RESUMO
Winlevi® (clascoterone) topical cream (1%, w/w) was approved by the U.S. FDA for the treatment of acne vulgaris in patients 12 years of age and older. The active ingredient, clascoterone, is not stable in physiological solutions and can hydrolyze to cortexolone at body temperature. Instability of clascoterone poses a significant challenge in accurately assessing the rate and extent of clascoterone permeation in vitro. Therefore, the purpose of this study was to develop an in vitro skin permeation test (IVPT) method, and a robust analytical method, that can minimize hydrolyzation of clascoterone during the study for quantification of clascoterone. Two IVPT methods, using either vertical diffusion cells or flow-through cells, were developed and compared to evaluate in vitro permeation of clascoterone from Winlevi. A liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to monitor the level of clascoterone and cortexolone in the IVPT samples. The analytical method features a 2-min high-throughput analysis with good linearity, selectivity, and showed a lower limit of quantitation (LLOQ) of 0.5 ng/mL for both clascoterone and cortexolone. The in vitro skin permeation of clascoterone and cortexolone was observed as early as 2 h in both IVPT methods. A substantive amount of clascoterone was found to hydrolyze to cortexolone when using the vertical static diffusion cells with aliquot sampling. Conversely, degradation of clascoterone was significantly minimized when using the flow-through diffusion cells with fractional sampling. The data enhanced our understanding of in vitro permeation of clascoterone following topical application of the Winlevi topical cream, 1% and underscores the importance of IVPT method development and optimization during product development.
Assuntos
Cortodoxona , Absorção Cutânea , Creme para a Pele , Espectrometria de Massas em Tandem , Absorção Cutânea/efeitos dos fármacos , Absorção Cutânea/fisiologia , Creme para a Pele/farmacocinética , Creme para a Pele/administração & dosagem , Cortodoxona/administração & dosagem , Cortodoxona/farmacocinética , Cortodoxona/metabolismo , Cortodoxona/análogos & derivados , Espectrometria de Massas em Tandem/métodos , Pele/metabolismo , Administração Cutânea , Cromatografia Líquida/métodos , Animais , Permeabilidade , Suínos , Humanos , PropionatosRESUMO
OBJECTIVE, DESIGN, AND METHODS: Although 17-hydroxyprogesterone (17OHP) has historically been the steroid assayed in the diagnosis of congenital adrenal 21-hydroxylase deficiency (CAH-21D), its C11-hydroxylated metabolite, 21-deoxycortisol (21DF), which is strictly of adrenal origin, is assayed in parallel in this pathology. This steroid (21DF) is oxidized by 11beta-hydroxysteroid dehydrogenase type 2 into 21-deoxycortisone (21DE). In the context of CAH-21D confirmation testing, confounding factors (such as intensive care unit admission, stress, prematurity, early sampling, and variations of sex development) can interfere with the interpretation of the gold-standard biomarkers (17OHP and 21DF). Since its tissue concentrations are especially high in the placenta, we hypothesized that 21DE quantification in the neonatal periods could be an interesting biomarker in addition to 17OHP and 21DF. To verify this hypothesis, we developed a new mass spectrometry-based assay for 21DE in serum and applied it to newborns screened for CAH-21D. RESULTS: In newborns with CAH-21D, the mean serum levels of 21DE reached 17.56â ng/mL (ranging from 8.58â ng/mL to 23.20â ng/mL), and the mean 21DE:21DF ratio was 4.99. In contrast, in newborns without CAH-21D, the 21DE serum levels were low and not statistically different from the analytical 21DE limit of quantification (0.01â ng/mL). CONCLUSION: Basal serum 21DE appears to be a novel sensitive and specific biomarker of CAH-21D in newborns.
Assuntos
Hiperplasia Suprarrenal Congênita , Biomarcadores , Cortodoxona , Humanos , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/sangue , Recém-Nascido , Feminino , Cortodoxona/sangue , Biomarcadores/sangue , Masculino , 17-alfa-Hidroxiprogesterona/sangue , Triagem Neonatal/métodos , Sensibilidade e EspecificidadeRESUMO
Acne is a common inflammatory condition of the skin worldwide. The skin is an endocrine organ and hormones are a key pathogenic factor in all types of acne with a particularly important role in adult female acne pathogenesis and management. In females, we have the unique opportunity to manipulate hormones systemically to successfully manage acne and, more recently with the approval of clascoterone 1% cream, we can target the hormones topically in both genders. The intent of this paper is to provide physicians with an up-to-date clinically relevant review of the role of hormones in acne, the impact of currently available contraceptives and therapies available to target hormones in acne.
