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.

Diagnostic performance of morning serum cortisol as an alternative to short synacthen test for the assessment of adrenal reserve; a retrospective study.

OBJECTIVE: The short synacthen test (SST) is widely used across the UK to assess adrenal reserve. The main objective of our study was to determine the morning serum cortisol level that will predict adrenal insufficiency (AI) thus reducing our reliance on SST. DESIGN: This was a single centre retrospective study of 393 SST tests measuring 0 and 60 min cortisol levels after administration of 250 µg of synacthen (synthetic ACTH). PATIENTS AND METHODS: All the SST tests for patients suspected of primary or secondary AI between April 2016 and October 2018 were included in this study. We used serum to determine circulating cortisol by a newer generation competitive electrochemiluminescence immunoassay (ECLIA) (Roche Diagnostics). A post-ACTH cortisol response of ≥420 nmol/L at 60 min was considered adequate to rule out AI. The data were analysed to ascertain the relationship between 0 min and 60 min serum cortisol. RESULTS: A total of 393 SST results were included in this study. Overall, a total of 332 (84.5%) subjects achieved sufficient serum cortisol level at 60 min, while 61 subjects (15.5%) showed insufficient response. Using the logistic regression, we determined that a morning basal serum cortisol level of ≥354 nmol/L was able to predict normal adrenal function with 100% sensitivity. We were unable to find a lower cut-off value below which SST will not be required. By using this proposed cut-off point, approximately 37% of the SSTs tests could be avoided. CONCLUSIONS: Basal morning serum cortisol can be safely used as a first step in the evaluation of patients with suspected AI. This will enhance the number of patients being screened for this condition.

Selective Glucocorticoid Replacement Following Unilateral Adrenalectomy for Hypercortisolism and Primary Aldosteronism.

CONTEXT: An institutional study previously demonstrated that cosyntropin stimulation testing on postoperative day 1 (POD1-CST) identified patients at risk for adrenal insufficiency (AI) following unilateral adrenalectomy (UA) for adrenal-dependent hypercortisolism (HC) and primary aldosteronism (PA), allowing for selective glucocorticoid replacement (GR). OBJECTIVE: This study re-evaluates the need for GR following UA for patients with HC and PA in a larger cohort. METHODS: A prospective database identified 108 patients who underwent UA for mild autonomous cortisol excess (MACE) (n = 47), overt hypercortisolism (OH) (n = 27), PA (n = 22), and concurrent PA/HC (n = 12) from September 2014 to October 2020; all underwent preoperative evaluation for HC. MACE was defined by the 1 mg dexamethasone suppression test (cortisol >1.8 µg/dL), with ≥5 defined as OH. GR was initiated for basal cortisol ≤5 or stimulated cortisol ≤14 (≤18 prior to April 2017) on POD1-CST. RESULTS: Fifty-one (47%) patients had an abnormal POD1-CST; 54 (50%) were discharged on GR (27 MACE, 20 OH, 1 PA, 6 PA/HC). Median duration of GR was OH: 6.0 months, MACE: 2.1 months, PA: 1 month, PA/HC: 0.8 months. Overall, 26% (n = 7) of patients with OH and 43% (n = 20) of patients with MACE did not require GR. Two (2%) patients with OH had normal POD1-CST but developed AI several weeks postoperatively requiring GR. None experienced life-threatening AI. CONCLUSION: POD1-CST identifies patients with HC at risk for AI after UA, allowing for selective GR. One-quarter of patients with OH and nearly half of patients with MACE can forgo GR after UA. Patients with PA do not require evaluation for AI if concurrent HC has been excluded preoperatively.

Repeat Adrenal Vein Sampling in Aldosteronism: Reproducibility and Interpretation of Persistently Discordant Results.

