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Drug Discovery Today Feb 2024Moderate-to-high doses of ionizing irradiation can lead to potentially life-threatening morbidities and increase mortality risk. In preclinical testing, 5-androstenediol... (Review)
Review
Moderate-to-high doses of ionizing irradiation can lead to potentially life-threatening morbidities and increase mortality risk. In preclinical testing, 5-androstenediol has been shown to be effective in protecting against hematopoietic acute radiation syndrome. This agent is important for innate immunity, serves to modulate cell cycle progression, reduces radiation-induced apoptosis, and regulates DNA repair. The drug has been evaluated clinically for its pharmacokinetics and safety. The United States Food and Drug Administration granted investigational new drug status to its injectable depot formulation (NEUMUNE). Its safety and efficacy profiles make it an attractive candidate for further development as a radiation countermeasure.
Topics: United States; Humans; Acute Radiation Syndrome; Radiation-Protective Agents; Androstenediol; Immunity, Innate
PubMed: 38097137
DOI: 10.1016/j.drudis.2023.103856 -
Frontiers in Endocrinology 2024The retina is a highly metabolically active tissue, and there is a lack of clarity about the relationship between metabolites and diabetic retinopathy (DR). This study...
INTRODUCTION
The retina is a highly metabolically active tissue, and there is a lack of clarity about the relationship between metabolites and diabetic retinopathy (DR). This study used two-sample bidirectional Mendelian randomization (MR) analyses to identify causal relationships between metabolites and DR.
METHODS
Genetic variants were selected from the open-access Genome-Wide Association Studies (GWAS) summary database as proxies for the 1400 most recently published metabolites. MR analysis was performed to examine associations between these metabolite traits and DR. Single nucleotide polymorphism (SNP) data that were significantly associated with exposure were screened through association analysis. Validated instrumental variables (IVs) were obtained by removing SNPs with linkage disequilibrium (LD) and F-statistic values below 10. MR analyses were performed using the inverse variance weighted (IVW) method as the primary approach. The robustness of the results was verified by sensitivity analyses, including assessments of heterogeneity, horizontal pleiotropy, and the leave-one-out method.
RESULTS
In the IVW approach and in the primary analysis of several sensitivity analyses, genetically determined glycolithocholate sulfate levels, androstenediol (3 beta, 17 beta) monosulfate (1) levels, 1-stearoyl-2-arachidonoyl-GPE (18:0/20:4) levels, 1-oleoyl-2-arachidonoyl-GPE (18:1/20:4) levels, 1-oleoyl-2-linoleoyl-GPE (18:1/18:2) levels, X-26109 levels, N6-methyllysine levels, (N6,N6-dimethyllysine levels), and (N2-acetyl,N6,N6-dimethyllysine levels) were negatively associated with the risk of DR. 5-hydroxymethyl-2-furoylcarnitine levels and the glutamate-to-alanine ratio were positively associated with the risk of DR. No reverse causal association was found between DR and metabolites.
DISCUSSION
This MR study suggests that nine metabolites may have a protective effect in DR, while two metabolites may be associated with an increased risk of DR. However, further research is needed to confirm these findings. Supplementation with beneficial metabolites may reduce DR risk and could potentially be a novel therapeutic approach to DR treatment.
Topics: Humans; Mendelian Randomization Analysis; Diabetic Retinopathy; Polymorphism, Single Nucleotide; Genome-Wide Association Study
PubMed: 38800471
DOI: 10.3389/fendo.2024.1359502 -
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 -
BMC Women's Health May 2023Associations of luteinizing hormone (LH) with androgens during the menopausal transition and associations between follicle-stimulating hormone (FSH) levels and various...
INTRODUCTION
Associations of luteinizing hormone (LH) with androgens during the menopausal transition and associations between follicle-stimulating hormone (FSH) levels and various diseases related to reproductive hormones in postmenopause have received much attention. LH and FSH are also known to be associated with activities of enzymes related to reproductive hormones. We examined the associations of LH and FSH with androgens and estrogens in each stage of the menopausal transition according to a classification from menopausal transition to postmenopause.
