cycle cancellation rates and reducing pregnancy rates. Although it is well known that dehydroepiandrosterone (DHEA) can be used as a dietary supplement for age-related diseases, its potential has gradually been shown for many diseases. In this review, we focus on the effects of DHEA on DOR, briefly analysing its clinical benefits and limitations and describing the mechanism of function and the clinical trials conducted. Therefore, we summarize the mechanisms and indications of DHEA for DOR.
Topics: Pregnancy; Female; Humans; Dehydroepiandrosterone; Ovarian Reserve; Fertilization in Vitro; Pregnancy Rate; Ovary
PubMed: 37019659
DOI: 10.5582/ddt.2022.01109 -
Journal of Ovarian Research Jul 2023Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder that frequently exhibits low-grade inflammation, pro-oxidant activity, and gut dysbiosis....
BACKGROUND
Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder that frequently exhibits low-grade inflammation, pro-oxidant activity, and gut dysbiosis. PCOS has become one of the leading causes of female infertility worldwide. Recently, omega-3 polyunsaturated fatty acids (PUFAs) have been proven to benefit metabolic disorders in PCOS patients. However, its roles in the regulation of metabolic and endocrinal balances in PCOS pathophysiology are not clear. In the present study, we aimed to explore how omega-3 PUFAs alleviate ovarian dysfunction and insulin resistance in mice with dehydroepiandrosterone (DHEA)-induced PCOS by modulating the gut microbiota.
METHODS
We induced PCOS in female mice by injecting them with DHEA and then treated them with omega-3 PUFAs. 16S ribosomal DNA (rDNA) amplicon sequencing, fecal microbiota transplantation (FMT) and antibiotic treatment were used to evaluate the role of microbiota in the regulation of ovarian functions and insulin resistance (IR) by omega-3 PUFAs. To further investigate the mechanism of gut microbiota on omega-3-mediated ovarian and metabolic protective effects, inflammatory and oxidative stress markers in ovaries and thermogenic markers in subcutaneous and brown adipose tissues were investigated.
RESULTS
We found that oral supplementation with omega-3 PUFAs ameliorates the PCOS phenotype. 16S rDNA analysis revealed that omega-3 PUFA treatment increased the abundance of beneficial bacteria in the gut, thereby alleviating DHEA-induced gut dysbiosis. Antibiotic treatment and FMT experiments further demonstrated that the mechanisms underlying omega-3 benefits likely involve direct effects on the ovary to inhibit inflammatory cytokines such as IL-1β, TNF-α and IL-18. In addition, the gut microbiota played a key role in the improvement of adipose tissue morphology and function by decreasing multilocular cells and thermogenic markers such as Ucp1, Pgc1a, Cited and Cox8b within the subcutaneous adipose tissues.
CONCLUSION
These findings indicate that omega-3 PUFAs ameliorate androgen-induced gut microbiota dysbiosis. The gut microbiota plays a key role in the regulation of omega-3-mediated IR protective effects in polycystic ovary syndrome mice. Moreover, omega-3 PUFA-regulated improvements in the ovarian dysfunction associated with PCOS likely involve direct effects on the ovary to inhibit inflammation. Our findings suggest that omega-3 supplementation may be a promising therapeutic approach for the treatment of PCOS by modulating gut microbiota and alleviating ovarian dysfunction and insulin resistance.
Topics: Animals; Female; Mice; Dehydroepiandrosterone; Gastrointestinal Microbiome; Insulin Resistance; Polycystic Ovary Syndrome; Fatty Acids, Omega-3; Dietary Supplements
PubMed: 37443082
DOI: 10.1186/s13048-023-01227-w -
Environmental Research Dec 2022Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Neighborhood walkability (NW) has been linked to increased physical activity, which in turn is associated with lower concentrations of sex hormones and higher concentration of SHBG in women. However, no study has directly examined the association of NW with female sex hormone levels.
OBJECTIVE
We conducted a cross-sectional study to evaluate the association between NW and circulating levels of sex hormones and SHBG in pre- and post-menopausal women.