CONTEXT: The reproducibility of adrenal vein sampling (AVS) is unknown. OBJECTIVE: This work aimed to determine reproducibility of biochemical results and diagnostic lateralization in patients undergoing repeat AVS. METHODS: A retrospective chart review was conducted of single-center, single-operator AVS procedures at a tertiary care center. Included were patients with confirmed primary aldosteronism (PA) undergoing repeat AVS because of concerns about technical success or discordant diagnostic results. Simultaneous AVS was performed by an experienced operator using a consistent protocol of precosyntropin and postcosyntropin infusion. Among successfully catheterized adrenal veins (selectivity index ≥ 2), the correlation of the adrenalaldosterone/cortisol (A/C) ratio was measured between the first and second AVS. The secondary outcome measure was diagnostic agreement on repeat AVS lateralization (lateralization index ≥ 3). RESULTS: There were 46 sets of AVS from 23 patients at a median of 3 months apart. There was moderate correlation in A/C ratios in the adrenal veins and inferior vena cava (Spearman r = 0.49-0.59, P < .05) pre cosyntropin. Post cosyntropin, the correlation was better (Spearman r = 0.67-0.76, P < .05). In technically successful AVS, there was moderate correlation between the repeated lateralization indices (Spearman r = 0.53, P < .05). In 15 patients in whom repeat AVS was performed because of apparent lateralization discordance with computed tomography imaging, the final diagnosis was the same in the second AVS procedure. Initial failed AVS was successful 75% of the time on repeat attempt. CONCLUSION: Repeat AVS was feasible and usually successful when an initial attempt failed. There was modest correlation between individual repeat adrenal A/C ratios and lateralization indices when AVS was performed twice. The final lateralization diagnosis was identical in all cases. This demonstrates that AVS is a reliable and reproducible localizing test in PA.

Comparison of Steroidogenic Exposure Following the Administration of Repository Corticotropin Injection With a Synthetic ACTH1-24 Depot and Methylprednisolone in Healthy Subjects.

The pharmacokinetics (PK) and pharmacodynamics (PD) of clinically relevant doses of repository corticotropin injection (Acthar Gel) and synthetic ACTH1-24 depot have not been fully characterized. We compared the steroidogenic exposure of repository corticotropin injection and synthetic ACTH1-24 depot in healthy adults at therapeutic doses using data from 2 separate phase 1 studies. Subjects were randomly assigned to repository corticotropin injection 40 or 80 IU subcutaneously twice weekly or 80 IU subcutaneously 3 times weekly for 15 days or to daily synthetic ACTH1-24 depot doses of 0.5 mg subcutaneously, 0.75 mg subcutaneously, 1 mg subcutaneously, or 1 mg intramuscularly for 5 days. A population PK/PD model was developed to simulate the free cortisol exposure of a clinically relevant dose of synthetic ACTH1-24 depot (1 mg subcutaneously twice weekly). Study drug doses were converted to methylprednisolone-equivalent doses using the steroidogenic exposure of methylprednisolone 16 mg daily as a conversion factor. Doses were also converted to prednisone equivalents using a coefficient of 1.25. These analyses revealed that the steroidogenic exposure of repository corticotropin injection at clinically relevant doses was substantially lower than that for synthetic ACTH1-24 depot. The 3 repository corticotropin injection regimens were equivalent to approximately 5, 8, and 16 mg of daily prednisone, respectively. On the basis of simulated free cortisol exposure, synthetic ACTH1-24 depot 1 mg subcutaneously twice weekly was comparable to 57 mg of daily prednisone. These results suggest that repository corticotropin injection has pharmacological effects that cannot be considered identical to synthetic ACTH1-24 depot.

ACTH Treatment of Infantile Spasms: Low-Moderate- Versus High-Dose, Natural Versus Synthetic ACTH-A Retrospective Cohort Study.