METHODS
This study was a cross-sectional design. We basically used the Stage of Reproductive Aging Workshop (STRAW) + 10. We divided the 173 subjects into 6 groups according to menstrual regularity and follicle-stimulating hormone level: mid reproductive stage (Group A), late reproductive stage (Group B), early menopausal transition (Group C), late menopausal transition (Group D), very early postmenopause (Group E) and early postmenopause (Group F). Levels of LH, FSH, dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and androstenediol were measured.
RESULTS
In Group A, LH showed significant positive correlations with androstenedione and estrone. In Group D, LH was positively associated with T and free T and was negatively associated with estradiol. In Groups B, C, D and F, LH showed significant positive correlations with FSH, and there was a tendency for an association between LH and FSH in Group E. FSH was associated with estradiol but not with estrone in Groups C and D.
CONCLUSION
The associations of LH and FSH with reproductive hormones are different depending on the stage of the menopausal transition.
TRIAL REGISTRATION
Trial registration number 2356-1; Date of registration: 18/02/2018, retrospectively registered.
Topics: Female; Humans; Androstenedione; Estrone; Follicle Stimulating Hormone; Cross-Sectional Studies; Luteinizing Hormone; Menopause; Estradiol; Androgens; Testosterone
PubMed: 37231423
DOI: 10.1186/s12905-023-02438-5 -
Journal of the Endocrine Society Jul 2022Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact...
CONTEXT
Fasting is stressful for the human body. It is managed by metabolic adaptations maintaining energy homeostasis and involves steroid hormone biosynthesis, but the exact interplay between energy and steroid metabolism remains elusive. Women with polycystic ovary syndrome (PCOS) suffer from disturbed metabolism and androgen excess, while in women with anorexia nervosa, cortisol and androgen production are decreased. By contrast, starvation of steroidogenic cells shifts adrenal steroid biosynthesis toward enhanced androgen production.
AIM
This study investigated the effect of fasting on steroid production in healthy women.
METHODS
Twenty healthy young women fasted for 48 hours; steroid profiles from plasma and urine samples were assessed at baseline, after 24 hours, and 48 hours by liquid and gas chromatography-mass spectrometry.
RESULTS
Fasting did not change overall steroidogenesis, although it increased progestogen production and lowered relative mineralocorticoid, glucocorticoid, and androgen production. The largest decrease in urine metabolites was seen for β-cortol, dehydroepiandrosterone, and androstenediol; higher levels were found for pregnanediol in urine and progesterone and aldosterone in serum. Activity of 17α-hydroxylase/17,20-lyase (CYP17A1), essential for androgen biosynthesis, was decreased after fasting in healthy women as were 21-hydroxylase (CYP21A2) and 5α-reductase activities. By contrast, hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) activity for cortisol inactivation seemed to increase with fasting.
CONCLUSION
Significant changes in steroid metabolism occurred after 48 hours of fasting in healthy women. In contrast to metabolic changes seen at baseline in PCOS women compared to healthy women, and after starving of steroidogenic cells, no androgen excess was observed after short-term fasting in healthy young women.
PubMed: 35668998
DOI: 10.1210/jendso/bvac075 -
Biomedicine & Pharmacotherapy =... Jan 2020In the present study, the therapeutic effects of 5-androstenediol on radiation-induced myeloid suppression and tissue damage in mice and the possible mechanism were...
