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Nutrients Jun 2024Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy...
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease which seriously affects public health. Gut microbiota remains a dynamic balance state in healthy individuals, and its disorder may affect health status and even results in metabolic diseases. Quercetin, a natural flavonoid, has been shown to have biological activities that can be used in the prevention and treatment of metabolic diseases. This study aimed to explore the mechanism of quercetin in alleviating T2DM based on gut microbiota. / mice were adopted as the model for T2DM in this study. After 10 weeks of administration, quercetin could significantly decrease the levels of body weight, fasting blood glucose (FBG), serum insulin (INS), the homeostasis model assessment of insulin resistance (HOMA-IR), monocyte chemoattractant protein-1 (MCP-1), D-lactic acid (D-LA), and lipopolysaccharide (LPS) in / mice. 16S rRNA gene sequencing and untargeted metabolomics analysis were performed to compare the differences of gut microbiota and metabolites among the groups. The results demonstrated that quercetin decreased the abundance of Proteobacteria, , and . Moreover, metabolomics analysis showed that the levels of L-Dopa and S-Adenosyl-L-methionine (SAM) were significantly increased, but 3-Methoxytyramine (3-MET), L-Aspartic acid, L-Glutamic acid, and Androstenedione were significantly decreased under quercetin intervention. Taken together, quercetin could exert its hypoglycemic effect, alleviate insulin resistance, repair the intestinal barrier, remodel the intestinal microbiota, and alter the metabolites of / mice.
Topics: Animals; Gastrointestinal Microbiome; Quercetin; Insulin Resistance; Mice; Diabetes Mellitus, Type 2; Male; Intestinal Mucosa; Blood Glucose; Disease Models, Animal; Insulin
PubMed: 38931226
DOI: 10.3390/nu16121870 -
Gynecological Endocrinology : the... Dec 2024To investigate the association between female sexual function and metabolic features among women with polycystic ovary syndrome (PCOS) during reproductive age.
OBJECTIVE
To investigate the association between female sexual function and metabolic features among women with polycystic ovary syndrome (PCOS) during reproductive age.
METHOD
This was a cross-sectional study in which 288 women with PCOS and 180 women without PCOS between the ages of 20 and 40 years were evaluated. All women had serum total testosterone, androstenedione, DHEA-S, fasting glucose, total cholesterol, HDL-C, LDL-C, and triglyceride levels analyzed. The McCoy Female Sexual Questionnaire (MFSQ) was applied to all studied women. Exploratory factor analysis and reliability analysis were done after data collection. The factor loadings of MFSQ domains were compared between women with PCOS and controls.
RESULTS
Average factor loadings of the MFSQ sexuality domain and MFSQ sexual partner domain were significantly lower in the PCOS group when compared to controls. There was no correlation between the two sexual function domains of the MFSQ and the PCOS features either in the PCOS group or the controls.
CONCLUSION
PCOS is a heterogeneous disease with different metabolic components, such as insulin resistance, obesity, and hyperandrogenism. Although sexual function among women with PCOS was lower than controls, no differences were found in metabolic features of the PCOS and non-PCOS groups with relation to sexual function determined by the MFSQ.
Topics: Humans; Female; Polycystic Ovary Syndrome; Adult; Cross-Sectional Studies; Turkey; Young Adult; Insulin Resistance; Sexual Dysfunction, Physiological; Testosterone; Surveys and Questionnaires; Case-Control Studies; Hyperandrogenism; Sexual Behavior; Androstenedione; Dehydroepiandrosterone Sulfate; Obesity
PubMed: 38913084
DOI: 10.1080/09513590.2024.2362249 -
The Journal of Asthma : Official... Jun 2024Female hormones and obesity have an impact on women with asthma. We aimed to describe how these components affect asthma inflammatory processes.
INTRODUCTION
Female hormones and obesity have an impact on women with asthma. We aimed to describe how these components affect asthma inflammatory processes.
METHODS
Sex hormones [FSH, LH, estradiol (E2), estrone (E1), testosterone and Δ4 androstenedione (A4)] and serum IL1β, IL13, IL17a, IL-5, IL6, TNF-a were measured from 11 to18 pre- and postmenopausal women with asthma.
RESULTS
Premenopausal normal weight women revealed higher levels of IL5 and IL17a than obese women on both days of the menstrual cycle (IL5: D1: 6.4 vs 1.4 pg/ml, = .036 and D14: 3 vs 1.4 pg/ml, = .045 and IL17a: D1: 13.7 pg/ml vs 10.6 pg/ml and D14: 12.4 pg/ml vs 10.6 pg/ml, = .009, respectively). In premenopausal women on D1, Δ4 Androstenedione was positively correlated with IL1β ( = .016, = 0.733), whereas on D14, Estradiol with IL1β ( = .009, = -.768) and TNF-a with Testosterone ( = .004, = -0.816), and Δ4 Androstenedione ( = .002, = -0.841) negatively. In postmenopausal women, TNF-a was negatively associated with FSH ( = .004, = -0.638), but positively with Testosterone ( = .025, = 0.526) and IL10 also positively with Estradiol ( = .007, = 0.610).
