Corticosteroid Levels Research Articles

Biochemical classification diagnosis of polycystic ovary syndrome based on serum steroid hormones

Polycystic ovary syndrome (PCOS) is a metabolic disorder with clinical heterogeneity. PCOS women with non-hyperandrogenemia (NA) might be misdiagnosed due to a lack of diagnostic markers. This study aims to systematically analyze the differences in steroid hormones between PCOS women with hyperandrogenemia (HA) and NA, and to screen classification diagnosis models for PCOS. The serum samples from 54 HA-PCOS, 79 NA-PCOS and 60 control women (Non-PCOS) aged between 18 and 35 were measured by an integrated steroid hormone-targeted quantification assay using LC-MS/MS. The levels of serum androgens, corticosteroids, progestins and estrogens in the steroid hormone biosynthesis pathway were analyzed in PCOS and Non-PCOS women. Eight machine learning methods including Linear Discriminant Analysis (LDA), K-nearest Neighbors (KNN), Boosted Logistic Regression (LogitBoost), Naive Bayes (NB), C5.0 algorithm (C5), Random Forest (RF), Support Vector Machines (SVM), and Neural Network (NNET) were performed, evaluated and selected for classification diagnosis of PCOS. A 10-fold cross-validation on the training set was performed. The whole metabolic flux from cholesterol to downstream steroid hormones increased significantly in PCOS, especially in HA-POCS women. The RF model was chosen for the classification diagnosis of HA-PCOS, NA-PCOS, and Non-PCOS women due to the maximum average accuracy (0.938, p<0.001), AUC (0.989, p<0.001), and kappa (0.906, p<0.001), and the minimum logLoss (0.200, p<0.001). Five steroid hormones including testosterone, androstenedione, total 2-methoxyestradiol, total 4-methoxyestradiol, and free estrone were selected as the decision trees for the simplified RF model. A total of 37 women were included in the validation set. The diagnostic sensitivity for HA-PCOS, NA-PCOS, and Non-PCOS was 100 %, 93.3 % and 91.7 %, respectively. HA-PCOS, NA-PCOS, and Non-PCOS women showed obvious different steroid hormone profiles. The simplified RF model based on two androgens and three estrogens could be effectively applied to the classification diagnosis of PCOS, further reducing the missed diagnosis rate of NA-PCOS.

Effect of long-term inhaled corticosteroids therapy on cognitive function in patients with bronchial asthma and chronic obstructive pulmonary disease.

Inhaled corticosteroids (ICS) are prominent therapies for managing both asthma and chronic obstructive pulmonary disease (COPD). It has been noted that cognitive impairment is usually linked to high levels of corticosteroids in the blood. This investigation aims to ascertain how long-term inhaled corticosteroid treatment affects individuals with bronchial asthma and COPD's cognitive performance. A total of 139 inpatients diagnosed with COPD and bronchial asthma were enrolled in the study of which 43 were newly diagnosed (group 1), 34 were taking ICS for 0.5-1 year (group 2) and 62 were on long-term ICS, that is, for >2 years (group 3). Patients with a score of at least 24 were considered to have normal cognitive function as prescribed by the Montreal Cognitive Assessment scale. It was observed that 56 patients (90.3%) were on long-term ICS treatment, 25 patients (73.5%) were on intermediate therapy and 27 patients (62.7%) who were newly diagnosed had cognitive impairment. In conclusion, the duration of ICS therapy was significantly associated with a decline in cognitive function.

Exploring the Antidepressant-like Effects of Wogonin: Analysis of Behavioural, Neurochemical, and Biochemical Parameters