METHODS
We included 797 premenopausal and 618 postmenopausal women from the New York University Women's Health Study (NYUWHS) who were healthy controls in previous nested case-control studies in which sex hormones (androstenedione, testosterone, DHEAS, estradiol and estrone) and SHBG had been measured in serum at enrollment. Baseline residential addresses were geo-coded and the Built Environment and Health Neighborhood Walkability Index (BEH-NWI) was calculated. Generalized Estimating Equations were used to assess the association between BEH-NWI and sex hormone and SHBG concentrations adjusting for individual- and neighborhood-level factors.
RESULTS
In premenopausal women, a one standard deviation (SD) increment in BEH-NWI was associated with a 3.5% (95% CI 0.9%-6.1%) lower DHEAS concentration. In postmenopausal women, a one SD increment in BEH-NWI was related to an 8.5% (95% CI 5.4%-11.5%) lower level of DHEAS, a 3.7% (95% CI 0.5%-6.8%) lower level of testosterone, a 1.8% (95% CI 0.5%-3.0%) lower level of estrone, and a 4.2% (95% CI 2.7%-5.7%) higher level of SHBG. However, the associations with respect to DHEAS and estrone became apparent only after adjusting for neighborhood-level variables. Sensitivity analyses using fixed effects meta-analysis and inverse probability weighting accounting for potential selection bias yielded similar results.
CONCLUSION
Our findings suggest that NW is associated with lower concentrations of androgens and estrone, and increased SHBG, in postmenopausal women, and lower levels of DHEAS in premenopausal women.
Topics: Androgens; Androstenedione; Cross-Sectional Studies; Dehydroepiandrosterone; Dehydroepiandrosterone Sulfate; Estradiol; Estrone; Female; Gonadal Steroid Hormones; Humans; Sex Hormone-Binding Globulin; Testosterone
PubMed: 36088991
DOI: 10.1016/j.envres.2022.114285 -
Anais Brasileiros de Dermatologia 2016The transforming growth factor-beta 1 (TGFβ1) promotes fibrosis, differentiating epithelial cells and quiescent fibroblasts into myofibroblasts and increasing... (Review)
Review
The transforming growth factor-beta 1 (TGFβ1) promotes fibrosis, differentiating epithelial cells and quiescent fibroblasts into myofibroblasts and increasing expression of extracellular matrix. Recent investigations have shown that PPAR (peroxisome proliferator-activated receptor*) is a negative regulator of fibrotic events induced by TGFβ1. Dehydroepiandrosterone (DHEA) is an immunomodulatory hormone essential for PPAR functions, and is reduced in some processes characterized by fibrosis. Although scarring alopecia characteristically develops in the female biological period in which occurs decreased production of DHEA, there are no data in the literature relating its reduction to fibrogenic process of this condition. This article aims to review the fibrogenic activity of TGFβ1, its control by PPAR and its relation with DHEA in the frontal fibrosing alopecia.
Topics: Alopecia; Dehydroepiandrosterone; Female; Fibroblasts; Fibrosis; Humans; Lichen Planus; PPAR gamma; Transforming Growth Factor beta1
PubMed: 28099600
DOI: 10.1590/abd1806-4841.20165029 -
The Cochrane Database of Systematic... Jan 2016Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development and relapse of psychotic disorders. Elevated cortisol secretion has been... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been implicated in the development and relapse of psychotic disorders. Elevated cortisol secretion has been positively linked with symptom severity in people with psychosis. Antiglucocorticoid and related drugs that target the HPA axis may be useful for the treatment of individuals with psychosis.
OBJECTIVES
1. To determine the effects of antiglucocorticoid and related drugs for the treatment of psychosis, when used alone or in combination with antipsychotic medication.2. To determine whether the effects of these medications differs between those in a prodromal phase or first episode of psychosis, and those with more established illness.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Trials Register (August 2009 and April 2014).
SELECTION CRITERIA
Randomised controlled trials (RCTs) comparing antiglucocorticoid and related drugs compared to placebo (either as a sole treatment or as an adjunct to atypical antipsychotics, typical antipsychotics, antidepressants or other combination treatment) for people with a primary diagnosis of a psychotic disorder, or for individuals at high risk of developing a psychotic disorder.