BACKGROUND: High dosages of natural adrenocorticotropic hormone are used in many centers in the United States for the treatment of infantile spasms. However, lower dosages of synthetic adrenocorticotropic hormone (tetracosactide) might be equally efficient as high dosages. We analyzed the treatment options for infantile spasms, especially regarding the adrenocorticotropic hormone dosage and the formulation (natural versus synthetic) and evaluated which options were more effective in a retrospective cohort from 1960 to 1976. METHODS: We compared the short-term response rates of patients treated with high dosages of natural adrenocorticotropic hormone (120 IU/day) (N = 31) (Group1) with those of patients treated with low-moderate dosages of natural adrenocorticotropic hormone (40 IU/day) (N = 52) (Group2). We also compared the short-term response rates of patients treated with natural adrenocorticotropic hormone (N = 83) with those of patients treated with synthetic adrenocorticotropic hormone, (N = 23) (Group3). The responses were evaluated clinically and by electroencephalography at two to three weeks after the onset of therapy. RESULTS: A response was seen in 24 of 31 children treated with high dosages and in 43 of 52 children treated with low-moderate dosages of natural adrenocorticotropic hormone (P = 0.56). All children with an unknown etiology responded to both high and low-moderate dosages of natural adrenocorticotropic hormone. The proportion of children with a good early response to synthetic adrenocorticotropic hormone (16 of 23) did not differ from the proportion of children with a good early response treated with natural adrenocorticotropic hormone (67 of 83) (P = 0.25). CONCLUSIONS: High dosages of adrenocorticotropic hormone are not more effective than low-moderate dosages in the short term for treating infantile spasms. Synthetic adrenocorticotropic hormone is equally effective as natural adrenocorticotropic hormone.

The Concordance Between Imaging and Adrenal Vein Sampling Varies With Aldosterone-Driver Somatic Mutation.

BACKGROUND: Correct subtyping of primary aldosteronism (PA) is critical for guiding clinical management. Adrenal imaging is less accurate than adrenal vein sampling (AVS); nonetheless, AVS is invasive, technically challenging, and scarcely available. OBJECTIVE: To identify predictors of concordance between cross-sectional imaging and lateralized AVS in patients with PA that could help circumvent AVS in a subset of patients. METHODS: We retrospectively studied all patients with PA who underwent AVS in a tertiary referral center from 2009 to 2019. AVS was performed before and after cosyntropin stimulation. Patients with lateralized AVS in at least one condition were included. Aldosterone synthase-guided next-generation sequencing was performed on available adrenal tissue. Logistic regression was implemented to identify predictors of imaging-AVS lateralization concordance. RESULTS: A total of 234 patients (62% men), age 20 to 79 years, 73% white, 23% black, and 2% Asian were included. AVS lateralization was found: 1) both pre- and post-cosyntropin (Uni/Uni) in 138 patients; 2) only at baseline (Uni/Bi) in 39 patients; 3) only after cosyntropin stimulation (Bi/Uni) in 29 patients. Catheterization partially failed in 28 patients. AVS-imaging agreement was higher in patients with KCNJ5 versus other aldosterone-driver somatic mutations (90.3% versus 64.6%; P < 0.001); in Asian and white versus black Americans (75%, 70%, and 36%, respectively); in younger patients; and those with left adrenal nodules and contralateral suppression. Conversely, AVS-imaging agreement was lowest in Uni/Bi patients (38% vs. 69% in Uni/Uni, and 62% in Bi/Uni; P = 0.007). CONCLUSIONS: While AVS-imaging agreement is higher in young white and Asian patients, who have KCNJ5-mutated aldosterone producing adenomas, no predictor confers absolute imaging accuracy.

Pharmacodynamic studies of nasal tetracosactide with salivary glucocorticoids for a noninvasive Short Synacthen Test.