Background: Wogonin, a bioactive compound isolated from S. barbata D. Don, has been identified in the literature as a potential inhibitor of monoamine oxidase (MAO), a key enzyme involved in the degradation of neurotransmitters associated with mood regulation. This study aims to investigate the antidepressant-like activity of wogonin in vivo, utilizing a preclinical model. The rationale for selecting wogonin stems from its documented MAO inhibitory properties, suggesting a potential role in modulating neurotransmitter levels implicated in depressive disorder. Method: The study employs a multifaceted approach, incorporating behavioural, neurochemical, and biochemical assessments. The Chronic Unpredictable Mild Stress model is utilized to induce depression-like behavior in rodents for 21 days. Two doses of wogonin (20 and 40 mg/kg per orally) and standard (fluoxetine, 20 mg/kg, and imipramine, 15 mg/kg) were administered to albino mice. Behavioural paradigms, including the Tail Suspension Test, Forced Swim Test, and Open Field Test, are employed to assess the impact of wogonin on depressive-like symptoms on the 21st day. Neurochemical analyses focus on alterations in 5-HT, NE, and DA levels within relevant brain regions, and MAO activity is quantified to ascertain wogonin's potential as an MAO inhibitor on the 22nd day. Biochemical assessments emphasize wogonin's antioxidant properties and its ability to mitigate oxidative stress, a significant factor in depression pathophysiology. Plasma nitrite levels are measured to elucidate wogonin's impact on nitric oxide signalling. Plasma corticosteroid levels are also quantified to delineate wogonin's effect on the hypothalamicpituitary- adrenal (HPA) axis, a central regulator of stress response. Results: Wogonin demonstrates significant antidepressant effects in a dose-dependent manner in the behavioural assessments, showing a marked reduction in depressive-like behaviours across all paradigms. Neurochemical analyses revealed a significant (p ≤ 0.05) restoration of monoamine neurotransmitter levels in the relevant brain regions as compared to CUMS-induced stress group. Additionally, wogonin exhibits a potent (p ≤ 0.05) inhibitory effect on MAO activity. Biochemical assessments demonstrate a significant (p ≤ 0.05) increase in antioxidant capacity and a reduction in oxidative stress markers. Plasma nitrite levels indicate an enhancement of nitric oxide signalling. Corticosteroid levels showed a modulation of the HPA axis, suggesting a regulatory effect on stress response. Conclusion: This comprehensive study establishes wogonin as a promising MAO inhibitor with notable antidepressant potential. The findings provide crucial insights into its mechanisms of action, indicating a multifaceted approach to alleviating depression. Wogonin's demonstrated efficacy across behavioural, neurochemical, and biochemical parameters presents a strong foundation for further research and development of wogonin-based antidepressant interventions.

#1584 Development and validation of risk prediction models according to different clinical settings of IgA nephropathy: nationwide multicenter cohort study

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis with a high risk of progression to end-stage renal disease (ESRD). Because machine learning models developed for research have limited use in clinical settings, this study developed and validated prediction models for IgAN according to different clinical settings. Method In this study, we analyzed data from 1,174 patients in the Japanese Nationwide Retrospective Cohort Study in IgAN, focusing on a 10-year observation period. We defined the derivation data from January 2002 to April 2004, and temporal validation data from May 2004 to December 2004. The composite renal outcome was defined as a 1.5-fold increase in creatinine or progression to ESRD. We developed and evaluated the three prediction models according to the different clinical settings: the primary care model for general physicians in primary care settings, the tertiary care model for specialists in tertiary care hospitals, and the research institute model, a machine learning-based approach for academic research institute settings. Results After excluding 82 patients for missing data, 114 and 14 patients experienced the composite renal outcome in the derivation (n = 874) and validation (n = 218) cohorts, respectively. The primary care model identified three variables—eGFR &amp;lt;45 mL/min/1.73 m², proteinuria ≥0.5 g/day, and non-use of corticosteroids—as significant predictors (C-statistic: 0.796; 95% CI: 0.686-0.895). The tertiary care model composed of three variables including glomerular number, histological severity and tubular/interstitial severity showed a slightly higher C-statistic (0.807; 95% CI: 0.713-0.886). When stratifying patients into risk groups, the primary care model showed a higher incidence of composite renal events in high-risk patients, and the tertiary care model effectively discriminated outcomes in all groups. The research institute model, which included 38 variables including proteinuria level, hypertension, eGFR, and non-use of corticosteroids as key predictors, showed comparable performance (C-statistic: 0.808; 95% CI: 0.689-0.886). Conclusion The primary care and tertiary care models provide simple yet effective predictive tools, competitive with the machine learning-based research institution model. These models are critical for predicting renal outcomes in patients with IgA nephropathy and for patient management according to different clinical settings.