Assuntos
Acne Vulgar , Humanos , Acne Vulgar/tratamento farmacológico , Feminino , Adulto , Cortodoxona/uso terapêutico , Cortodoxona/análogos & derivados , PropionatosRESUMO
Acne vulgaris is prevalent among adolescents and adults worldwide and can significantly impact patients' quality of life. Steroidal molecules, including oral and intralesional corticosteroids, combined oral contraceptives (COCs), oral spironolactone, and topical clascoterone, are an important part of the acne treatment armamentarium. The recommended use, mechanism of action, and available evidence supporting the use of steroids for acne treatment are reviewed, and differences in acne clinical presentation and treatment approaches based on patient characteristics relevant to the selection of an appropriate steroid are also discussed. Steroid-based approaches target the systemic or local hormones (ie, testosterone and androgens) and inflammation that contribute to acne pathogenesis. Oral corticosteroids are primarily used as a short-term adjunctive therapy early in treatment, whereas intralesional corticosteroid injections are used for individual acne lesions. COCs and oral spironolactone are limited to female patients who wish to avoid pregnancy. Topical clascoterone can be used by female and male patients 12 years of age and older. Patients' characteristics (including age and patients with darker skin color) and preferences for the route of administration can impact treatment response and adherence, respectively. Overall, healthcare providers must be aware of the differences among steroidal acne treatments and use shared decision-making to select the optimal therapy. J Drugs Dermatol. 2024;23(6):404-409. doi:10.36849/JDD.7846.
Assuntos
Acne Vulgar , Espironolactona , Humanos , Acne Vulgar/tratamento farmacológico , Espironolactona/administração & dosagem , Espironolactona/efeitos adversos , Resultado do Tratamento , Feminino , Masculino , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Qualidade de Vida , Corticosteroides/administração & dosagem , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Anticoncepcionais Orais Combinados/efeitos adversos , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/uso terapêutico , Administração Cutânea , Administração Oral , Cortodoxona/análogos & derivados , PropionatosRESUMO
BACKGROUND: Clascoterone cream 1% is a topical androgen receptor inhibitor approved to treat acne vulgaris in patients =>12 years of age. This report provides details of patients who developed laboratory signs of hypothalamic-pituitary-adrenal (HPA) axis suppression without clinical signs of adrenal suppression during the clascoterone development program. METHODS: Two open-label, multicenter, Phase 2 trials evaluated HPA axis suppression in patients with moderate-to-severe acne vulgaris. Study 1 (NCT01831960) enrolled cohorts of adults =>18 years of age and adolescents =>12 to <18 years of age. Study 2 (NCT02720627) enrolled adolescents 9 to <12 years of age. Patients applied clascoterone twice daily at maximum-exposure dosages for 14 days. Adrenal suppression was evaluated via cosyntropin stimulation test (CST) at baseline and day 14. Patients with an abnormal CST result (serum cortisol level =<18 µg/dL) had a follow-up CST approximately 4 weeks later. Blood was collected for pharmacokinetic analysis. Other safety assessments included adverse events (AEs), physical examination/vital signs, and electrocardiography. RESULTS: Overall, 5/69 clascoterone-treated patients had an abnormal CST result on day 14, including 1/20 adults, 2/22 patients aged =>12 to <18 years, and 2/27 patients aged 9 to <12 years. All patients had normal cortisol levels at follow-up testing approximately 4 weeks later. No relationship was observed between abnormal CST results and clascoterone plasma concentrations or the amount of study drug applied. No clinically relevant AEs or clinically significant changes in safety measures were observed in patients with adrenal suppression. CONCLUSION: Clascoterone induced laboratory evidence of mild, reversible HPA axis suppression under maximum-use exposure. J Drugs Dermatol. 2024;23(6):433-437. doi:10.36849/JDD.7997.