CONTEXT: The Short Synacthen Test (SST) is the gold standard for diagnosing adrenal insufficiency. It requires invasive administration of Synacthen, venous sampling, and is resource-intensive. OBJECTIVE: To develop a nasally administered SST, with salivary glucocorticoids measurement, to assess the adrenal response. DESIGN: We conducted 5 studies: 4 open-label, sequence-randomized, crossover, pharmacodynamic studies testing 6 doses/formulations and a repeatability study. Additionally, pharmacokinetic analysis was undertaken using our chosen formulation, 500 µg tetracosactide with mucoadhesive chitosan, Nasacthin003, in our pediatric study. SETTING: Adult and children's clinical research facilities. PARTICIPANTS: A total of 36 healthy adult males and 24 healthy children. INTERVENTION: We administered all 6 nasal formulations using an European regulator endorsed atomization device. The IV comparators were 250 µg or 1 µg SST. MAIN OUTCOME MEASURES: We analyzed paired blood and saliva samples for plasma cortisol and salivary cortisol and cortisone. RESULTS: The addition of chitosan to tetracosactide and dose escalation increased peak cortisol response (P = 0.01 and 0.001, respectively). The bioavailability of Nasacthin003 was 14.3%. There was no significant difference in plasma cortisol at 60 minutes between 500 µg Nasacthin003 and 250 µg IV Synacthen (P = 0.17). The repeatability coefficient at 60 minutes was 105 nmol/L for IV Synacthen and salivary cortisol and cortisone was 10.3 and 21.1 nmol/L, respectively. The glucocorticoid response in children was indistinguishable from that of adults. CONCLUSIONS: Nasal administration of Nasacthin003 generates equivalent plasma cortisol values to the 250-µg IV SST and, with measurement at 60 minutes of salivary cortisol or cortisone, provides a noninvasive test for adrenal insufficiency.

Androgen excess and diagnostic steroid biomarkers for nonclassic 21-hydroxylase deficiency without cosyntropin stimulation.

OBJECTIVES: The clinical presentation of patients with nonclassic 21-hydroxylase deficiency (N21OHD) is similar with that for other disorders of androgen excess. The diagnosis of N21OHD typically requires cosyntropin stimulation. Additionally, the management of such patients is limited by the lack of reliable biomarkers of androgen excess. Herein, we aimed to: (1.) compare the relative contribution of traditional and 11-oxyandrogens in N21OHD patients and (2.) identify steroids that accurately diagnose N21OHD with a single baseline blood draw. DESIGN: We prospectively enrolled patients who underwent a cosyntropin stimulation test for suspected N21OHD in two tertiary referral centers between January 2016 and August 2019. METHODS: Baseline sera were used to quantify 15 steroids by liquid chromatography-tandem mass spectrometry. Logistic regression modeling was implemented to select steroids that best discriminate N21OHD from controls. RESULTS: Of 86 participants (72 females), median age 26, 32 patients (25 females) had N21OHD. Age, sex distribution, and BMI were similar between patients with N21OHD and controls. Both testosterone and androstenedione were similar in patients with N21OHD and controls, while four 11-oxyandrogens were significantly higher in patients with N21OHD (ratios between medians: 1.7 to 2.2, P < 0.01 for all). 17α-Hydroxyprogesterone (6.5-fold), 16α-hydroxyprogesterone (4.1-fold), and 21-deoxycortisol (undetectable in 80% of the controls) were higher, while corticosterone was 3.6-fold lower in patients with N21OHD than in controls (P < 0.001). Together, baseline 17α-hydroxyprogesterone, 21-deoxycortisol, and corticosterone showed perfect discrimination between N21OHD and controls. CONCLUSIONS: Adrenal 11-oxyandrogens are disproportionately elevated compared to conventional androgens in N21OHD. Steroid panels can accurately diagnose N21OHD in unstimulated blood tests.

ACTH Infusion Impairs Baroreflex Sensitivity-Implications for Cardiovascular Hypoglycemia-Associated Autonomic Failure.

CONTEXT: Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality. OBJECTIVE: The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1-24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day. DESIGN: A double-blind, placebo-controlled, random-order, cross-over study was conducted. SETTING: This study took place in a clinical research center. PARTICIPANTS: Participants included healthy men and women. INTERVENTIONS: Interventions included an intravenous infusion of cosyntropin (70 µg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo. MAIN OUTCOME MEASURES: Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions. RESULTS: Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ±â€…1.38 vs 17.0 ±â€…2.07; during 14.4 ±â€…1.43 vs 17.3 ±â€…1.65; and next day 14.8 ±â€…1.42 vs 18.9 ±â€…2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected. CONCLUSIONS: ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

Adrenal function evaluation in critically ill dogs with low doses of synthetic ACTH / Avaliação da função adrenal em cães portadores de doenças críticas com baixa dose de ACTH sintético