CONCLUSION
Obesity shows a protective role in asthma through the suppression of IL5 and IL17. Estrogens seem to inhibit Th1 and Th2 inflammation, while androgens have a dual role with negative and positive correlations with neutrophilic biomarkers.
PubMed: 38900498
DOI: 10.1080/02770903.2024.2362859 -
International Journal of Biological... Jun 2024The synthesis of steroids is challenging through multistep steroidal core modifications with high site-selectivity and productivity. In this work, a novel enzymatic...
The synthesis of steroids is challenging through multistep steroidal core modifications with high site-selectivity and productivity. In this work, a novel enzymatic cascade system was constructed for synthesis of testolactone by specific C17 lactonization/Δ-dehydrogenation from inexpensive androstenedione using an engineered polycyclic ketone monooxygenase (PockeMO) and an appropriate 3-ketosteroid-Δ-dehydrogenase (ReKstD). The focused saturation mutagenesis in the substrate binding pocket was implemented for evolution of PockeMO to eliminate the bottleneck effect. A best mutant MU3 (I225L/L226V/L532Y) was obtained with 20-fold higher specific activity compared to PockeMO. The catalytic efficiency (k/Km) of MU3 was 171-fold higher and the substrate scope shifted to polycyclic ketones. Molecular dynamic simulations suggested that the activity was improved by stabilization of the pre-lactonization state and generation of productive orientation of 4-AD mediated by distal L532Y mutation. Based on that, the three genes, MU3, ReKstD and a ketoreductase for NADPH regeneration, were rationally integrated in one cell via expression fine-tuning to form the efficient single cell catalyst E. coli S9. The single whole-cell biocatalytic process was scaled up and could generate 9.0 g/L testolactone with the high space time yield of 1 g/L/h without steroidal by-product, indicating the potential for site-specific and one-pot synthesis of steroid.
PubMed: 38897507
DOI: 10.1016/j.ijbiomac.2024.133229 -
Endocrinology May 2024Follicular androgens are important for successful ovulation and fertilization. The classical nuclear androgen receptor (AR) is a transcription factor expressed in the...
Follicular androgens are important for successful ovulation and fertilization. The classical nuclear androgen receptor (AR) is a transcription factor expressed in the cells of the ovarian follicle. Androgen actions can also occur via membrane androgen receptor SLC39A9. Studies in fish ovary demonstrated that androgens bind to SLC39A9 and increase intracellular zinc to regulate ovarian cell function. To determine if SLC39A9 is expressed and functional in the key cell types of the mammalian ovulatory follicle, adult female cynomolgus macaques underwent ovarian stimulation. Ovaries or ovarian follicular aspirates were harvested at 0, 12, 24, and 36 hours after human chorionic gonadotropin (hCG). SLC39A9 and AR mRNA and protein were present in granulosa, theca, and vascular endothelial cells across the entire 40-hour ovulatory window. Testosterone, bovine serum albumin-conjugated testosterone (BSA-T), and androstenedione stimulated zinc influx in granulosa, theca, and vascular endothelial cells. The SLC39A9-selective agonist (-)-epicatechin also stimulated zinc influx in vascular endothelial cells. Taken together, these data support the conclusion that SLC39A9 activation via androgen induces zinc influx in key ovarian cells. Testosterone, BSA-T, and androstenedione each increased proliferation in vascular endothelial cells, indicating the potential involvement of SLC39A9 in ovulatory angiogenesis. Vascular endothelial cell migration also increased after treatment with testosterone, but not after treatment with BSA-T or androstenedione, suggesting that androgens stimulate vascular endothelial cell migration through nuclear AR but not SLC39A9. The presence of SLC39A9 receptors and SLC39A9 activation by follicular androstenedione concentrations suggests that androgen activation of ovarian SLC39A9 may regulate ovulatory changes in the mammalian follicle.
Topics: Animals; Female; Receptors, Androgen; Ovarian Follicle; Ovulation; Macaca fascicularis; Zinc; Testosterone; Endothelial Cells; Cation Transport Proteins; Cell Membrane; Theca Cells; Granulosa Cells; Chorionic Gonadotropin
PubMed: 38889246
DOI: 10.1210/endocr/bqae071 -
The Journal of Clinical Endocrinology... Jun 2024Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme 11β-hydroxylase (CYP11B1) executes the final step...
