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The synthesis site of steroids is zona fasciculata layer of the adrenal cortex. Today, the expression of corticosteroid, an important treatment option in many diseases, reflects both glucocorticoid and mineralocorticoid. Glucocorticoids are physiologically synthesized as cortisol 10-20 mg per day and contain a little mineralocorticoid activity. They bind to receptors in peripheral cell cytoplasms and are transferred to the nucleus and exert their effects. Apart from replacement therapy in adrenal insufficiency, exogenous administration to the body has various clinical effects due to its mineralocorticoid properties. Therefore, by modifying the chemical structure of synthetic synthesized derivatives for medicinal purposes, glucocorticoid effects were strengthened by reducing mineralocorticoid effects. The success of treatment in synthetic glucocorticoids of various forms is determined by the type, dosage, route of administration, duration of the usage and the mixed effect which it provides on various body functions. The statement of \"Double-edged sword\" is associated with the natural physiological effects of molecular, cellular and organ-based side effects. Therefore, the effects of the drug, the necessity and the form of usage should be explained in detail to the patients at the beginning of the treatment. Patients should be advised about diet, social habits, and exercise and awareness should be raised about the mutual side effect monitoring after the basic clinical evaluation of the physician. The rationale for the use of steroids, despite all the incredible scientific advances in modern medical technology, can be summarized as \"in the right place, as much as necessary and as few as possible\".

Abstract Context Adrenal insufficiency (AI) is usually diagnosed by low plasma cortisol levels following a short Synacthen test (SST). Most plasma cortisol is bound to corticosteroid-binding globulin, which is increased by estrogen in combined estrogen-progestin oral contraceptives (COCs). Women with AI using COCs are therefore at risk of having an apparently normal plasma cortisol level during SST, which would not adequately reflect AI. Objective This work aimed to test whether salivary cortisol or cortisone during SST is more robust against the COC effect and to calculate the lower reference limits (LRLs) for these to be used as tentative diagnostic cutoffs to exclude AI. Methods Forty-one healthy women on COCs and 46 healthy women without exogenous estrogens underwent an SST with collection of plasma and salivary samples at 0, 30, and 60 minutes after Synacthen injection. The groups were compared using regression analysis with age as covariate and the LRLs were calculated parametrically. Results SST-stimulated plasma cortisol levels were significantly higher in the COC group vs controls, while mean salivary cortisol and cortisone levels were slightly lower in the COC group. Importantly, COC use did not significantly alter LRLs for salivary cortisol or cortisone. The smallest LRL difference between groups was seen for salivary cortisone. Conclusion Salivary cortisol and especially salivary cortisone are considerably less affected by COC use than plasma cortisol during SST. Due to similar LRLs, a common cutoff for salivary cortisol and cortisone during SST can be used to exclude AI in premenopausal women irrespective of COC use.

Salivary cortisol is widely used to investigate stress–periodontitis interactions, but its measurement is affected by methodological limitations. Cortisone, the predominant salivary glucocorticoid, may offer analytical advantages, yet its role in periodontitis remains unexplored. This study evaluated salivary cortisone in relation to periodontal disease severity and compared its performance with cortisol. Sixty-seven periodontitis patients were classified as Stage I/II (n = 32) or Stage III/IV (n = 35). A comprehensive periodontal examination was performed, including FMPS, FMBS, PPD, CAL, BoP, and the BL/Age ratio. Unstimulated morning saliva samples were analyzed for cortisone and cortisol using liquid chromatography–tandem mass spectrometry, and for IL-1β and IL-6 using ELISA. Both cortisone and cortisol levels were significantly higher in Stage III/IV periodontitis (p = 0.014). Cortisone correlated strongly with cortisol (ρ = 0.523, p < 0.001) and was positively associated with IL-6 (ρ = 0.322, p = 0.008) and multiple clinical indicators of periodontal disease severity. ROC analysis showed comparable discriminatory performance for cortisone and cortisol (AUC = 0.675), with cortisone demonstrating higher specificity (94%) for Stage III/IV periodontitis. Our findings suggest that salivary cortisone performs similarly to cortisol and warrants further investigation as an alternative salivary glucocorticoid marker in periodontal research.