The hypothalamus-pituitary-adrenal axis function may be impaired in patients with critical illnesses, especially cases of sepsis, named critical illness-related corticosteroid insufficiency (CIRCI). This study examined the function of the hypothalamic-pituitary-adrenal axis in normal dogs (n = 10) and dogs with critical diseases (n = 16), through determinations of endogenous ACTH (adrenocorticotropic hormone), basal cortisol and cortisol after stimulation in low doses of synthetic ACTH (1.0µg/kg/IV). The stimulation test with ACTH dose tested was verified as effective for evaluation of adrenal function in healthy and sick dogs. Ill dogs differed from healthy dogs by presenting higher basal cortisol values. Eight sick dogs presented a decrease in endogenous ACTH, basal cortisol, or Δ-cortisol. No significant differences were found between the control groups and critically ill dogs for the values of endogenous ACTH, cortisol after stimulation or Δ-cortisol. We concluded that the stimulation test with low-dose ACTH was effective for evaluation of adrenal function, as well as the fact that a considerable portion of critically ill dogs studied here, especially with sepsis, had evidence of inadequate corticosteroid response to stress.(AU)

A função do eixo hipotálamo-hipófise-adrenal pode estar comprometida em pacientes com doenças críticas, em especial casos de sepse, sendo nomeada de Insuficiência Corticosteroide Relacionada à Doença Crítica (ICRDC). O presente trabalho analisou a função do eixo hipotálamo-hipófise-adrenal em cães normais (n=10) e cães portadores de doenças críticas (n=16), por meio de determinações de ACTH (hormônio adrenocorticotrófico) endógeno, de cortisol basal e de cortisol após estímulo com baixa dose de ACTH sintético (1,0µg/kg/IV). Constatou-se que o teste de estimulação com ACTH na dose testada se mostrou eficaz para avaliação da função adrenal em cães sadios e doentes. Os cães doentes diferiram dos sadios ao apresentar valores maiores de cortisol basal. Oito cães doentes apresentaram diminuição do ACTH endógeno, do cortisol basal ou do Δ-cortisol. Não foram encontradas diferenças significativas entre os grupos Controle e Criticamente enfermos para os valores de ACTH endógeno, cortisol após estimulação ou Δ-cortisol. Concluiu-se que o teste de estimulação com baixa dose de ACTH mostrou-se eficaz para avaliação da função adrenal, assim como, uma parcela considerável da população de cães críticos aqui estudados, em especial com sepse, apresentaram evidências de resposta corticosteroide inadequada frente ao estresse.(AU)

Utility of microcatheter in adrenal venous sampling for primary aldosteronism.

OBJECTIVE: To evaluate the utility of microcatheter in adrenal venous sampling (AVS) for assessing aldosterone hypersecretion and the laterality in patients with primary aldosteronism. METHODS: This retrospective study was approved by the institutional review board of Gifu University Hospital, and written informed consent was waived. A total of 37 consecutive patients with primary aldosteronism underwent AVS by inserting a microcatheter into the right adrenal central vein (RCV), left adrenal central vein (LCV), and left adrenal common trunk (CT) followed by AVS with 5-French (5-Fr) catheter. The diagnosis of aldosterone hypersecretion was confirmed if the plasma aldosterone level after the administration of cosyntropin injection was ≥14,000 pg/ml. The laterality of aldosterone hypersecretion was determined based on the lateralized and contralateral ratios. Aldosterone hypersecretion and the laterality were diagnosed and compared based on the results obtained using 5-Fr catheter and microcatheter. RESULTS: Plasma aldosterone levels were significantly higher in the RCV, LCV, and CT selected using microcatheter than in the right and left adrenal veins (LAVs) selected using 5-Fr catheter (p < 0.0001-0.029). More aldosterone hypersecretion from the left adrenal gland was observed in the LCV (n = 28) and CT (n = 25) selected using microcatheter compared to the LAV selected using 5-Fr catheter (n = 6) (p < 0.0001). Diagnostic changes in the laterality from unilateral to bilateral were noted in 3 (8%) patients using microcatheter. CONCLUSION: Microcatheter can effectively assess aldosterone hypersecretion and the laterality, especially in the LAV. ADVANCES IN KNOWLEDGE: Especially for the left adrenal venous sampling, the tip of microcatheter could certainly reach the left adrenal vein orifice compared with 5-Fr catheter, therefore correct diagnosis is made and this leads to appropriate treatment.

