Use of overnight metyrapone test in suspected secondary adrenal insufficiency: A retrospective single centre-study.

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.

Guidelines of care for the management of acne vulgaris.

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.

Integrated Short-Term and Long-Term Efficacy of Topical Clascoterone Cream 1% in Patients Aged 12 Years or Older With Acne Vulgaris.

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.

Hypothalamic-Pituitary-Adrenal Axis Response in Patients With Acne Vulgaris Treated With Clascoterone.

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.

Steroids Used to Treat Acne Vulgaris: A Review of Efficacy, Safety, and Clinical Considerations.

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.

Adult Female Acne: Managing the Hormones.

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.

Evaluation of in vitro Skin Permeation of Clascoterone From Clascoterone Topical Cream, 1% (w/w).

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.

A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics.

INTRODUCTION: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. METHODS: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 µg/L) and a pathological (11-deoxycortisol <70 µg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. RESULTS: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 µg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%). CONCLUSION: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

Glucocorticoid signature of preterm infants developing bronchopulmonary dysplasia.

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.

Report from the HarmoSter study: inter-laboratory comparison of LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone.

OBJECTIVES: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) panels that include glucocorticoid-related steroids are increasingly used to characterize and diagnose adrenal cortical diseases. Limited information is currently available about reproducibility of these measurements among laboratories. The aim of the study was to compare LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone at eight European centers and assess the performance after unification of calibration. METHODS: Seventy-eight patient samples and commercial calibrators were measured twice by laboratory-specific procedures. Results were obtained according to in-house and external calibration. We evaluated intra-laboratory and inter-laboratory imprecision, regression and agreement against performance specifications derived from 11-deoxycortisol biological variation. RESULTS: Intra-laboratory CVs ranged between 3.3 and 7.7%, 3.3 and 11.8% and 2.7 and 12.8% for corticosterone, 11-deoxycortisol and cortisone, with 1, 4 and 3 laboratories often exceeding the maximum allowable imprecision (MAI), respectively. Median inter-laboratory CVs were 10.0, 10.7 and 6.2%, with 38.5, 50.7 and 2.6% cases exceeding the MAI for corticosterone, 11-deoxycortisol and cortisone, respectively. Median laboratory bias vs. all laboratory-medians ranged from -5.6 to 12.3% for corticosterone, -14.6 to 12.4% for 11-deoxycortisol and -4.0 to 6.5% for cortisone, with few cases exceeding the total allowable error. Modest deviations were found in regression equations among most laboratories. External calibration did not improve 11-deoxycortisol and worsened corticosterone and cortisone inter-laboratory comparability. CONCLUSIONS: Method imprecision was variable. Inter-laboratory performance was reasonably good. However, cases with imprecision and total error above the acceptable limits were apparent for corticosterone and 11-deoxycortisol. Variability did not depend on calibration but apparently on imprecision, accuracy and specificity of individual methods. Tools for improving selectivity and accuracy are required to improve harmonization.

Unmet Needs in the Management of Acne Vulgaris: A Consensus Statement.

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.

Individual Article: Clascoterone Cream 1%: Mechanism of Action, Efficacy, and Safety of a Novel, First-in-Class Topical Antiandrogen Therapy for Acne.

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.

[Effect of different delivery modes on the level of cortical hormones in cord artery and vein blood].

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.

21-Deoxycortisol is a Key Screening Marker for 21-Hydroxylase Deficiency.

OBJECTIVES: To assess whether 21-deoxycortisol (21deoxy) can be used to predict 21-hydroxylase deficiency (21OHD) in newborns and to evaluate the influence of gestational age and the timing of collection on 21deoxy concentrations. STUDY DESIGN: 17-hydroxyprogesterone (17OHP) and 21deoxy levels were measured in 906 newborn screening specimens (851 unaffected newborns, 55 confirmed cases of 21OHD) to compare their ability to identify babies with 21OHD. In addition, these 2 steroids were assessed in the unaffected cohort to determine the influence of gestational age (ranging from 23 to 42 weeks) and the timing of specimen collection on the measured concentrations. RESULTS: The gestational age of the newborn impacted both 17OHP and 21deoxy concentrations, but the degree of influence was more substantial for 17OHP. Timing of collection did not affect 21deoxy concentration. Moreover, 21deoxy was a better predictor of 21OHD status compared with 17OHP, with little overlap in concentrations between the unaffected population and confirmed cases of 21OHD. A streamlined decision tree using solely 21deoxy (cutoff value, 0.85 ng/mL) yielded a 91.7% positive predictive value for 21OHD screening. CONCLUSIONS: Our findings demonstrate that 21deoxy is a key disease marker of 21OHD and can be used to improve the accuracy of newborn screening for this disorder.

Are current cut-off values of 11-DOC in children useful for assessing suspected nonclassical congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency?