Assuntos
Acne Vulgar , Hidrocortisona , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Humanos , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Acne Vulgar/tratamento farmacológico , Adolescente , Masculino , Feminino , Adulto , Criança , Adulto Jovem , Hidrocortisona/sangue , Cortodoxona/administração & dosagem , Cortodoxona/análogos & derivados , Cortodoxona/sangue , Administração Cutânea , Creme para a Pele/administração & dosagem , Creme para a Pele/efeitos adversos , Antagonistas de Receptores de Andrógenos/administração & dosagem , Antagonistas de Receptores de Andrógenos/efeitos adversos , Resultado do Tratamento , Cosintropina/administração & dosagem , PropionatosRESUMO
BACKGROUND: The relationship between glucocorticoids and hypertension has shown inconsistent findings in previous studies. To address this, our study employed a nested case-control design in rural areas to further investigate the association between serum glucocorticoid levels and hypertension, and blood pressure-related indicators. METHODS: This study employed a nested case-control design, involving 560 pairs of hypertensive cases and matched controls. The concentrations of serum cortisol (F), cortisone (E) and 11-deoxycortisol (S) were determined using liquid chromatography-tandem mass spectrometry. We employed various methods, including generalized linear model (GLM), conditional logistic regression model, restricted cubic spline regression, subgroup analysis, interaction, and joint effects, with adjustments for multiple covariates to analyze the relationships between glucocorticoids, hypertension, and blood pressure-related indicators. RESULTS: After multivariable adjustments, ln-F, ln-F/E, and ln-S were positively associated with SBP, DBP, pulse pressure (PP), and mean arterial pressure (MAP), while ln-E was negatively associated with DBP and MAP ( P â<â0.05). Interestingly, ln-S showed no statistically significant association with hypertension prevalence ( P â>â0.05), whereas ln-F and ln-F/E were positively associated with it ( P â<â0.05). The adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were 1.153 (1.011-1.315) for ln-F and 2.072 (1.622-2.645) for ln-F/E, respectively. In contrast, ln-E exhibited a negative association with hypertension prevalence (adjusted ORâ=â0.837, 95% CI 0.714-0.982). Moreover, a significant association was observed between the combined use of high-dose F/E and high-dose S with hypertension prevalence (adjusted ORâ=â3.273, 95% CI 2.013-5.321). Blood pressure indicators and hypertension prevalence significantly increased with elevated serum F and F/E concentrations ( P â<â0.05). Interaction analysis further revealed that among women, the positive association between F/E and hypertension prevalence was more pronounced than in men ( P â<â0.05), and S exhibited a more significant positive association with hypertension prevalence in the overweight population ( P â<â0.05). CONCLUSION: Serum F/E and S levels demonstrated positive associations with hypertension and blood pressure-related indicators, and their combined influence exhibited a synergistic effect on hypertension. Notably, F, F/E, and S were associated with heightened hypertension risk, warranting particular attention in women and overweight populations.
Assuntos
Pressão Sanguínea , Glucocorticoides , Hipertensão , População Rural , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Estudos de Casos e Controles , Masculino , Feminino , China/epidemiologia , Pessoa de Meia-Idade , Glucocorticoides/sangue , Idoso , Hidrocortisona/sangue , Adulto , Cortisona/sangue , Cortodoxona/sangueRESUMO
OBJECTIVES: This study aimed to evaluate the effectiveness of topical clascoterone (TC) compared to oral spironolactone for acne vulgaris treatment. METHODS: A computerized search through PubMed/MEDLINE, SCOPUS, and the Cochrane Library was conducted to find relevant papers. We used the "netmeta" and "meta" packages for network meta-analysis (NMA) in RStudio 1.2.5019 (2009-2019 RStudio, Inc.) to conduct all of our statistical tests. RESULTS: Seven articles (n = 2,006 patients) were included. The fixed-effect size showed that TC 1% bis in die (BID) showed potential effectiveness in reducing the inflammatory and non-inflammatory lesion count compared to placebo (Standardized mean difference, SMD = -0.27, 95% CI: -0.36 to -0.17) and (SMD = -0.31, 95% CI: -0.41 to -0.22), respectively. The random-effect size showed that TC 1% BID was significantly associated with a 12-week treatment success compared to placebo (Odds ratio, OR = 2.44, 95% CI: 1.12 to 5.30). Spironolactone 200 mg was associated with a significant reduction in total lesion count (SMD = -4.46, 95% CI: -5.60 to -3.32). CONCLUSION: TC appears to reduce both inflammatory and non-inflammatory lesion count and may lead to treatment success. Spironolactone at 200 mg showed potential effectiveness in terms of total lesion count reduction. These results suggest that both TC and Spironolactone could be beneficial in treating patients with acne vulgaris.
Assuntos
Acne Vulgar , Metanálise em Rede , Espironolactona , Acne Vulgar/tratamento farmacológico , Humanos , Espironolactona/uso terapêutico , Espironolactona/administração & dosagem , Resultado do Tratamento , Administração Tópica , Cortodoxona/análogos & derivados , PropionatosRESUMO
BACKGROUND: Acne vulgaris commonly affects adults, adolescents, and preadolescents aged 9 years or older. OBJECTIVE: The objective of this study was to provide evidence-based recommendations for the management of acne. METHODS: A work group conducted a systematic review and applied the Grading of Recommendations, Assessment, Development, and Evaluation approach for assessing the certainty of evidence and formulating and grading recommendations. RESULTS: This guideline presents 18 evidence-based recommendations and 5 good practice statements. Strong recommendations are made for benzoyl peroxide, topical retinoids, topical antibiotics, and oral doxycycline. Oral isotretinoin is strongly recommended for acne that is severe, causing psychosocial burden or scarring, or failing standard oral or topical therapy. Conditional recommendations are made for topical clascoterone, salicylic acid, and azelaic acid, as well as for oral minocycline, sarecycline, combined oral contraceptive pills, and spironolactone. Combining topical therapies with multiple mechanisms of action, limiting systemic antibiotic use, combining systemic antibiotics with topical therapies, and adding intralesional corticosteroid injections for larger acne lesions are recommended as good practice statements. LIMITATIONS: Analysis is based on the best available evidence at the time of the systematic review. CONCLUSIONS: These guidelines provide evidence-based recommendations for the management of acne vulgaris.