The profile of steroid hormones in human fetal and adult ovaries.

Reproduction in women is at risk due to exposure to chemicals that can disrupt the endocrine system during different windows of sensitivity throughout life. Steroid hormone levels are fundamental for the normal development and function of the human reproductive system, including the ovary. This study aims to elucidate steroidogenesis at different life-stages in human ovaries. We have developed a sensitive and specific LC-MS/MS method for 21 important steroid hormones and measured them at different life stages: in media from cultures of human fetal ovaries collected from elective terminations of normally progressing pregnancy and in media from adult ovaries from Caesarean section patients, and follicular fluid from women undergoing infertility treatment. Statistically significant differences in steroid hormone levels and their ratios were calculated with parametric tests. Principal component analysis (PCA) was applied to explore clustering of the ovarian-derived steroidogenic profiles. Comparison of the 21 steroid hormones revealed clear differences between the various ovarian-derived steroid profiles. Interestingly, we found biosynthesis of both canonical and "backdoor" pathway steroid hormones and corticosteroids in first and second trimester fetal and adult ovarian tissue cultures. 17α-estradiol, a less potent naturally occurring isomer of 17β-estradiol, was detected only in follicular fluid. PCA of the ovarian-derived profiles revealed clusters from: adult ovarian tissue cultures with relatively high levels of androgens; first trimester and second trimester fetal ovarian tissue cultures with relatively low estrogen levels; follicular fluid with the lowest androgens, but highest corticosteroid, progestogen and estradiol levels. Furthermore, ratios of specific steroid hormones showed higher estradiol/ testosterone and estrone/androstenedione (indicating higher CYP19A1 activity, p < 0.01) and higher 17-hydroxyprogesterone/progesterone and dehydroepiandrosterone /androstenedione (indicating higher CYP17A1 activity, p < 0.01) in fetal compared to adult ovarian tissue cultures. Human ovaries demonstrate de novo synthesis of non-canonical and "backdoor" pathway steroid hormones and corticosteroids. Elucidating the steroid profiles in human ovaries improves our understanding of physiological, life-stage dependent, steroidogenic capacity of ovaries and will inform mechanistic studies to identify endocrine disrupting chemicals that affect female reproduction.

The potential modulatory impact of garlic-selenium nanoparticles coated with synthetic tocopherol polyethylene glycol-succinate against lead acetate toxicity in male rabbits

Toxic heavy metal lead enters in the environment due to industrial and anthropogenic activity threatens ecosystems and public health. Natural garlic extract (GE) exhibits antioxidant properties and various applications against several ailments. Therefore, this study scrutinized the protective effects of tocopherol polyethylene glycol succinate-coated garlic selenium (TPGS-GSNP) against lead acetate (LA) toxicity in rabbits. Sixty-four mature male rabbits were involved and divided into 8 equal groups. They received distilled water (negative control; T1), 30 mg/kg bw of LA (positive control; T2), 800 mg/kg bw of GE (T3), GE + LA (T4), 1 mg/kg bw of TPGS-Selenium (T5), TPGS-S + LA (T6), 1 mg/kg bw of TPGS-GSNP (T7), and TPGS-GSNP + LA (T8). Consequently, treatments were administered three times a week for 12 weeks. Following the treatment period, serum oxidant-antioxidant, protein, and lipid profiles, liver and kidney function, histopathological findings of the adrenal, liver, and kidneys, femur bone marrow chromosomal aberrations, and mitotic activity were collected and analysed. LA exposure showed significant reductions in antioxidant levels, organ weights, and mitotic activity while increasing oxidative stress, corticosteroid levels, and chromosomal aberrations. Importantly, TPGS-GSNP administration significantly improved these markers compared to the LA group. In addition, histological analysis revealed structural improvements of the studied organs in the TPGS-GSNP group compared to the LA group, which displayed high cellular necrotic and degenerative changes. In conclusion, synthetic TPGS-GSNP demonstrated higher protective efficacy against LA-induced toxicity compared to natural GE or selenium alone. However, more future studies could be conducted to explore the potential of TPGS-GSNP as an anticancer or immunomodulatory agent.