CONTEXT
Androstenedione (A4) and testosterone (T) are produced by both the adrenal glands and the gonads. The adrenal enzyme 11β-hydroxylase (CYP11B1) executes the final step in cortisol synthesis; CYP11B1 also uses A4 and T as substrates, generating 11-hydroxyandrostenedione and 11-hydroxytestosterone, respectively. It has been suggested that CYP11B1 is expressed in the gonads, yet the circulating levels of all 11-oxygenated androgens (11-oxyandrogens) are similar in males and females of reproductive ages, despite enormous differences in T.
OBJECTIVE
To assess the gonadal contribution to the circulating pool of 11-oxyandrogens.
METHODS
We used liquid chromatography-tandem mass spectrometry to measure 13 steroids, including traditional and 11-oxyandrogens in: (I) paired gonadal and peripheral vein blood samples obtained during gonadal venograms from 11 patients (7 women), median age 37 (range 31-51 years); and (II) 17 women, median age 57 (range 41-81 years) before and after bilateral salpingo-oophorectomy (BSO). We also compared CYP11B1, 17α-hydroxylase/17,20-lyase (CYP17A1), and 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) mRNA expression in adrenal, ovarian, and testicular tissue.
RESULTS
A4, T, estradiol, estrone, progesterone, 17α- and 16α-hydroxyprogesterone were all higher in gonadal veins vs. periphery (p < 0.05 for all), while four 11-oxyandrogens were similar between matched gonadal and peripheral vein samples. Equally, in women who underwent BSO, A4 (median [interquartile range]: 59.7 [47.7-67.6] ng/dL vs. 32.7 [27.4-47.8] ng/dL, p < 0.001) and T (24.1 [16.4-32.3] vs.15.5 [13.7-19.0] ng/dL, p < 0.001) declined, while 11-oxyandrogens remained stable. Gonadal tissue displayed negligible CYP11B1 mRNA.
CONCLUSION
Despite producing substantial amounts of A4 and T, human gonads are not relevant sources of 11-oxyandrogens.
PubMed: 38885296
DOI: 10.1210/clinem/dgae420 -
Cell Communication and Signaling : CCS Jun 2024Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the...
Sex-specific gonadal differentiation is directed by complex signalling promoting development in either male or female direction, while simultaneously inhibiting the opposite pathway. In mice, the WNT/β-catenin pathway promotes ovarian development and the importance of actively inhibiting this pathway to ensure normal testis development has been recognised. However, the implications of alterations in the tightly regulated WNT/β-catenin signalling during human fetal gonad development has not yet been examined in detail. Thus, the aim of this study was to examine the consequences of dysregulating the WNT/β-catenin signalling pathway in the supporting cell lineage during sex-specific human fetal gonad development using an established and extensively validated ex vivo culture model. Inhibition of WNT/β-catenin signalling in human fetal ovary cultures resulted in only minor effects, including reduced secretion of RSPO1 and reduced cell proliferation although this was not consistently found in all treatment groups. In contrast, promotion of WNT/β-catenin signalling in testes severely affected development and function. This included disrupted seminiferous cord structures, reduced cell proliferation, reduced expression of SOX9/AMH, reduced secretion of Inhibin B and AMH as well as loss of the germ cell population. Additionally, Leydig cell function was markedly impaired with reduced secretion of testosterone, androstenedione and INSL3. Together, this study suggests that dysregulated WNT/β-catenin signalling during human fetal gonad development severely impairs testicular development and function. Importantly, our study highlights the notion that sufficient inhibition of the opposite pathway during sex-specific gonadal differentiation is essential to ensure normal development and function also applies to human fetal gonads.
Topics: Humans; Male; Wnt Signaling Pathway; Testis; Female; Sex Differentiation; Fetus; Cell Differentiation; Cell Proliferation; beta Catenin; Leydig Cells; Ovary
PubMed: 38879537
DOI: 10.1186/s12964-024-01704-9 -
International Journal of Hygiene and... Jul 2024Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet....