Evaluation of the effectiveness and tolerance of tetracosactide in the treatment of post-dural puncture headaches (ESYBRECHE): a study protocol for a randomised controlled trial.

BACKGROUND: Post-dural puncture headache (PDPH) is one of the most common complications of neuraxial anaesthesia. It limits patients' general activity and increases the length of hospital stays and the use of care. It is particularly disabling during the postpartum period, when mothers have to take care of their child. Epidural blood patch is the standard treatment for PDPH. However, it is an invasive procedure that may result in rare but serious complications. Recent evidence has suggested that adrenocorticotropic hormone (ACTH) is effective in the management of PDPH. The aim of this study is to assess the efficacy and safety of tetracosactide (Synacthen®), a synthetic analogue of ACTH, for PDPH treatment in patients who receive neuraxial anaesthesia during labour. METHODS: This randomised, double-blind, placebo-controlled, parallel-arm trial, is performed in two French university hospitals. Eligible patients are those suffering from postpartum PDPH, who are randomised to receive either 1 mg of tetracosactide intravenously over 20 min or to 0.9% saline (placebo). The primary endpoint is the rate of epidural blood patch within a 15-day follow-up period. Headache duration, pain intensity, reduction of general activity, increase in length of hospital stay, adverse events, analgesic use (type and duration) and number of blood patches per patient in each group are recorded. DISCUSSION: We expect a decrease in the use of epidural blood patch in those receiving tetracosactide, thus indicating a decrease in PDPH symptoms in these patients. This will define the therapeutic success of tetracosactide and the possibility to use this treatment as a non-invasive alternative to blood patch for PDPH treatment. TRIAL REGISTRATION: Primary Registry ClinicalTrials.gov Protocol Registration and Results System Date of Registration 24 June 2016 Unique Protocol ID 69HCL15_0429 Secondary IDs EudraCT Number 2015-003357-17 ClinicalTrials.gov ID NCT02813655 ANSM 160214A-31 Protocol version V4 28/09/2018.

Continuous Free Cortisol Profiles in Healthy Men.

CONTEXT: In humans, approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. It is only the free fraction that is biologically active and can activate signaling pathways via glucocorticoid hormone receptors in cells. Microdialysis is a well-established technique that enables the sampling of molecules in different compartments of the body, including extracellular fluid. This is the first study validating a rapid sampling microdialysis method measuring free cortisol in the subcutaneous and blood compartments of healthy volunteers. METHODS: Healthy nonsmoking volunteers (42 men, aged 18-24 years; body mass index 18-25 kg/m2) received placebo (saline), 250 µg Synacthen, or 1 mg dexamethasone with 10-minute sampling to measure total and free cortisol (subcutaneous, intravenous, and saliva) for an hour before and 4 hours after administration. RESULTS: Following stimulation by Synacthen, total serum cortisol and free cortisol in both compartments rose significantly, achieving and maintaining maximum levels between 2 and 3 hours following the stimulus. A decline in cortisol levels was evident after the administration of dexamethasone or placebo, but there was a clear pulsatile activity around lunchtime in the latter group, which was prominent in the blood compartment (total and free cortisol). There was good correlation between serum total and free cortisol (subcutaneous and intravenous) in the Synacthen and dexamethasone groups with no significant delay (less than 5 minutes) between total and free cortisol. CONCLUSIONS: This seminal study demonstrated the dynamic responses of total blood cortisol and microdialysis derived free cortisol in blood, subcutaneous tissue, and saliva in men.

Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization.

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

Do we need 30 min cortisol measurement in the short synacthen test: a retrospective study.