Early morphological and neurochemical changes of the bed nucleus of stria terminalis (BNST) in gestational protein-restricted male offspring

ABSTRACT Background The bed nucleus of the stria terminalis (BNST) is a structure with a peculiar neurochemical composition involved in modulating anxietylike behavior and fear. Aim The present study investigated the effects on the BNST neurochemical composition and neuronal structure in critical moments of the postnatal period in gestational protein-restricted male rats' offspring. Methods Dams were maintained during the pregnancy on isocaloric rodent laboratory chow with standard protein content [NP, 17%] or low protein content [LP, 6%]. BNST from male NP and age-matched LP offspring was studied using the isotropic fractionator method, Neuronal 3D reconstruction, dendritic-tree analysis, blotting analysis, and high-performance liquid chromatography. Results Serum corticosterone levels were higher in male LP offspring than NP rats in 14-day-old offspring, without any difference in 7-day-old progeny. The BNST total cell number and anterodorsal BNST division volume in LP progeny were significantly reduced on the 14th postnatal day compared with NP offspring. The BNST HPLC analysis from 7 days-old LP revealed increased norepinephrine levels compared to NP progeny. The BNST blot analysis from 7-day-old LP revealed reduced levels of GR and BDNF associated with enhanced CRF1 expression compared to NP offspring. 14-day-old LP offspring showed reduced expression of MR and 5HT1A associated with decreased DOPAC and DOPA turnover levels relative to NP rats. In Conclusion, the BNST cellular and neurochemical changes may represent adaptation during development in response to elevated fetal exposure to maternal corticosteroid levels. In this way, gestational malnutrition alters the BNST content and structure and contributes to already-known behavioral changes.

Chronic activation of the small-conductance, calcium-activated potassium channel precipitates age-dependent depressive-like behavior and cognitive deficits and reduces klotho concentration.

Depression is a common mood disorder with a multifaceted, complex pathophysiology. An abnormal level of corticosteroids in the brain can cause structural change in the hippocampus. It may cause an imbalance in calcium homeostasis leading to functional impairment in the activity of the voltage-insensitive, small conductance, calcium-activated potassium channel (SKC). Deficit in the longevity protein klotho is also implicated in stress-induced depression. We ascertained whether chronic activation of SKCs can cause age-dependent depressive-like behavior and cognitive deficits, accompanied by disturbances in klotho concentration. We tested the effect of repeated activation of SKCs by the potent SKC agonist, 1-EBIO (1.0 mg/kg, IP, once daily for 15 days) in young (3 months) and mid-life (12 months) male BALB/c mice. We conducted a battery of behavioral tests to investigate depressive-like behavior and cognitive functions. Then, we used an enzyme-linked immunosorbent assay (ELISA) on brain homogenates to determine the change in total klotho concentration in the prefrontal cortex, hippocampus, and dorsal raphe. We found that chronic 1-EBIO treatment decreased locomotor activity, sucrose preference, and alternation index in an age-dependent manner. The drug does not affect stress-coping behavior in the forced swim test. The behavioral deficits were accompanied by a significant decrease in total klotho concentration in the hippocampus but not in the prefrontal cortex or dorsal raphe, observed in an age-dependent manner. Based on these results, we surmise that chronic activation of SKCs results in concurrent cognitive and depressive-like phenotypes in mid-aged mice. Therefore, this could represent a putative therapeutic target for age-related psycho-affective disorders.

In vitro antiandrogenic effects of the herbicide linuron and its metabolites

Although the herbicide linuron is banned for use in the EU due to its reproductive and developmental toxicity, it can still be found in randomly sampled foods grown in and outside the EU. It is not clear if metabolites of linuron can contribute to the endocrine disrupting effects following exposure to the parent compound. To address this gap, we analysed linuron and the metabolites 1-(3,4-dichlorophenyl) urea (DCU), 3,4-dichloroaniline (DCA) and 1-(3,4-dichlorophenyl)-3-methoxyurea (DCXU) for androgen receptor (AR) activities and effects on steroidogenesis. Generally, linuron and the metabolites showed qualitatively similar antiandrogenic profiles, but potencies varied. All compounds were AR antagonists, with linuron showing highest potency (IC50 of 2.8 μM). The overall picture of effects on steroidogenesis showed that linuron and metabolites increased the levels of estrogens and corticosteroids, whereas the synthesis of androgens was inhibited. The metabolite DCU was by far the most potent inhibitor of testosterone synthesis (IC50 of 6.7 μM compared to IC50 of 51.1 μM for linuron). We suggest that it is likely that the metabolites contribute to the antiandrogenic effects of linuron in vivo, especially by inhibiting testosterone synthesis.