Assuntos
Acne Vulgar , Antibacterianos , Peróxido de Benzoíla , Fármacos Dermatológicos , Ácidos Dicarboxílicos , Doxiciclina , Isotretinoína , Ácido Salicílico , Espironolactona , Humanos , Acne Vulgar/tratamento farmacológico , Isotretinoína/administração & dosagem , Isotretinoína/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/uso terapêutico , Peróxido de Benzoíla/administração & dosagem , Peróxido de Benzoíla/uso terapêutico , Ácidos Dicarboxílicos/administração & dosagem , Ácidos Dicarboxílicos/uso terapêutico , Espironolactona/administração & dosagem , Espironolactona/uso terapêutico , Doxiciclina/administração & dosagem , Doxiciclina/uso terapêutico , Ácido Salicílico/administração & dosagem , Ácido Salicílico/uso terapêutico , Medicina Baseada em Evidências/normas , Administração Oral , Retinoides/administração & dosagem , Retinoides/uso terapêutico , Tetraciclinas/administração & dosagem , Tetraciclinas/uso terapêutico , Adolescente , Minociclina/administração & dosagem , Minociclina/uso terapêutico , Criança , Administração Cutânea , Anticoncepcionais Orais Combinados/administração & dosagem , Anticoncepcionais Orais Combinados/uso terapêutico , Quimioterapia Combinada , Feminino , Corticosteroides/administração & dosagem , Corticosteroides/uso terapêutico , Injeções Intralesionais , Adulto , Cortodoxona/análogos & derivados , PropionatosRESUMO
BACKGROUND: Clascoterone cream 1% is approved for the treatment of acne vulgaris in patients aged 12 years or older based on results from two identical pivotal Phase 3 trials. Integrated efficacy of clascoterone in patients aged 12 years or older with acne vulgaris from the pivotal trials (NCT02608450 and NCT02608476) and long-term extension (LTE) study (NCT02682264) is reported. METHODS: In the pivotal trials, patients with moderate-to-severe acne vulgaris were randomized 1:1 to twice-daily application of clascoterone cream 1% or vehicle for 12 weeks; they could then enter the LTE study, where all patients applied clascoterone to the face and, if desired, trunk for up to 9 additional months. Efficacy was assessed from treatment success based on Investigator's Global Assessment scores (IGA 0/1) in patients aged 12 years or older in the intention-to-treat population; lesion counts were assessed through week 12. Missing data were handled using multiple imputation in the pivotal studies and were not imputed in the LTE study. RESULTS: Of 1421 patients enrolled, 1143 (clascoterone, 576; vehicle, 567) completed week 12; 600 entered and 343 completed the LTE study. The treatment success rate and most lesion count reductions following clascoterone vs placebo treatment reached statistical significance at week 12; the overall treatment success rate increased to 30.2% for facial acne after 12 months and 31.7% for truncal acne after 9 months of treatment. CONCLUSIONS: The efficacy of clascoterone cream 1% for the treatment of acne vulgaris continued to increase over time for up to 12 months in patients aged 12 years or older with acne vulgaris. J Drugs Dermatol. 2024;23(1):1278-1283. doi:10.36849/JDD.7719.
Assuntos
Acne Vulgar , Procedimentos de Cirurgia Plástica , Propionatos , Humanos , Acne Vulgar/diagnóstico , Acne Vulgar/tratamento farmacológico , Cortodoxona , EmolientesRESUMO
Adolescence is marked by the maturation of systems involved in emotional regulation and by an increased risk for internalizing disorders (anxiety/depression), especially in females. Hypothalamic-pituitary-adrenal (HPA)-axis function and redox homeostasis (balance between reactive oxygen species and antioxidants) have both been associated with internalizing disorders and may represent critical factors for the development of brain networks of emotional regulation. However, sex-specific interactions between these factors and internalizing symptoms and their link with brain maturation remain unexplored. We investigated in a cohort of adolescents aged 13-15 from the general population (n = 69) whether sex-differences in internalizing symptoms were associated with the glutathione (GSH)-redox cycle homeostasis and HPA-axis function and if these parameters were associated with brain white matter microstructure development. Female adolescents displayed higher levels of internalizing symptoms, GSH-peroxidase (GPx) activity and cortisol/11-deoxycortisol ratio than males. There was a strong correlation between GPx and GSH-reductase (Gred) activities in females only. The cortisol/11-deoxycortisol ratio, related to the HPA-axis activity, was associated with internalizing symptoms in both sexes, whereas GPx activity was associated with internalizing symptoms in females specifically. The cortisol/11-deoxycortisol ratio mediated sex-differences in internalizing symptoms and the association between anxiety and GPx activity in females specifically. In females, GPx activity was positively associated with generalized fractional anisotropy in widespread white matter brain regions. We found that higher levels of internalizing symptoms in female adolescents than in males relate to sex-differences in HPA-axis function. In females, our results suggest an important interplay between HPA-axis function and GSH-homeostasis, a parameter strongly associated with brain white matter microstructure.