Abstract Context Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism. Objective This work aimed to study cortisol metabolism during DR-HC and TID-HC. Design A randomized, 12-week, crossover study was conducted. Intervention and Participants DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls. Main Outcome Measures Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections. Results Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity. Conclusions The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

Steroid hormone dysregulations have frequently been implicated in posttraumatic stress disorder (PTSD) pathogenesis. However, the translation into naturalistic clinical settings as markers of symptomatology and treatment success remains complex. Particularly, there is little longitudinal data on steroid secretion over the course of interventions. This study examined the potential of long-term steroid hormone secretion assessed in hair as diagnostic and intervention-related biomarkers among medicated, multimorbid inpatients with PTSD. As part of a secondary analysis of a randomised controlled trial, 54 female inpatients with a primary diagnosis of PTSD received standardised treatment and provided hair samples at pre-treatment, post-treatment, and 3-month follow-up. Cortisol, cortisone, and dehydroepiandrosterone (DHEA) were determined, alongside clinical assessments. Cross-sectional results showed a negative association of pre-treatment DHEA with anxiety symptoms and a trend-level association with lifetime trauma exposure. While inpatients improved in PTSD symptomatology during treatment, neither pre-treatment steroids, nor treatment-induced steroid changes predicted PTSD symptoms at post-treatment or 3-month follow-up. The study highlights the challenges of establishing biomarkers in naturalistic clinical populations. While the association of attenuated DHEA with anxiety symptoms warrants further exploration, our data points towards the potential necessity of patient sub-sample selection to understand, and in the long run clinically target, the endocrine mechanisms in PTSD.

Salivary cortisol (sa-cortisol) and salivary cortisone correlate well with serum cortisol (s-cortisol) but validated reference ranges for healthy individuals are lacking. To establish cutoff levels for sa-cortisol and cortisone following cosyntropin testing and assess their diagnostic utility in adrenal insufficiency (AI). Steroids in saliva were assayed using liquid chromatography tandem mass spectrometry before and after administration of a 250-µg cosyntropin test in 128 healthy subjects (16 on oral estrogens) and 59 patients with suspected AI, of whom 26 were diagnosed with AI with conventional serum cortisol criteria. The cutoff level for AI was defined as the 2.5th percentile in healthy subjects not receiving estrogens. Performance was evaluated by calculating diagnostic accuracy and analyzing receiver operating characteristic curves. The sa-cortisol cutoff 60 minutes after cosyntropin stimulation was 12.6 nmol/L (accuracy 89%, sensitivity 85%, and specificity 90%). Salivary cortisone and the sum of sa-cortisol and cortisone exhibited poorer diagnostic performance than sa-cortisol. The correlation between sa-cortisol and s-cortisol was best described by a model incorporating 2 regression lines (R2 = 0.80). Segmented regression analysis identified a breakpoint at sa-cortisol 9.7 nmol/L and s-cortisol 482 nmol/L, likely corresponding to saturation of cortisol binding globulin. Healthy subjects on oral estrogens demonstrated a linear agreement between s- and sa-cortisol through all measurements. Seventeen healthy subjects repeated the test, with similar outcomes, but reproducibility in terms of intraclass coefficient and correlation was poor. Sa-cortisol in cosyntropin-test has high diagnostic accuracy in detecting adrenal insufficiency and is particularly useful in women on oral estrogens. An sa-cortisol ≥ 12.6 nmol/L assayed with liquid chromatography tandem mass spectrometry 60 minutes after 250 µg cosyntropin is normal.

Abstract Context Long-term glucocorticoid levels in scalp hair (HairGCs), including cortisol and the inactive form cortisone, represent the cumulative systemic exposure to glucocorticoids over months. HairGCs have repeatedly shown associations with cardiometabolic and immune parameters, but longitudinal data are lacking. Design We investigated 6341 hair samples of participants from the Lifelines cohort study for cortisol and cortisone levels and associated these to incident cardiovascular diseases (CVD) during 5 to 7 years of follow-up. We computed the odds ratio (OR) of HairGC levels for incident CVD via logistic regression, adjusting for classical cardiovascular risk factors, and performed a sensitivity analysis in subcohorts of participants < 60 years and ≥ 60 years of age. We also associated HairGC levels to immune parameters (total leukocytes and subtypes). Results Hair cortisone levels (available in n = 4701) were independently associated with incident CVD (P < .001), particularly in younger individuals (multivariate-adjusted OR 4.21, 95% CI 1.91-9.07 per point increase in 10-log cortisone concentration [pg/mg], P < .001). All immune parameters except eosinophils were associated with hair cortisone (all multivariate-adjusted P < .05). Conclusion In this large, prospective cohort study, we found that long-term cortisone levels, measured in scalp hair, represent a relevant and significant predictor for future CVD in younger individuals. These results highlight glucocorticoid action as possible treatment target for CVD prevention, where hair glucocorticoid measurements could help identify individuals that may benefit from such treatments.