Impaired glucocorticoid receptor function attenuates herpes simplex virus 1 production during explant-induced reactivation from latency in female mice.

A correlation exists between stress and increased episodes of human alpha-herpes virus 1 reactivation from latency. Stress increases corticosteroid levels; consequently, the glucocorticoid receptor (GR) is activated. Recent studies concluded that a GR agonist, but not an antagonist, accelerates productive infection and reactivation from latency. Furthermore, GR and certain stress-induced transcription factors cooperatively transactivate promoters that drive the expression of infected cell protein 0 (ICP0), ICP4, and VP16. This study revealed female mice expressing a GR containing a serine to alanine mutation at position 229 (GRS229A) shed significantly lower levels of infectious virus during explant-induced reactivation compared to male GRS229A or wild-type parental C57BL/6 mice. Furthermore, female GRS229A mice contained fewer VP16 + TG neurons compared to male GRS229A mice or wild-type mice during the early stages of explant-induced reactivation from latency. Collectively, these studies revealed that GR transcriptional activity has female-specific effects, whereas male mice can compensate for the loss of GR transcriptional activation.

The Effect of Administering Forest Honey to Rats Exposed to Physical Stress on Corticosteroid Levels, Folliculogenesis and the Number of Corpus Luteum

Livestock that has stress releases glucocorticoids in response to it, and it causes inhibition of the hypothalamus-pituitary-gonadal axis (HPG) signaling pathway so that it reduces reproductive efficiency. Forest honey can reduce corticosteroid levels as a stress response from physical stress induction which is expected to increase reproductive efficiency including folliculogenesis and the formation of the corpus luteum. This study aims to determine the effect of forest honey on rats (Rattus novergicus) exposed to physical stress on corticosteroid levels, folliculogenesis, and the number of corpus luteum. This study is an experimental laboratory one using 32 rats which were divided into 4 treatment groups; control positive (C) treated with physical stress, treatment 1 (T1) treated with physical stress + honey 2 g/rat/day PO, treatment 2 (T2) treated with physical stress + honey 4 g/rat/day PO and treatment 3 (T3) treated with physical stress + honey 6 g/rat/day PO. All treatments were carried out for 14 days. The results showed that T1 had the lowest corticosteroid level compared to all treatment groups and the corticosteroid level of this group was significantly different (p &lt;0.05) compared to that of C and T3. The folliculogenesis profile showed that the number of primary secondary, tertiary, and Graafian follicles of group T1 was significantly different (p&lt;0.05) compared to that of C, T2, and T3. In terms of the number of corpus luteum, it showed that T1 had the highest number of corpus luteum, and the number of corpus luteum in this group was significantly different (p&lt;0.05) from that of C, T2, and T3. It can be concluded that the administration of forest honey at a dose of 2g/rat/day could reduce corticosteroid levels, improve the folliculogenesis profile, and increase the number of corpus luteum in rats exposed to physical stress. The use of forest honey could reduce corticosteroid levels as a stress response from physical stress induction which was expected to increase reproductive efficiency.