OBJECTIVE: The short synacthen test (SST) is widely used across the UK to assess adrenal reserve but there remains no consensus on the timing of cortisol sampling to help diagnose adrenal insufficiency. The main objective of our study was to see if both 30 and 60 min sample are required following administration of synacthen to investigate suspected adrenal insufficiency (AI). DESIGN: This was a single-centre retrospective study of 393 SSTs measuring 0, 30 and 60 min cortisol levels after administration of 250 µg of synacthen. PATIENTS AND METHODS: All the SSTs for patients suspected of primary or secondary AI between April 2016 and October 2018 were included in this study. The tests were performed as per our hospital protocol. A post-adrenocorticotropic hormone (ACTH) cortisol response of 420 nmol/L at any time point was considered adequate to rule out AI. The data were analysed to ascertain the proportion of patients who achieved this level at 30 and/or 60 min. RESULTS: A total of 393 SST results were included in this study. Patients were divided into two groups depending on whether (group A) or not (group B) they were on steroids. Overall, a total of 313 (79.6%) subjects achieved cortisol level of ≥420 nmol/L at 30 and 60 min while 19 (4.8%) had late response (ie, insufficient 30 min cortisol levels, rising to ≥420 nmol/L at 60 min). Another 61 subjects (15.5%) showed insufficient response at both 30 and 60 min (ie, failed to achieved level of ≥420 nmol/L). Importantly, there was no patient in either group who had adequate response at 30 min and then failed at 60 min. Patients in group A were more likely to have inadequate response at both 30 and 60 min while patients in group B were more likely to have normal response at both time points. CONCLUSIONS: Our results suggest that about 5% of people undergoing SST may be inappropriately diagnosed as having AI (and subjected to long-term unnecessary steroid treatment) if the 60 min sample is not maintained. We suggest that 30 min sample does not add any additional diagnostic utility and can be omitted thus simplifying SST even further and saving on cost and resources. We propose that single measurement after 60 min of administration of synthetic ACTH is a sufficient screening test for AI.

Comparative evaluation of 30 and 60 minutes cortisol levels during short synacthen test for diagnosis of adrenal insufficiency.

OBJECTIVE: To assess and compare diagnostic value of 30-minute cortisol level over 60-minute level in the diagnosis of adrenal insufficiency. METHODS: The comparative cross-sectional study was conducted at the Armed Forces Institute of Pathology, Rawalpindi, Pakistan, from August 2017 to May 2018, and comprised patients referred to the facility for short synacthen test with suspicion of adrenal insufficiency. Blood samples for serum cortisol were taken at time-0 and then 30 and 60 minutes after the adreno-cortico-tropic hormone injection. Total serum cortisol was measured. Adrenal insufficiency was defined as stimulated cortisol level <500 nmol/l at 30 and 60 minutes post-stimulation. SPSS 24 was used for data analysis. RESULTS: Of the 111 subjects, 56(50.4%) were males and 55(49.5%) were females. Overall mean age was 34±20 years. Mean basal serum cortisol level was 110±98 nmol/l in patients with adrenal insufficiency and it was 294±164 nmol/l in patients with intact adrenal functions. Cortisol level at both 30 and 60 minutes was significant (p<0.001). Receiver Operating Characteristics curve was plotted which showed area under curve of 0.83 and 0.82 for 60 and 30 minutes respectively. CONCLUSIONS: The 30-minute cortisol level post-stimulation carried no diagnostic value . Measuring cortisol level once at 60-minute post-stimulation would be of more value apart from being cost-effective in the diagnosis of adrenal insufficiency.

Enhancement of hypothalamic-pituitary activity in male athletes: evidence of a novel hormonal mechanism of physical conditioning.

