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The Journal of Steroid Biochemistry and... Nov 2021Associations of androstenediol, which has both androgenic and estrogenic activities, with circulating reproductive hormones and stress hormone in women during the...
Associations of androstenediol, which has both androgenic and estrogenic activities, with circulating reproductive hormones and stress hormone in women during the menopausal transition may be different depending on the menopausal stage. The aim of this study was to determine the changes in circulating androstenediol during the menopausal transition in Japanese women and the associations of androstenediol with estrogen, androgen and cortisol for each stage of the menopausal transition. We divided the 104 subjects into 6 stages by menstrual regularity and follicle-stimulating hormone level: mid reproductive stage, late reproductive stage, early menopausal transition, late menopausal transition, very early postmenopause and early postmenopause. Levels of dehydroepiandrosterone sulfate (DHEAS), estradiol, estrone, testosterone (T), free T, androstenedione and cortisol were measured. Serum androstenediol concentration was measured by using liquid chromatography mass spectrometry. There were no significant differences in androstenediol levels among the 6 stages. Levels of DHEA-S and testosterone showed significant and positive correlations with androstenediol in all stages. Estradiol levels showed negative correlations with androstenediol levels in the late menopausal transition and very early postmenopause (r=-0.452, p = 0.052 and r=-0.617, p = 0.006, respectively). Cortisol levels showed significant and positive correlations with androstenediol levels in the mid and late reproductive stages (r = 0.719, p = 0.003 and r = 0.808, p < 0.001, respectively).The associations of androstenediol with estradiol and cortisol were different depending on the stage of the menopausal transition. Androstenediol may play a compensatory role for estrogen deficiency from late menopausal transition to very early postmenopause.
Topics: Adult; Androgens; Androstenediol; Androstenedione; Cross-Sectional Studies; Dehydroepiandrosterone Sulfate; Estradiol; Estrogens; Female; Humans; Hydrocortisone; Japan; Menopause; Outpatients; Postmenopause; Testosterone
PubMed: 34571175
DOI: 10.1016/j.jsbmb.2021.106009 -
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 -
Steroids Mar 2020Glioblastoma (GBM) is the most aggressive local brain tumor and effective treatments are lacking. Many studies have proposed an important participation of steroid...
Glioblastoma (GBM) is the most aggressive local brain tumor and effective treatments are lacking. Many studies have proposed an important participation of steroid hormones in the development of gliomas. Evidence was provided by statistics analysis where the incidence in adult population is 50% higher in men than in women. Female patients have a better prognosis for survival compared to male patients with GBM. Also, the expression of receptors to estrogen, progesterone and androgens in glioma cell lines and tumor biopsies, and glucocorticoid receptors in GBM cell lines had been reported. Here we have investigated the effect of the pharmacological inhibition of 5-α reductases on the capacity of GBM derived cell lines C6 (rat) and U87 (human) to synthesize neurosteroids. As the knowledge of the pathways used to synthesize neurosteroids by GBM derived cells was incomplete, we have investigated the synthesis of these steroids by C6 and U87 cells using tritiated precursors and thin layer chromatography (TLC). Increasing concentrations of finasteride and dutasteride were added to U87 culture media that was collected after 24 and 48 h. The results of the study showed that C6 cells incubated with H-cholesterol yielded dihydroandrosterone, hydroxytestosterone, androstenediol, androstenedione and estriol, while U87 cells also synthesized progesterone, and androstanedione. Incubation with H-androstenedione or H-testosterone mainly yielded dihydrotestosterone, androsterone, dihydroandrosterone, hydroxytestosterone, and estradiol in both lines. To note, we showed here for the first time that U87 cells synthesize corticosteroids. Addition of finasteride or dutasteride to U87 cells reduced androgen and estrogen synthesis. Dutasteride also decreased the synthesis of dihydrocorticosterone and allotetrahydrodesoxycorticosterone while deoxycorticosterone was accumulated. In summary, both GBM cell lines synthesize numerous neurosteroids, including 5-α reductase products and 3α-HSD pathways that were inhibited by finasteride and dutasteride. These inhibitors may be considered as tools to control neurosteroid synthesis of potential relevance for GBM survival.
Topics: Animals; Dose-Response Relationship, Drug; Dutasteride; Finasteride; Glioblastoma; Humans; Neurosteroids; Rats; Tumor Cells, Cultured
PubMed: 31866547
DOI: 10.1016/j.steroids.2019.108556 -
Neuroscience and Biobehavioral Reviews Jan 2024The greater prevalence and incidence of Parkinson's disease (PD) in men suggest a beneficial effect of sex hormones. Neuroactive steroids have neuroprotective activities... (Review)
Review
The greater prevalence and incidence of Parkinson's disease (PD) in men suggest a beneficial effect of sex hormones. Neuroactive steroids have neuroprotective activities thus offering interesting option for disease-modifying therapy for PD. Neuroactive steroids are also neuromodulators of neurotransmitter systems and may thus help to control PD symptoms and side effect of dopamine medication. Here, we review the effect on sex hormones (estrogen, androgen, progesterone and its metabolites) as well as androstenediol, pregnenolone and dehydroepiandrosterone) in human studies and in animal models of PD. The effect of neuroactive steroids is reviewed by considering sex and hormonal status to help identify specifically for women and men with PD what might be a preventive approach or a symptomatic treatment. PD is a complex disease and the pathogenesis likely involves multiple cellular processes. Thus it might be useful to target different cellular mechanisms that contribute to neuronal loss and neuroactive steroids provide therapeutics options as they have multiple mechanisms of action.
Topics: Male; Animals; Humans; Female; Parkinson Disease; Neurosteroids; Gonadal Steroid Hormones; Estrogens; Progesterone; Animals, Laboratory; Neurotransmitter Agents
PubMed: 38007170
DOI: 10.1016/j.neubiorev.2023.105479 -
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 -
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 -
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 -
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