Ocular steroidome in human eyes and in eyes with complex central serous chorioretinopathy (CSCR)

The exact link between systemic and ocular endogenous corticoids (steroidome) is unclear and whether the ocular steroidome is altered in CSCR eyes is unknown. The aims of this study were to analyze the human steroidome in the aqueous humor as a function of age, sex and time of the day, to correlate systemic and ocular steroidome and to analyze the ocular steroidome in long lasting complex inactive CSCR. Based on our results, we present two CSCR cases treated by the combination of oral mineralocorticoid antagonist and glucocorticoids drops. In a cross-sectional study, aqueous humor (AH) was collected between 8am and 6 pm from 50 unaffected individuals (25 men and 25 women) and from 14 patients with chronic CSCR, during cataract surgery. In addition, simultaneous serum and AH were collected from 27 individuals undergoing cataract surgery and, simultaneous AH and vitreous were collected from 9 patients undergoing cataract and vitrectomy to estimate corticoids levels in the different compartments. The steroidome was determined using a LC–MS/MS method that quantifies 13 endogenous corticoids from the gluco, mineralocorticoid and androgen pathways. In AH and vitreous, the highest corticoid level is reached by cortisol (F), that represents less than 10% of F serum level. The cortisol levels in the serum did not correlate with ocular cortisol levels. Serum and ocular cortisone (E) levels correlate, although less than 5% of circulating E reaches the eye. The only mineralocorticoids measured in the AH were corticosterone (B) and its inactive form, the 11-desoxycorticosterone (A). There was no influence of circadian rhythm on cortisol ocular levels and there was no correlation between the age or the sex and the level of F, E, A, and B. In eyes with chronic inactive CSCR, the levels of the active glucocorticoid form F was lower than in control eyes and the F/E ratio was reduced by 50% but the B/A ratio was higher indicating imbalance towards active mineralocorticoids. Base on this observation, we propose to combine an antagonist of the mineralocorticoid receptor together with topical glucocorticoids in two CSCR patients, resistant to all other treatments, with favorable outcome. Our results indicate that the ocular psteroidome is highly regulated suggesting a local metabolism of ocular corticoids. In eyes with long-lasting complex inactive CSCR, the steroidome analysis shows lower active glucocorticoids and higher active mineralocorticoids.

Abstract P3019: During Salt-sensitive Hypertension, CD8+ T Cells Increase Renal Sodium Transporters, NKCC2 And ENaC

Hypertension originates in part from impaired salt handling by the kidneys. However, the exact identity of this kidney defect remains unknown. As established recently, the adaptive immunity, T cells in particular, acts as an important contributor to the pathogenesis of hypertension. In this regard, our laboratory has reported that CD8+ T cells (CD8Ts) adoptively transferred from salt-sensitive hypertensive mice to normotensive mice stimulate Sodium Chloride Cotransporter (NCC) increasing sodium retention. However, whether other sodium transporters within the nephron are affected by CD8Ts and contribute to this pathogenesis of hypertension remains uncharacterized. We hypothesize CD8Ts will also have an impact on other sodium channels. Through in vivo studies, we employed a CD8T-adoptive transfer model as described in our previous publications. The kidneys from mice receiving adoptive transfer of hypertensive CD8Ts were harvested and protein levels of NKCC, αENaC, βENaC, and γENaC were analyzed by western blot. In vitro, we co-cultured mouse CD8Ts with Collecting Duct epithelial cells (CDs, M1 cells) to examine the direct interaction between CD8Ts and CDs in media containing various levels of corticosteroids. Similar western blots were performed after this co-culture, as well as measurement of sodium retention through an intracellular sodium indicator and flow cytometry, as reported previously. In vivo, we found that the kidneys of mice receiving adoptive transfer of hypertensive CD8Ts demonstrated higher expression of NKCC, βENaC and γENaC, but no change in αENaC. As for in vitro, we further found that in charcoal-stripped co-culture conditions, pre-activated CD8Ts stimulate higher expression of ENaC subunits and ENaC-mediated sodium retention in M1 cells. However, these effects are masked in culture conditions with physiological or with additional corticosteroid levels. Overall, our results suggest that, as a potential kidney defect, hypertensive CD8Ts strongly stimulate NCC and NKCC in the kidney to mediate excessive salt retention and any effect of CD8Ts in increasing ENaC may be masked in physiologic conditions.

Fatty acid desaturase 2 determines the lipidomic landscape and steroidogenic function of the adrenal gland.

Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of Fads2-/- mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, FADS2 expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.

Pulsatile Subcutaneous Hydrocortisone Replacement in Primary Adrenal Insufficiency.