Zearalenone (ZEN) is a fungal-derived toxin found in global food supplies including cereal grains and processed foods, impacting populations worldwide through diet. Because the chemical structure of ZEN and metabolites closely resembles 17β-estradiol (E2), they interact with estrogen receptors α/β earning their designation as 'mycoestrogens'. In animal models, gestational exposure to mycoestrogens disrupts estrogen activity and impairs fetal growth. Here, our objective was to evaluate relationships between mycoestrogen exposure and sex steroid hormone concentrations in maternal circulation and cord blood for the first time in humans. In each trimester, pregnant participants in the UPSIDE study (n = 297) provided urine for mycoestrogen analysis and serum for hormone analysis. At birth, placental mycoestrogens and cord steroids were measured. We fitted longitudinal models examining log-transformed mycoestrogen concentrations in relation to log-transformed hormones, adjusting for covariates. Secondarily, multivariable linear models examined associations at each time point (1st, 2nd, 3rd trimesters, delivery). We additionally considered effect modification by fetal sex. ZEN and its metabolite, α-zearalenol (α-ZOL), were detected in >93% and >75% of urine samples; >80% of placentas had detectable mycoestrogens. Longitudinal models from the full cohort exhibited few significant associations. In sex-stratified analyses, in pregnancies with male fetuses, estrone (E1) and free testosterone (fT) were inversely associated with ZEN (E1 %Δ: -6.68 95%CI: -12.34, -0.65; fT %Δ: -3.22 95%CI: -5.68, -0.70); while α-ZOL was positively associated with E2 (%Δ: 5.61 95%CI: -1.54, 9.85) in pregnancies with female fetuses. In analysis with cord hormones, urinary mycoestrogens were inversely associated with androstenedione (%Δ: 9.15 95%CI: 14.64, -3.30) in both sexes, and placental mycoestrogens were positively associated with cord fT (%Δ: 37.13, 95%CI: 4.86, 79.34) amongst male offspring. Findings support the hypothesis that mycoestrogens act as endocrine disruptors in humans, as in animal models and livestock. Additional work is needed to understand impacts on maternal and child health.
Topics: Humans; Female; Fetal Blood; Pregnancy; Zearalenone; Adult; Male; Gonadal Steroid Hormones; Maternal Exposure; Cohort Studies; Zeranol; Estradiol; Young Adult; Placenta
PubMed: 38878407
DOI: 10.1016/j.ijheh.2024.114405 -
Clinical Chemistry and Laboratory... Jun 2024Steroid hormone levels of patients may be monitored via dried blood spot (DBS) sampling at home. Stability of steroid hormones in DBS samples, however, needs to be...
OBJECTIVES
Steroid hormone levels of patients may be monitored via dried blood spot (DBS) sampling at home. Stability of steroid hormones in DBS samples, however, needs to be established.
METHODS
DBS samples from healthy volunteers were collected and stored at various temperatures. Steroid hormone concentrations in DBS were measured directly, at day 2, day 7 and day 14 following storage at 37 °C and after 7 days, 14 days, 3 months and 6 months following storage at -20 °C, 4 °C and room temperature (RT). Cortisol, cortisone, corticosterone, testosterone, androstenedione, and 17-hydroxyprogesterone (17-OHP) were assessed using LC-MS/MS.
RESULTS
All steroids were stable (±15 %) up to 14 days when stored at 37 °C, except for cortisone (only stable until 2 days). All steroids were stable up to 6 months when stored at -20 °C, 4 °C and RT. However, there were some exceptions, for androstenedione at RT (only stable until 7 days), for 17-OHP when stored at -20 °C (only stable until 3 months), for cortisone at RT and 4 °C (only stable until 14 days), and cortisol at RT (only stable until 3 months).
CONCLUSIONS
Overall, we demonstrated stability of steroid hormone concentrations in DBS under various conditions which may be encountered during shipping to the diagnostic laboratory and during long-term storage before analysis.
PubMed: 38874994
DOI: 10.1515/cclm-2024-0142 -
The Journal of Clinical Endocrinology... Jun 2024Androgen could impact cervical remodelling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific...
BACKGROUND
Androgen could impact cervical remodelling during pregnancy, and a higher level is associated with adverse pregnancy outcomes. A population-based gestation age-specific reference interval (RI) of total testosterone (TT), androstenedione (A4), and 17-hydroxyprogesterone (17-OHP) can help to diagnose maternal hyperandrogenism.
METHODS
We enrolled 600 healthy Chinese women to obtain longitudinal serum samples across gestation. The serum androgen profile was measured by liquid chromatography-tandem mass spectrometry. The equations for medians of TT, A4, and 17-OHP were generated by MedCal, and the variances adjusted for 2-level modeling were generated by MLwiN, a system for the specification and analysis of a range of multilevel models.
RESULTS
A4 and TT levels increased across the gestation, and they closely correlated with each other (R = 0.90, P=<0.001), whereas 17-OHP level decreased from 5th gestational week to 16th gestational week and then increased afterward towards the end of pregnancy. Women diagnosed with preeclampsia (PE) were found to have a significantly higher level of A4, TT, and 17-OHP when compared with non-PE cases with p ≤0.01, whereas mothers carrying male versus female fetuses have comparable levels of A4, TT, and 17-OHP.
CONCLUSION
The study highlights a methodology for constructing gestational age-specific TT, A4, and 17-OHP levels to provide a better interpretation of results in a cohort of healthy Chinese women. The observation in PE supports previous findings, and the higher levels of TT, A4, and 17-OHP were observed before the onset of PE.
PubMed: 38870268
DOI: 10.1210/clinem/dgae382