OBJECTIVE: A nonclassic form of 11ß-hydroxylase deficiency (NC11ß-OHD) has been reported to cause mild androgen excess symptoms. Currently, the gold standard for biochemical diagnosis is elevated 11-deoxycortisol (11-DOC) levels after corticotropin stimulation test (ACTHstimT). However, there are no clear 11-DOC level cutoffs. One of the accepted references for 11-DOC levels for the paediatric population was published in 1991 by Lashansky et al. AIM: To determine the correlation between 11-DOC levels measured during ACTHstimT and clinical symptoms attributed to NC11ß-OHD. DESIGN: A retrospective study including all paediatric patients who underwent ACTHstimT at Shamir Medical Center between 2007 and 2015. Clinical data were collected from the patients' medical files. Outcome measures included the number of patients with hyperandrogenism signs and predefined elevated 11-DOC cut-off levels according to Lashansky for sex and age, and according to commercial kit cut-offs. RESULTS: Data were complete at presentation for 136 patients. Long-term clinical data were documented for 98 patients, mean follow-up duration of 3.1 years (1.37-5.09). There was no statistically significant difference in the number of cases with elevated 11-DOC according to both cut-offs and early puberty, premature adrenarche nor acne. Follow-up data demonstrated no statistically significant difference in the number of cases with elevated 11-DOC levels among patients with compromised final adult height, polycystic ovarian syndrome or hyperandrogenism. CONCLUSIONS: Basal and corticotropin stimulated 11-DOC levels were not significantly elevated above the 1.5 times cut-offs according to paediatric-specific norms or the commercial assay in paediatric individuals with possible clinical suspicion of NC11ß-OHD.

Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.

RATIONALE: Steroid profiles in combination with a corticotropin stimulation test provide information about steroidogenesis and its functional reserves in critically ill patients. OBJECTIVES: We investigated whether steroid profiles before and after corticotropin stimulation can predict the risk of in-hospital death in sepsis. METHODS: An exploratory data analysis of a double blind, randomized trial in sepsis (HYPRESS [HYdrocortisone for PRevention of Septic Shock]) was performed. The trial included adult patients with sepsis who were not in shock and were randomly assigned to placebo or hydrocortisone treatment. Corticotropin tests were performed in patients prior to randomization and in healthy subjects. Cortisol and precursors of glucocorticoids (17-OH-progesterone, 11-desoxycortisol) and mineralocorticoids (11-desoxycorticosterone, corticosterone) were analyzed using the multi-analyte stable isotope dilution method (LC-MS/MS). Measurement results from healthy subjects were used to determine reference ranges, and those from placebo patients to predict in-hospital mortality. MEASUREMENTS AND MAIN RESULTS: Corticotropin tests from 180 patients and 20 volunteers were included. Compared to healthy subjects, patients with sepsis had elevated levels of 11-desoxycorticosterone and 11-desoxycortisol, consistent with activation of both glucocorticoid and mineralocorticoid pathways. After stimulation with corticotropin, the cortisol response was subnormal in 12% and the corticosterone response in 50% of sepsis patients. In placebo patients (n = 90), a corticotropin-stimulated cortisol-to-corticosterone ratio > 32.2 predicted in-hospital mortality (AUC 0.8 CI 0.70-0.88; sensitivity 83%; and specificity 78%). This ratio also predicted risk of shock development and 90-day mortality. CONCLUSIONS: In this exploratory analysis, we found that in sepsis mineralocorticoid steroidogenesis was more frequently impaired than glucocorticoid steroidogenesis. The corticotropin-stimulated cortisol-to-corticosterone ratio predicts the risk of in-hospital death. Trial registration Clinical trial registered with www. CLINICALTRIALS: gov Identifier: NCT00670254. Registered 1 May 2008, https://clinicaltrials.gov/ct2/show/NCT00670254 .

Associations of residential greenness, ambient air pollution, biological sex, and glucocorticoids levels in rural China.