Pulsatile endogenous cortisol secretion is critical for physiological glucocorticoid gene signaling. Conventional glucocorticoid replacement therapy does not mimic endogenous cortisol pulsing in primary adrenal insufficiency. In an open-labeled, two-week, nonrandomized cross-over study of five patients with adrenal insufficiency (Addison's disease in two, bilateral adrenalectomy in one, and congenital adrenal hyperplasia in two patients) we compared pulsatile and continuous cortisol pump treatment and conventional oral glucocorticoid therapy with respect to 24-h serum corticosteroid levels and plasma adrenocorticotropic hormone (ACTH). Pulsed pump restored ultradian rhythmicity as demonstrated by five peaks of serum (all patients) and subcutaneous tissue cortisol (four patients). Morning subcutaneous cortisol and cortisone were higher in continuous and pulsed pump treatment than in oral therapy despite nearly similar serum cortisol levels in all treatment arms. ACTH was within the physiological range during pulsed pump treatment in all patients except for slightly elevated levels in the morning hours 04:00-08:00 h. During oral therapy, ACTH was very high in patients with Addison's disease and suppressed in patients with congenital adrenal hyperplasia. In conclusions, mimicking endogenous cortisol rhythmicity by ultradian subcutaneous infusion of cortisol is feasible. It was superior to both continuous pump and oral therapy in maintaining normal ACTH levels throughout the 24-h cycle. Our results demonstrate a low free cortisol bioavailability on thrice daily oral replacement therapy compared to both types of subcutaneous infusion.

Elevated third trimester corticosteroid levels are associated with fewer offspring infections

Respiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10–7 to 0.002) and improved lung function metrics (P = 0.020–0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life.Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226.

The influence of feed additive “Sylimevit” on indicators of the immune system of piglets at weaning

In the development of adaptive reactions during weaning, biological mechanisms are involved with the complete mobilization of the functional reserve, an increase in the level of catecholamines, corticosteroids, and mediators, which is accompanied by a violation of the nitrogen balance in the body, enzymopathy, and endotoxemia—the work aimed to investigate humoral and non-specific immunity indicators in piglets after weaning. Experiments were conducted based on the Ltd “KOSHET” of the Mukachiv district of the Zakarpattia region. Two groups of piglets were formed – control and experimental in the number of 10 individuals in each group, selected according to the principle of analogs – age, breed, and body weight. Weaning piglets from sows at 28 days suppress the humoral link of natural resistance. A decrease in lysocin and bactericidal activity of blood serum was established at 40.56 ± 1.75 and 21.22 ± 1.05 %. The content of circulating immune complexes in the blood of piglets of the control group remained high after weaning. Along with a decrease in the activity of the humoral link of immunity in weaned piglets, suppression of the non-specific link of the immune system was established, manifested by a decrease in phagocytic activity and a decrease in the number of phagocytes. Feeding the feed supplement “Sylimevit” to the piglets of the research group helped to strengthen the immune status of the piglets' bodies. In piglets of the research group on the 35th day of life, when feeding the feed additive “Sylimevit”, an increase in the phagocytic activity of neutrophils by 4.26 % was established. Similar differences were obtained regarding the effect of the Butaselmevit-plus feed additive on the phagocytic number and the phagocytic index, in particular, in piglets of the experimental group on the 35th day of the experiment; they were 7.63 and 11.1 % higher than in control. These research results confirm the effectiveness of using milk thistle, methifen, selenium, and vitamins as part of the feed supplement “Sylimevit” for piglets before and after weaning to activate the protective systems of their body.

Early life corticosteroid overexposure: Epigenetic and fetal origins of adult diseases.