Assuntos
Hidrocortisona , Substância Branca , Humanos , Masculino , Adolescente , Feminino , Substância Branca/diagnóstico por imagem , Cortodoxona , Encéfalo/diagnóstico por imagem , Oxirredução , Sistema Hipotálamo-Hipofisário/fisiologia , Sistema Hipófise-Suprarrenal/fisiologia , Antioxidantes , Estresse PsicológicoRESUMO
OBJECTIVE: Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). Data on OMT use and its safety are scarce. We aimed to describe the indications and safety of outpatient OMT and compare OMT to the cosyntropin stimulation test (CST). DESIGN: Single-centre retrospective study of adult patients undergoing OMT between 1 April 2018 and 27 January 2023. MEASUREMENTS: OMT-related adverse events, post-OMT diagnosis of SAI, and OMT comparison to CST. RESULTS: OMT was performed in 114 patients (81, 71% women) at a median age of 48 (interquartile range 37-58). The pretest probability for SAI was low in 52 (46%) patients, moderate in 48 (42%) patients and high in 14 (12%) patients. Adverse events were reported in 7 (6.1%) patients and were mild except for one hospitalization. No baseline or OMT-related factors were associated with the development of adverse events. Prevalence of the OMT-based SAI diagnosis was 26 (23%) and 47 (46%) using 11-deoxycortisol cutoff <7 and <10 mcg/dL, respectively. Higher pretest probability was associated with the OMT-based diagnosis of SAI. Post-OMT 11-deoxycortisol cutoff of 10 mcg/dL was used most to diagnose SAI. Compared to the OMT-based diagnosis of SAI (11-deoxycortisol cutoff of 10 mcg/dL), the specificity of CST was 100%, but the sensitivity was only 52%. CONCLUSIONS: OMT was well tolerated and used in patients with low and moderate pretest probability for SAI. CST can erroneously exclude patients with SAI. Thus, OMT should be considered in selected patients with normal CST.
Assuntos
Insuficiência Adrenal , Metirapona , Adulto , Humanos , Feminino , Masculino , Estudos Retrospectivos , Cortodoxona , Insuficiência Adrenal/diagnóstico , Cosintropina , HidrocortisonaRESUMO
BACKGROUND: Exposure to 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used hormonal herbicide, may disrupt steroid hormone homeostasis. However, evidence from population-based studies is limited, especially for one-month-old infants whose steroid hormones are in a state of adjustment to extrauterine life and can be important indicators of endocrine development. This study aimed to explore the associations between maternal 2,4-D exposure during early pregnancy and infant steroid hormone levels. METHODS: The 885 mother-infant pairs were from a birth cohort in Wuhan, China. Maternal exposure to 2,4-D was determined in urine samples from early pregnancy, and nine steroid hormones were determined in infant urine. The associations of maternal 2,4-D exposure with infant steroid hormones and their product-to-precursor ratios were estimated based on generalized linear models, and bioinformatic analysis was conducted with public databases to explore the potential mechanisms involved. RESULTS: The detection frequency of 2,4-D was 99.32 %, and the detection frequency of steroid hormones ranged from 98.42 % to 100.00 %. After adjusting for covariates, an interquartile range increase in 2,4-D concentrations was associated with a 7.84 % decrease in 11-deoxycortisol (95 % confidence interval, CI: -14.12 %, -1.10 %), an 8.09 % decrease in corticosterone (95 % CI: -14.56 %, -1.14 %), an 8.67 % decrease in cortisol (95 % CI: -14.43 %, -2.52 %), a 13.00 % decrease in cortisone (95 % CI: -20.64 %, -4.62 %), and an 11.17 % decrease in aldosterone (95 % CI: -19.62 %, -1.83 %). Maternal 2,4-D was also associated with lower infant cortisol/17α-OH-progesterone, cortisol/pregnenolone, and aldosterone/pregnenolone ratios. In bioinformatic analysis, pathways/biological processes related to steroid hormone synthesis and secretion were enriched from target genes of 2,4-D exposure. CONCLUSIONS: Maternal urinary 2,4-D during early pregnancy was associated with lower infant urinary 11-deoxycortisol, corticosterone, cortisol, cortisone, and aldosterone, reflecting that 2,4-D exposure may interfere with infant steroid hormone homeostasis. Further efforts are still needed to study the relevant health effects of exposure to 2,4-D, particularly for vulnerable populations.