Abstract Disclosure: T.I. Muamar: None. B. Holmquist: None. Introduction: The Labcorp Endocrine Sciences / Esoterix laboratory has offered saliva cortisol testing for several decades to assist with Late Night Saliva Cortisol (LNSC) testing in accordance with the Endocrine Society guideline on the diagnosis of Cushing’s syndrome. In 2008 the method was converted from RIA to LC-MS/MS and in 2018 the assay was modified to include cortisone as an internal tool to detect exogenous interference of hydrocortisone cream (cortisol) from the patient’s hands during collection. Methods An analytical method was developed using a TX-4 HPLC system (Thermo-Fisher) with Agilent® 1200 pumps (Agilent Technologies, Inc.) and a Sciex® 5000 (Danaher) triple quadrupole mass spectrometer. Calibration curve based on powdered Cortisol and Cortisone (Sigma) was prepared in protein-enriched phosphate buffered saline. Metrology was verified by comparison to traceable reference materials (ChromSystems). Sample preparation consisted of isotope dilution using deuterated heavy isotope internal standard (ASI, Inc) followed by liquid-liquid extraction, evaporation and reconstitution. A reversed phase 3mm x 50mm C18 fused core analytical column (Phenomenex) was used with an acidified water/acetonitrile/methanol solvent gradient to achieve chromatographic separation of both analytes. Positive mode electrospray ionization (ESI) was used for detection in Multiple Reaction Monitoring (MRM) mode. Results Analytical range was 0.01 - 1 μg/dL. Inter-assay precision ranged from 9.8-12.4% and inter-assay accuracy ranged from 90.2 - 101.4%. Specimen stability was interrogated at ambient, refrigerated and frozen conditions. Multiple saliva collection devices and/or containers from different vendors were evaluated for suitability. Reference interval for adults were developed using residual specimen collected from employees at specific times. Clinical Utility Using historical data, thresholds for suspected interference were developed by monitoring the ratio of the two glucocorticoids. Retrospective analysis of our data (17 years for cortisol, five years for cortisone) has allowed us to evaluate contamination rate for specimens as well as perform indirect reference range analyses for both analytes at multiple collection times within the circadian cycle. Presentation: Sunday, July 13, 2025

Stress, the physiological reaction to a stressor, is initiated in teleost fish by hormone cascades along the hypothalamus-pituitary-interrenal (HPI) axis. Cortisol is the major stress hormone and contributes to the appropriate stress response by regulating gene expression after binding to the glucocorticoid receptor. Cortisol is inactivated when 11β-hydroxysteroid dehydrogenase (HSD) type 2 catalyzes its oxidation to cortisone. In zebrafish, Danio rerio, cortisone can be further reduced to 20β-hydroxycortisone. This reaction is catalyzed by 20β-HSD type 2, recently discovered by us. Here, we substantiate the hypothesis that 20β-HSD type 2 is involved in cortisol catabolism and stress response. We found that hsd11b2 and hsd20b2 transcripts were up-regulated upon cortisol treatment. Moreover, a cortisol-independent, short-term physical stressor led to the up-regulation of hsd11b2 and hsd20b2 along with several HPI axis genes. The morpholino-induced knock down of hsd20b2 in zebrafish embryos revealed no developmental phenotype under normal culture conditions, but prominent effects were observed after a cortisol challenge. Reporter gene experiments demonstrated that 20β-hydroxycortisone was not a physiological ligand for the zebrafish glucocorticoid or mineralocorticoid receptor but was excreted into the fish holding water. Our experiments show that 20β-HSD type 2, together with 11β-HSD type 2, represents a short pathway in zebrafish to rapidly inactivate and excrete cortisol. Therefore, 20β-HSD type 2 is an important enzyme in stress response.