In the present study, the therapeutic effects of 5-androstenediol on radiation-induced myeloid suppression and tissue damage in mice and the possible mechanism were explored. The mice were subjected to whole-body irradiation, and 5-androstenediol was administered subcutaneously at different times and doses. The evaluation of the survival rate showed that the administration of 5-androstenediol every three days post-irradiation was the most effective in decreasing the death of the mice. Additionally, 5-androstenediol dose-dependently reduced the death caused by 9 Gy radiation. The pharmacological mechanism was investigated by blood analysis, western blot analysis, immunofluorescence and immunohistochemistry. 5-Androstenediol significantly ameliorated myeloid suppression, as demonstrated by elevated levels of total white blood cells, including neutrophils and platelets, in the peripheral blood. By H&E staining, we found that radiation-induced myeloid suppression in the bone marrow and spleen, as well as tissue damage in the lung and colon, was significantly ameliorated by treatment with 5-androstenediol. Immunohistochemistry showed elevated phosphorylation of p65 in the bone marrow and spleen, indicating the activation of NF-κB signaling. Moreover, 5-androstenediol markedly hampered the radiation-induced activation of caspase-1 and GSDMD in the colon by decreasing the interaction between AIM2 and ASC. Taken together, our results suggest that, by promoting NF-κB signaling and inhibiting inflammasome-mediated pyroptosis, 5-androstenediol can be used as a radioprotective drug.
Topics: Anabolic Agents; Androstenediol; Animals; DNA-Binding Proteins; Dose-Response Relationship, Drug; Female; Inflammasomes; Mice; Mice, Inbred C57BL; NF-kappa B; Radiation Injuries; Radiation-Protective Agents; Signal Transduction
PubMed: 31726369
DOI: 10.1016/j.biopha.2019.109597 -
Nutrients Jun 2023The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in...
The effects of vitamin E supplementation on cancer and other chronic diseases are not clear. We compared the serum metabolomic profile of differing vitamin E dosages in order to re-examine the previously observed changes in a novel C lactone sulfate compound, androgenic steroids, and other metabolites. A total of 3409 women and men previously selected for metabolomics studies in the PLCO Cancer Screening Trial were included in this investigation. Serum metabolites were profiled using ultrahigh-performance liquid and gas chromatography/tandem mass spectrometry. Seventy known metabolites including C lactone sulfate and androgens were significantly associated with vitamin E supplementation. In the sex-stratified analysis, 10 cofactors and vitamins (e.g., alpha-CEHC sulfate and alpha-CEHC glucuronide), two carbohydrates (glyceric and oxalic acids), and one lipid (glycocholenate sulfate) were significantly associated with vitamin E dose in both males and females (FDR-adjusted -value < 0.01). However, the inverse association between C lactone sulfate and daily vitamin E supplementation was evident in females only, as were two androgenic steroids, 5-androstenediol and androsterone glucuronide. Our study provides evidence of distinct steroid hormone pathway responses based on vitamin E dosages. Further studies are needed to gain biological insights into vitamin E biochemical effects relevant to cancer and other chronic diseases.
Topics: Male; Humans; Female; Prostate; Early Detection of Cancer; Gas Chromatography-Mass Spectrometry; Vitamin E; Dietary Supplements; Metabolomics; Steroids; Lung; Ovarian Neoplasms; Colorectal Neoplasms
PubMed: 37447163
DOI: 10.3390/nu15132836 -
Diabetes Jun 2022Metabolomic signatures of incident diabetes remain largely unclear for the U.S. Hispanic/Latino population, a group with high diabetes burden. We evaluated the...
Metabolomic signatures of incident diabetes remain largely unclear for the U.S. Hispanic/Latino population, a group with high diabetes burden. We evaluated the associations of 624 known serum metabolites (measured by a global, untargeted approach) with incident diabetes in a subsample (n = 2,010) of the Hispanic Community Health Study/Study of Latinos without diabetes and cardiovascular disease at baseline (2008-2011). Based on the significant metabolites associated with incident diabetes, metabolite modules were detected using topological network analysis, and their associations with incident diabetes and longitudinal changes in cardiometabolic traits were further examined. There were 224 incident cases of diabetes after an average 6 years of follow-up. After adjustment for sociodemographic, behavioral, and clinical factors, 134 metabolites were associated with incident diabetes (false discovery rate-adjusted P < 0.05). We identified 10 metabolite modules, including modules comprising previously reported diabetes-related metabolites (e.g., sphingolipids, phospholipids, branched-chain and aromatic amino acids, glycine), and 2 reflecting potentially novel metabolite groups (e.g., threonate, N-methylproline, oxalate, and tartarate in a plant food metabolite module and androstenediol sulfates in an androgenic steroid metabolite module). The plant food metabolite module and its components were associated with higher diet quality (especially higher intakes of healthy plant-based foods), lower risk of diabetes, and favorable longitudinal changes in HOMA for insulin resistance. The androgenic steroid module and its component metabolites decreased with increasing age and were associated with a higher risk of diabetes and greater increases in 2-h glucose over time. We replicated the associations of both modules with incident diabetes in a U.S. cohort of non-Hispanic Black and White adults (n = 1,754). Among U.S. Hispanic/Latino adults, we identified metabolites across various biological pathways, including those reflecting androgenic steroids and plant-derived foods, associated with incident diabetes and changes in glycemic traits, highlighting the importance of hormones and dietary intake in the pathogenesis of diabetes.