The relationship between events occurring during intrauterine development and later-life predisposition to long-term disease, has been described. The fetus responds to excess intrauterine exposure to high levels of corticosteroids, modifying their physiological development and stopping their growth. Fetal exposure to elevated levels of either endogenous (alterations in fetal hypothalamic-pituitary-adrenal axis) or synthetic corticosteroids, is one model of early-life adversity; to developing adult disease. At the molecular level, there are transcriptional changes in metabolic and growth pathways. Epigenetic mechanisms participate in transgenerational inheritance, not genomic. Exposures that change 11β-hydroxysteroid dehydrogenase type 2 enzyme methylation status in the placenta can result in transcriptional repression of the gene, causing the fetus to be exposed to higher levels of cortisol. More precise diagnosis and management of antenatal corticosteroids for preterm birth, would potentially decrease the risk of long-term adverse outcomes. More studies are needed to understand the potential roles of factors to alter fetal corticosteroid exposure. Long-term infant follow-up is required to determine whether methylation changes in placenta may represent useful biomarkers of later disease risk. This review, summarize recent advances in the programming of fetal effects of corticosteroid exposure, the role of corticosteroids in epigenetic gene regulation of placental 11β-hydroxysteroid dehydrogenase type 2 enzyme expression and transgenerational effects.

When the history of the disease is the key to diagnosis: About a challenging case of congenital adrenal hyperplasia

Background: A 17 alpha-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH). Congenital adrenal hyperplasia (CAH) is a group of disorders resulting from defect of one of enzymes necessary for biosynthesis of cortisol. Case: A 33-year-old female suffered from 17OHD. She presented with primary amenorrhea, lack of secondary sexual characteristics, and hypertension complicated by ruptured cerebral aneurysm. Laboratory tests showed hypokalemia, low levels of androgens (testosterone and dehydroepiandrosterone), corticosteroid, and high levels of adrenocorticotropic hormone and progesterone. The clinical manifestations, imaging and laboratory results appeared to be consistent with a diagnosis of CAH in the patient, due to the observed 17α‑hydroxylase deficiency. Conclusion: 17OHD is a rare disease associated with primary amenorrhea and hypertension. This case shows the importance of vital signs measurement, medical history and commitment to a systematic approach.

Phase 2 randomised placebo-controlled trial of spironolactone and dexamethasone versus dexamethasone in COVID-19 hospitalised patients in Delhi

BackgroundIn this phase 2 randomised placebo-controlled clinical trial in patients with COVID-19, we hypothesised that blocking mineralocorticoid receptors using a combination of dexamethasone to suppress cortisol secretion and spironolactone is safe and may reduce illness severity.MethodsHospitalised patients with confirmed COVID-19 were randomly allocated to low dose oral spironolactone (50 mg day 1, then 25 mg once daily for 21 days) or standard of care in a 2:1 ratio. Both groups received dexamethasone 6 mg daily for 10 days. Group allocation was blinded to the patient and research team. Primary outcomes were time to recovery, defined as the number of days until patients achieved WHO Ordinal Scale (OS) category ≤ 3, and the effect of spironolactone on aldosterone, D-dimer, angiotensin II and Von Willebrand Factor (VWF).ResultsOne hundred twenty patients with PCR confirmed COVID were recruited in Delhi from 01 February to 30 April 2021. 74 were randomly assigned to spironolactone and dexamethasone (SpiroDex), and 46 to dexamethasone alone (Dex). There was no significant difference in the time to recovery between SpiroDex and Dex groups (SpiroDex median 4.5 days, Dex median 5.5 days, p = 0.055). SpiroDex patients had significantly lower D-dimer levels on days 4 and 7 (day 7 mean D-dimer: SpiroDex 1.15 µg/mL, Dex 3.15 µg/mL, p = 0.0004) and aldosterone at day 7 (SpiroDex 6.8 ng/dL, Dex 14.52 ng/dL, p = 0.0075). There was no difference in VWF or angiotensin II levels between groups. For secondary outcomes, SpiroDex patients had a significantly greater number of oxygen free days and reached oxygen freedom sooner than the Dex group. Cough scores were no different during the acute illness, however the SpiroDex group had lower scores at day 28. There was no difference in corticosteroid levels between groups. There was no increase in adverse events in patients receiving SpiroDex.ConclusionLow dose oral spironolactone in addition to dexamethasone was safe and reduced D-dimer and aldosterone. Time to recovery was not significantly reduced. Phase 3 randomised controlled trials with spironolactone and dexamethasone should be considered.Trial registrationThe trial was registered on the Clinical Trials Registry of India TRI: CTRI/2021/03/031721, reference: REF/2021/03/041472. Registered on 04/03/2021.