Assuntos
Cortisona , Herbicidas , Gravidez , Lactente , Feminino , Humanos , Exposição Materna , Hidrocortisona , Corticosterona , Aldosterona , Cortodoxona , Progesterona , Pregnenolona , Ácido 2,4-DiclorofenoxiacéticoRESUMO
BACKGROUND: Endogenous steroid hormones have significant effects on inflammatory and immune processes, but the immunological activities of steroidogenesis precursors remain largely unexplored. METHODS: We conducted a systematic approach to examine the association between steroid hormones profile and immune traits in a cohort of 534 healthy volunteers. Serum concentrations of steroid hormones and their precursors (cortisol, progesterone, testosterone, androstenedione, 11-deoxycortisol and 17-OH progesterone) were determined by liquid chromatography-tandem mass spectrometry. Immune traits were evaluated by quantifying cellular composition of the circulating immune system and ex vivo cytokine responses elicited by major human pathogens and microbial ligands. An independent cohort of 321 individuals was used for validation, followed by in vitro validation experiments. FINDINGS: We observed a positive association between 11-deoxycortisol and lymphoid cellular subsets numbers and function (especially IL-17 response). The association with lymphoid cellularity was validated in an independent validation cohort. In vitro experiments showed that, as compared to androstenedione and 17-OH progesterone, 11-deoxycortisol promoted T cell proliferation and Candida-induced Th17 polarization at physiologically relevant concentrations. Functionally, 11-deoxycortisol-treated T cells displayed a more activated phenotype (PD-L1high CD25high CD62Llow CD127low) in response to CD3/CD28 co-stimulation, and downregulated expression of T-bet nuclear transcription factor. INTERPRETATION: Our findings suggest a positive association between 11-deoxycortisol and T-cell function under physiological conditions. Further investigation is needed to explore the potential mechanisms and clinical implications. FUNDING: Found in acknowledgements.
Assuntos
Cortodoxona , Progesterona , Humanos , Androstenodiona , Esteroides , FenótipoRESUMO
Improving agricultural products by the stimulation of plant growth and defense mechanisms by priming with plant extracts is needed to attain sustainability in agriculture. This study focused to consider the possible improvement in Vigna radiata L. seed germination rate, plant growth, and protection against the natural stress by increasing the defense mechanisms through the incorporation of Sesamum indicum phytochemical compounds with pre-sowing seed treatment technologies. The gas chromatography coupled with mass spectroscopy (GC-MS) analysis revealed that the methanol extract of S. indicum leaf extract contained eight major bioactive compounds, namely, 2-ethylacridine (8.24%), tert-butyl (5-isopropyl-2-methylphenoxy) dimethylsilane (13.25%), tris(tert-butyldimethylsilyloxy) arsane (10.66%), 1,1,1,3,5,5,5-heptamethyltrisiloxane (18.50%), acetamide, N-[4-(trimethylsilyl) phenyl (19.97%), 3,3-diisopropoxy-1,1,1,5,5,5-hexamethyltrisiloxane (6.78%), silicic acid, diethyl bis(trimethylsilyl) ester (17.71%) and cylotrisiloxane, hexamethyl-(4.89%). The V. radiata seeds were treated with sesame leaf extract seeds at concentrations 0, 10, 25, 50, and 100 mg/L. Sesame leaf extract at 50 and 100 mg/L concentrations was effective in increasing the germination percentage and the fresh and dry weights of roots and shoots. The increased peroxidase activity was noticed after treatment with S. indicum extract. In addition, disease percentage (< 60%) of both fungal pathogens (Rhizoctonia and Macrophomina) was significantly reduced in V. radiata plants treated with 100 mg/L of sesame leaf extract. These results revealed that physiochemical components present in S. indicum mature leaf extract significantly enhanced growth and defense mechanism in green gram plants.