BACKGROUND: Exercise is known to induce multiple beneficial conditioning processes. Conversely, although exercise may generate several hormonal effects, an intrinsic hormonal conditioning process has not been reported. In the Endocrine and Metabolic Responses on Overtraining Syndrome (EROS) study, we observed inherent and independent conditioning processes of the hypothalamic-pituitary axes in athletes. Our objective is to describe the theory of the novel hormonal conditioning mechanism using the findings from the EROS study. METHODS: In this cross-sectional study, we selected 25 healthy athletes (ATL) and 12 non-physically active healthy controls (NPAC), 18-50 years old, males, with BMI 20-30 kg/m2, with similar baseline characteristics, who underwent gold-standard exercise-independent tests: cosyntropin stimulation test (CST) and insulin tolerance test (ITT), to evaluate cortisol response to CST, and ACTH, cortisol, GH, and prolactin responses to an ITT. RESULTS: Responses to ITT were significantly earlier and higher in ATL than NPAC for cortisol [Mean ± SD: 21.7 ± 3.1 vs 16.9 ± 4.1 µg/dL; p < 0.001], GH [Median (95% CI): 12.73 (1.1-38.1) vs 4.80 (0.33-27.36) µg/L; p = 0.015], and prolactin [24.3 (10.5-67.45) vs 10.50 (6.21-43.44) ng/mL; p = 0.002]. Cortisol response to CST was similar between ATL and NPAC. During ITT, cortisol, GH, and ACTH mean increase in ATL were 52.2, 265.2, and 18.6% higher than NPAC, respectively. Prolactin response was absent in NPAC, while present in ATL. CONCLUSIONS: We found sufficient evidence to propose the existence of a diffuse enhancement of the hypothalamic-pituitary activity in athletes, not restricted to any axis, showing an intrinsic and independent process of "hormonal conditioning" in athletes, similar to those observed in the cardiovascular and neuromuscular systems. This novel conditioning process may be the missing link for understanding the improved responses observed in athletes to harmful situations, traumas, infections, inflammations, and psychiatric conditions.

Chemical sympathectomy attenuates lipopolysaccharide-induced increase of plasma cytokine levels in rats pretreated by ACTH.

The sympathetic nervous system participates significantly in the regulation of immune functions. In support of this, data indicate that besides vagal afferent and efferent pathway, sympathetic nerves represent crucial component of inflammatory reflex. In addition, it was shown that efferent arm of this reflex might be activated by ACTH. Therefore, we investigated the effect of chemical sympathectomy on lipopolysaccharide (LPS)-induced increases in plasma IL-1ß, IL-6, and TNF-α levels in rats. Plasma IL-10 and corticosterone levels were also evaluated. We also investigated the effect of sympathectomy in rats pretreated with ACTH (1-24). We found that sympathectomy significantly attenuated LPS-induced increases of plasma IL-1ß levels. Administration of ACTH (1-24) reduced LPS-induced increases of plasma IL-1ß and IL-6 and exaggerated the rise of IL-10. In animals treated with ACTH (1-24) sympathectomy attenuated LPS-induced increases of IL-1ß, IL-6, and IL-10 plasma levels. Plasma levels of TNF-α and corticosterone were not affected by any interventions. These data indicate that during acute immune challenge, sympathetic nerves stimulate the immune response. In addition, our data indicate that sympathetic nerves are not significantly involved in the anti-inflammatory effect of ACTH (1-24) and that the anti-inflammatory effect of ACTH (1-24) is independent of plasma corticosterone levels.

Pharmacologically-induced stress has minimal impact on judgement and attention biases in sheep.

The emotional impact of exposure to stressors has not been well quantified in animals. We hypothesised that exogenous induction of stress in sheep would induce a pessimistic judgement bias and increased attention towards a threatening stimulus, suggestive of a negative emotional state. Stress was induced pharmacologically by administering synthetic adrenocorticotropic hormone. Judgement bias was assessed using a spatial go/no-go task after exposure to acute stress (one injection), chronic stress (21 daily injections) and acute-on-chronic stress (2 min isolation after 28 daily injections). Attention bias was assessed during chronic stress only (22 daily injections). In contrast with our hypotheses, there was no strong evidence that Synacthen administration altered judgement bias or attention bias at any stage of the experiment. Stressed sheep were more likely to approach ambiguous locations than saline Control animals, however, statistical evidence for models fitting treatment group was very weak. Overall, our findings suggest that elevated levels of cortisol may not fully explain changes to judgement bias observed in previous studies after environmentally-induced stress. Further studies are required to better understand which aspects of environmentally-induced stress alter judgement bias and to further validate cognitive methods of assessing affect in sheep.