DATA COLLECTION AND ANALYSIS
Review authors independently selected trials, assessed methodological quality and extracted data. We used a fixed-effect meta-analysis. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) and standardised mean differences (SMDs) with 95% CIs for continuous measures. We assessed risk of bias for included studies and used GRADE (Grading of Recommendations Assessment, Development and Evaluation) to create a 'Summary of findings' table.
MAIN RESULTS
We included 11 studies that randomly assigned 509 people with schizophrenia, schizoaffective disorder or psychotic depression. No trials were conducted in patients at their first episode of psychotic illness and none included populations at high risk for developing psychosis. Our pre-stated outcomes of interest were mental state, global state, general functioning, adverse effects and quality of life.Two trials compared antiglucocorticoid drugs (mifepristone) versus placebo as sole treatment. Limited data from one trial showed no difference in the proportion responding to mifepristone when mental state was assessed immediately post intervention using the Brief Psychiatric Rating Scale (BPRS) (n = 5, 1 RCT, MD -5.20, 95% CI -17.91 to 7.51; very low-quality evidence); depressive symptoms (Hamilton Rating Scale for Depression (HAMD) total) were also similar between groups (n = 5, 1 RCT, MD 1.67, 95% CI -16.44 to 19.78; very low-quality evidence). However, a significant difference favoured treatment at short-term follow-up for global state (30% reduction in total BPRS, n = 221, 1 RCT, RR 0.58, 95% CI 0.38 to 0.89; low-grade quality evidence). This effect was also seen for short-term positive psychotic symptoms (50% reduction in BPRS positive symptom subscale, n = 221, 1 RCT, RR 0.60, 95% CI 0.43 to 0.84; low-grade quality evidence). Participants receiving mifepristone experienced a similar overall number of adverse effects as those receiving placebo (n = 226, 2 RCTs, RR 0.92, 95% CI 0.77 to 1.09; moderate-quality evidence). No data on general functioning or quality of life were available.One trial compared an antiglucocorticoid, dehydroepiandrosterone (DHEA), as an adjunct to atypical antipsychotic treatment to adjunctive placebo. Data for main outcomes of interest were of low quality, and analysis of useable data showed no significant effects of treatment on mental state or adverse effects. Data on global state, general functioning and quality of life were not available.Data from six trials comparing antiglucocorticoid drugs as an adjunct to combination treatment versus adjunctive placebo showed no significant differences between groups in mean endpoint scores for overall psychotic symptoms (n = 171, 6 RCTs, SMD 0.01, 95% CI - 0.29 to 0.32) or positive psychotic symptoms (n = 151, 5 RCTs, SMD -0.07, 95% CI - 0.40 to 0.25). Data from three trials showed no differences between groups in mean endpoint scores for negative symptoms (n = 94, 3 RCTs, MD 2.21, 95% CI -0.14 to 4.55). One study found improvements in global state that were similar between groups (n = 30, 1 RCT, RR 0.58, 95% CI 0.32 to 1.06; very low-quality evidence). In this comparison, pooled results showed that antiglucorticoids caused a greater overall number of adverse events (n = 199, 7 RCTs, RR 2.66, 95% CI 1.33 to 5.32; moderate quality evidence), but no quality of life data were available.
AUTHORS' CONCLUSIONS
Good evidence is insufficient to conclude whether antiglucocorticoid drugs provide effective treatment for psychosis. Some global state findings suggest a favourable effect for mifepristone, and a few overall adverse effect findings favour placebo. Additional large randomised controlled trials are needed to justify findings.
Topics: Dehydroepiandrosterone; Dexamethasone; Glucocorticoids; Humans; Hypothalamo-Hypophyseal System; Ketoconazole; Mifepristone; Pituitary-Adrenal System; Psychotic Disorders; Randomized Controlled Trials as Topic
PubMed: 26725721
DOI: 10.1002/14651858.CD006995.pub2