Assuntos
Ascomicetos , Sesamum , Vigna , Rhizoctonia , Agricultura , Cortodoxona , Mecanismos de DefesaRESUMO
OBJECTIVE: To investigate the difference of cortical hormones in cord artery and vein blood of newborns with different delivery modes. METHODS: A total of 65 pregnant women who delivered in the People's Hospital of Danyang City, Jiangsu Province from June to September 2021 were selected as the study subjects, including 26 cases of spontaneous delivery and 39 cases of cesarean section. The basic information of 65 pregnant women and newborns was collected by questionnaire survey. According to the mode of delivery, the levels of corticosteroids in umbilical vein and umbilical artery blood were determined by liquid chromatography-tandem mass spectrometry(LC-MS/MS), including corticosterone, 11-desoxycorticosterone, aldosterone, cortisol, 11-deoxycortisol and cortisone. The data were statistically analyzed using IBM SPSS Statistics 26.0 statistical software. RESULTS: The levels of cortisol, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in the umbilical vein blood of the spontaneous delivery group were(2.44±1.87), (0.64±0.29), (0.49±0.35), (54.95±40.80), (3.20±1.23) and(142.27±57.42)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in umbilical artery blood were(4.51±4.47), (0.57±0.28), (0.42±0.29), (60.79±45.53), (2.69±1.25) and(123.10±46.32)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisone, aldosterone, cortisol, 11-deoxycortisone and cortisone in umbilical vein blood of cesarean section group were(0.94±1.09), (0.47±0.14), (0.26±0.14), (22.63±19.82), (2.30±0.90) and(84.51±29.49)ng/mL, respectively. The levels of corticosterone, 11-deoxycortisol, aldosterone, cortisol, 11-deoxycortisol and cortisone in umbilical artery blood were(2.22±2.24), (0.43±0.17), (0.27±0.14), (30.09±25.93), (1.87±0.76) and(75.03±24.90)ng/mL, respectively. The levels of corticosterone, 11-desoxycorticosterone, aldosterone, cortisol, 11-deoxycortisol and cortisone in cord vein blood and cord artery blood in spontaneous labor group were significantly higher than those in cesarean section group(P<0.05). The levels of corticosterone and cortisol in cord vein blood were significantly lower in spontaneous labor group and cesarean section group than those in cord artery blood(P<0.05), the levels of 11-desoxycorticosterone, 11-deoxycortisol and cortisone in cord vein blood were significantly higher in spontaneous labor group and cesarean section group than those in cord artery blood(P<0.05). CONCLUSION: There are differences in the level of cortical hormones in cord artery and vein blood in different delivery modes.
Assuntos
Corticosterona , Cortisona , Feminino , Recém-Nascido , Gravidez , Humanos , Hidrocortisona , Aldosterona , Cortodoxona , Cesárea , Cromatografia Líquida , Espectrometria de Massas em Tandem , Desoxicorticosterona , Sangue Fetal , ArtériasRESUMO
CONTEXT: Nonclassic congenital adrenal hyperplasia (NCCAH) requires exclusion before diagnosing polycystic ovary syndrome (PCOS). Increasing use of liquid chromatography and tandem mass spectrometry (LC-MS/MS) necessitates revision of immunoassay-based criteria for NCCAH. Measurement of 21-deoxycortisol (21DF) may simplify the diagnosis of heterozygosity (HTZ), the presence of 1 affected CYP21A2 allele, which currently relies on complex molecular studies. OBJECTIVE: We aimed to determine LC-MS/MS-specific criteria for NCCAH and HTZ and compare the diagnostic accuracy of 21DF and 17-hydroxyprogesterone (17OHP). METHODS: A cross-sectional study involving 99 hyperandrogenic females was performed. We identified females who had undergone both a synacthen stimulation test (SST) and CYP21A2 genotyping from 2010 to 2017, and prospectively recruited females referred for an SST to investigate hyperandrogenic symptoms from 2017 to 2021. Steroids were compared between genetically confirmed NCCAH, HTZ, and PCOS. Optimal 17OHP and 21DF thresholds for HTZ and NCCAH were determined by receiver operating characteristic analysis. RESULTS: Basal 17OHP, stimulated 17OHP, and 21DF were measured in 99, 85, and 42 participants, respectively. Optimal thresholds for NCCAH were 3.0 nmol/L and 20.7 nmol/L for basal and stimulated 17OHP, respectively. Basal and stimulated 21DF thresholds of 0.31 nmol/L and 13.3 nmol/L provided 100% sensitivity with specificities of 96.8% and 100% for NCCAH, respectively. Diagnostic thresholds for HTZ of 8.0 nmol/L, 1.0 nmol/L, and 13.6 for stimulated 17OHP, 21DF, and the ratio (21DF + 17OHP)/cortisol each provided 100% sensitivity with specificities of 80.4%, 90.5%, and 85.0%, respectively. CONCLUSION: LC-MS/MS-specific 17OHP thresholds for NCCAH are lower than those based on immunoassay. LC-MS/MS-quantified 17OHP and 21DF accurately discriminate HTZ and NCCAH from PCOS.