AIMS: To evaluate the associations between residential greenness and glucocorticoid levels and whether air pollutants and sex modify the relationship between greenness and glucocorticoid level in Chinese rural adults. METHODS: We collected cross-sectional survey data from 6055 participants from the Henan Rural cohort. The three-year average residential greenness for participants was assessed using normalized difference vegetation index (NDVI) values from a satellite platform. Liquid chromatography-tandem mass spectrometry was employed to quantify the concentrations of glucocorticoids, which were measured by morning blood draw after at least 8 hr of fasting. A random forest model was employed to obtain the average concentrations of PM1, PM2.5, and PM10. A general linear regression model was performed to estimate the associations of NDVI500-m values with cortisol, 11-deoxycortisol, and cortisone. Furthermore, interaction plots were used to present the interaction effects of particulate matter, sex, and green space on glucocorticoid levels. RESULTS: After adjusting for multiple variables, an elevated average NDVI500-m value in the total population was associated with a decrease in cortisol levels (ß = -0.063, 95 % confidence interval (CI): - 0.118, - 0.008), and 11-deoxycortisol levels (ß = -0.118, 95 % CI: -0.190, -0.047), as well as an increase in cortisone levels (ß = 0.130, 95 % CI: 0.079, 0.181). By adding the interaction terms of air pollutants and residential greenness into the regression model, interaction effects between air pollutants and residential greenness were found (cortisol, PM2.5: P interaction=:0.018; PM10: P interaction=0.016; 11-deoxycortisol, all pollutants: P interaction< 0.001), suggesting that the protective effect of residential greenness on serum glucocorticoids disappeared accompanying with increased concentrations of particulate matter. Moreover, trends towards modification in the association between green space and glucocorticoid levels were also evident by sex, but these did not reach statistical significance (for all glucocorticoids: P interaction> 0.05). CONCLUSION: Long-term exposure to green space was negatively correlated with cortisol and 11-deoxycortisol levels, and positively correlated with cortisone levels. There may be sex differences in these associations. Moreover, the protective effect of residential greenness on serum glucocorticoids was altered by high levels of particulate matter.

Topical Clascoterone for Acne Vulgaris.

The pathogenesis of acne is multifactorial and involves inflammation, bacterial dysbiosis, and androgen stimulation. Existing systemic therapies target hormonal pathways to mitigate acne lesions; however, their use is limited to the female population and associated with systemic adverse effects. Clascoterone is the first topical therapy to target the hormonal pathogenesis of acne approved to treat acne vulgaris. In two identical phase 3 trials, clascoterone showed favorable efficacy over placebo in treating acne, with higher treatment success and a greater reduction in acne lesions. Large scale trials are required to assess the efficacy of clascoterone against its comparators and in combination with existing acne therapies; however, results from the current phase 3 trials support the therapeutic value of clascoterone, suggesting that this novel topical androgen inhibitor represents a valuable addition to the catalogue of acne therapy.

Reassessment of predictive values of ACTH-stimulated serum 21-deoxycortisol and 17-hydroxyprogesterone to identify CYP21A2 heterozygote carriers and nonclassic subjects.

INTRODUCTION: Heterozygotes (HZs) for 21-hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complex and narrowly available. Adrenocorticotropic hormone (ACTH)-stimulated serum 17-hydroxyprogesterone (17P) and 21-deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS/MS). OBJECTIVE: This study was performed to reassess former LC-MS/MS-defined post-ACTH 21DF, 17P and cortisol (F) cutoffs in family members at risk for 21OHD. DESIGN AND PATIENTS: Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post-ACTH steroid phenotypes with subsequent genotypes. RESULTS: Post-ACTH 21DF, 17P, F and (21DF + 17P)/F ratio segregate NC, HZ and wild-type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve-defined cutoffs for post-ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty-six of 33 HZ and all 6 NC (82.1%) had post-ACTH 21DF > 60 and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post-ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively. CONCLUSIONS: Reassessed ACTH-stimulated 21DF and 17P cutoffs by LC-MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor-to-product ratio ([21DF + 17P]/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.

11-Deoxycortisol is a stress responsive and gluconeogenic hormone in a jawless vertebrate, the sea lamprey (Petromyzon marinus).

Although corticosteroid-mediated hepatic gluconeogenic activity in response to stress has been extensively studied in fishes and other vertebrates, there is little information on the stress response in basal vertebrates. In sea lamprey (Petromyzon marinus), a representative member of the most basal extant vertebrate group Agnatha, 11-deoxycortisol and deoxycorticosterone are the major circulating corticosteroids. The present study examined changes in circulating glucose and 11-deoxycortisol concentrations in response to a physical stressor. Furthermore, the gluconeogenic actions of 11-deoxycortisol and deoxycorticosterone were examined. Within 6 h of exposure of larval and juvenile sea lamprey to an acute handling stress, plasma 11-deoxycortisol levels increased 15- and 6-fold, respectively, and plasma glucose increased 3- and 4-fold, respectively. Radiometric receptor binding studies revealed that a corticosteroid receptor (CR) is present in the liver at lower abundance than in other tissues (gill and anterior intestine) and that the binding affinity of the liver CR was similar for 11-deoxycortisol and deoxycorticosterone. Transcriptional tissue profiles indicate a wide distribution of cr transcription, kidney-specific transcription of steroidogenic acute regulatory protein (star) and liver-specific transcription of phosphoenolpyruvate carboxykinase (pepck). Ex vivo incubation of liver tissue with 11-deoxycortisol resulted in dose-dependent increases in pepck mRNA levels. Finally, intraperitoneal administration of 11-deoxycortisol and deoxycorticosterone demonstrated that only 11-deoxycortisol resulted in an increase in plasma glucose. Together, these results provide the first direct evidence for the gluconeogenic activity of 11-deoxycortisol in an agnathan, indicating that corticosteroid regulation of plasma glucose is a basal trait among vertebrates.