Topics: Adult; Diabetes Mellitus; Hispanic or Latino; Humans; Metabolomics; Public Health; Risk Factors; Steroids
PubMed: 35293992
DOI: 10.2337/db21-1056 -
Animal : An International Journal of... Feb 2021Optimal management of gilt reproduction requires oestrus synchronization. Hormonal treatments are used for this purpose, but there is a growing demand for non-hormonal...
Optimal management of gilt reproduction requires oestrus synchronization. Hormonal treatments are used for this purpose, but there is a growing demand for non-hormonal alternatives, especially in organic farms. The boar effect is an important alternative opportunity to induce and synchronize oestrus without hormones. Before puberty, gilts exhibit a 'waiting period' during which boar exposure could induce and synchronize the first ovulation. We searched for salivary biomarkers of this period of boar effect receptivity to improve detection of the gilts to stimulate with the perspective of enhancing the efficacy of the boar effect. Saliva samples were collected from 30 Large-White×Landrace crossbred gilts between 140 and 175 days of age. Gilts were exposed twice a day to a boar and subjected to oestrus detection from 150 to 175 days of age. Among the 30 gilts, 10 were detected in oestrus 4 to 7 days after the first introduction of the boar and were considered receptive to the boar effect, 14 were detected in oestrus more than 8 days after first boar contact, and six did not show oestrus and were considered non-receptive. Saliva samples from six receptive and six non-receptive gilts were analyzed for steroidome and for metabolome using gas chromatography coupled to tandem mass spectrometry and H nuclear magnetic resonance spectroscopy, respectively. Four saliva samples per gilt were analyzed: 25 days and 11 days before boar introduction, the day of boar introduction, 3 days later for receptive gilts or 7 days later for non-receptive gilts. Twenty-nine steroids and 31 metabolites were detected in gilt saliva. Salivary concentrations of six steroids and three metabolites were significantly different between receptive and non-receptive gilts: progesterone and glycolate 25 days before boar introduction, 3α5β20α- and 3β5α20β-hexahydroprogesterone, dehydroepiandrosterone, androstenediol, succinate, and butyrate 11 days before boar introduction, and 3β5α-tetrahydroprogesterone on the day of boar introduction. Thus, nine potential salivary biomarkers of boar effect receptivity were identified in our experimental conditions. Further studies with higher numbers of gilts and salivary sampling points are necessary to ascertain their reliability.
Topics: Animals; Biomarkers; Female; Gas Chromatography-Mass Spectrometry; Male; Metabolome; Reproducibility of Results; Saliva; Sexual Maturation; Swine
PubMed: 33573980
DOI: 10.1016/j.animal.2020.100095 -
Biomolecules Mar 2024In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized...
The Effects of the Steroids 5-Androstenediol and Dehydroepiandrosterone and Their Synthetic Derivatives on the Viability of K562, HeLa, and Wi-38 Cells and the Luminol-Stimulated Chemiluminescence of Peripheral Blood Mononuclear Cells from Healthy Volunteers.
In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30-50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties.
Topics: Humans; Androstenediol; Dehydroepiandrosterone; Luminol; Leukocytes, Mononuclear; Healthy Volunteers; K562 Cells; Luminescence; Propionates; Steroids
PubMed: 38540791
DOI: 10.3390/biom14030373