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Hiperplasia Suprarrenal Congênita , Cortodoxona , Feminino , Humanos , 17-alfa-Hidroxiprogesterona , Hiperplasia Suprarrenal Congênita/diagnóstico , Androgênios , Cromatografia Líquida , Cosintropina , Estudos Transversais , Esteroide 21-Hidroxilase/genética , Espectrometria de Massas em Tandem , Cortodoxona/sangueRESUMO
BACKGROUND: Systemic inflammation plays a key role in the development of bronchopulmonary dysplasia (BPD). Cortisol is known to dampen inflammation. However, adrenal function following preterm birth is characterized by insufficient cortisol levels for the degree of inflammation, and a relative abundancy of cortisol precursors. We investigated whether this pattern could contribute to the development of BPD in preterm infants born <30 weeks of gestation. METHODS: Cortisol, cortisone, 17-OH progesterone (17-OHP) and 11-deoxycortisol were measured in serum obtained at postnatal days 1, 3, 7, 14 and 28, using liquid-chromatography-tandem-mass-spectrometry. The presence of BPD was ascertained at 36 weeks postmenstrual age. RESULTS: Sixty-five infants were included for analysis, of whom 32 (49%) developed BPD. Preterm infants developing BPD, as compared to those without BPD, had higher levels of 17-OHP, 11-deoxycortisol and cortisone relative to cortisol in their first week of life, but not at birth or beyond day 7. CONCLUSION: Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in their first week of life than infants without BPD. These findings suggest that BPD is preceded by an activated hypothalamus-pituitary-adrenal axis that could not meet the high cortisol demands, which may predispose to inflammation and BPD. IMPACT: Relative adrenal insufficiency is common in the first weeks after preterm birth, resulting in insufficient cortisol production for the degree of inflammation and a relative abundance of cortisol precursors; Whether this pattern contributes to the development of bronchopulmonary dysplasia (BPD) is not fully elucidated, since most studies focused on cortisol levels; Preterm infants developing BPD had higher levels of cortisol precursors and cortisone relative to cortisol in the first week of life, suggestive of a hypothalamus-pituitary-adrenal-axis activation during BPD development which cannot meet the high cortisol demands in tissues; This glucocorticoid pattern is likely to dispose to inflammation and BPD.
Assuntos
Displasia Broncopulmonar , Cortisona , Nascimento Prematuro , Lactente , Feminino , Recém-Nascido , Humanos , Glucocorticoides , Recém-Nascido Prematuro , Hidrocortisona , Cortodoxona , InflamaçãoRESUMO
Acne vulgaris is the most common skin condition in the US, affecting up to 50 million Americans. The American Academy of Dermatology (AAD) guidelines on acne treatment were developed to provide recommendations for the diagnosis, grading, and treatment of acne in adolescents and adults to support clinicians in their therapeutic decision-making process. The most recent acne guidelines were published in 2016, and the approach to care and the therapeutic landscape of acne have evolved since that time. The Acne Management Consensus Roundtable was convened in 2022 to discuss unmet needs in the management of acne. The main focus of the meeting was the role of androgens in acne pathology; the evaluation of clascoterone, the first topical anti-androgen that specifically addresses sebum production in acne; and the identification of the place of clascoterone in therapy. Clascoterone was approved by the US Food and Drug Administration for the treatment of acne in patients 12 years and older in 2020. This report aims to highlight important limitations of the 2016 AAD treatment guidelines and to familiarize practitioners with clascoterone and its indication, efficacy and safety profile, and potential use across diverse patient populations. With its new mechanism of action, clascoterone may be able to fulfill important unmet needs in acne treatment. Baldwin H, Farberg AS, Frey C, et al. Unmet needs in the management of acne vulgaris: a consensus statement. J Drugs Dermatol. 2023;22(6):582-587. doi:10.36849/JDD.7587.
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Acne Vulgar , Adulto , Adolescente , Humanos , Acne Vulgar/diagnóstico , Acne Vulgar/tratamento farmacológico , Propionatos , Cortodoxona , Sebo , Resultado do TratamentoRESUMO
Acne is a prevalent chronic inflammatory disease that can cause severe psychiatric effects and physical scarring of the skin. Historically, although systemic antiandrogen acne medications have been effective in women, the utility of these systemic medications has been limited due to potential systemic side effects in men and pregnant women. Therefore, research has been focused on developing topical formulations of antiandrogen therapy for acne. Topical clascoterone cream 1% is the first topical anti-androgen medication approved for the treatment of acne vulgaris in patients 12 years and older and represents a breakthrough in acne treatment. Clascoterone, or cortexolone-17α propionate, is an androgen receptor inhibitor with highly localized activity. Thismedication is thought to compete with dihydrotestosterone (DHT) for androgen receptors located in pilosebaceous units, thus inhibiting the acnegenic downstream effects of DHT such as lipid synthesis and inflammatory cytokine production in a dose-dependent manner. Two phase III clinical trials have been conducted thus far; both trials have shown clascoterone 1% cream applied BID to be significantly more effective than placebo cream at treating acne vulgaris in patients ages 12 and older with moderate-to-severe acne. Clascoterone has also been shown to have a similar safety profile to that of placebo cream in clinical studies, without any systemic antiandrogenic effects observed in the clinical setting. Due to its novel mechanism of action and activity limited to the skin, clascoterone presents an exciting opportunity for dermatologists to further optimize care for eligible acne patients, either as a monotherapy or in combination with other anti-acne medications. J Drugs Dermatol. 2023;22:56(Suppl 1):s7-14.