Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment.

CONTEXT: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. OBJECTIVE: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. DESIGN AND SETTING: Cross-sectional study conducted in a tertiary medical center. PARTICIPANTS: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). MEASUREMENTS: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). MAIN OUTCOME MEASURES: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. RESULTS: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). CONCLUSIONS: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Impact of loneliness on diurnal cortisol in youth.

Loneliness is associated with multiple forms of psychopathology in youth. However, we do not yet know how loneliness gets "under the skin" in ways that may impact the long-term health and development of early adolescents. In particular, loneliness may influence youths' patterns of diurnal cortisol, an index of hypothalamic-pituitary-adrenal (HPA) axis functioning and a central predictor of health across the lifespan. The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2, or COVID-19) pandemic represents a salient period in which to study the consequences of loneliness, as recent work has provided evidence that the physical-distancing measures put in place to contain the virus have resulted in greater loneliness, particularly among youth. Thus, the current study aimed to examine the prospective association between loneliness during the COVID-19 pandemic and diurnal cortisol in early adolescents. We found that greater loneliness was associated with higher levels of cortisol at waking and a blunted cortisol awakening response (CAR). These results held even when controlling for covariates that can influence diurnal trajectories of cortisol. Critically, this pattern of HPA-axis functioning increases risk for adverse mental and physical health outcomes across adolescence and into adulthood. This study is the first to examine the prospective association between loneliness and diurnal cortisol in early adolescence, and the first to identify mechanisms that contribute to biological markers of distress during the COVID-19 pandemic. Findings underscore the importance of developing and distributing strategies to mitigate feelings of loneliness among youth.

Normal Adrenal and Thyroid Function in Patients Who Survive COVID-19 Infection.

CONTEXT: The COVID-19 pandemic continues to exert an immense burden on global health services. Moreover, up to 63% of patients experience persistent symptoms, including fatigue, after acute illness. Endocrine systems are vulnerable to the effects of COVID-19 as many glands express the ACE2 receptor, used by the SARS-CoV-2 virion for cellular access. However, the effects of COVID-19 on adrenal and thyroid gland function after acute COVID-19 remain unknown. OBJECTIVE: Our objectives were to evaluate adrenal and thyroid gland function in COVID-19 survivors. METHODS: A prospective, observational study was undertaken at the Clinical Research Facility, Imperial College NHS Healthcare Trust, including 70 patients ≥18 years of age, at least 3 months after diagnosis of COVID-19. Participants attended a research study visit (8:00-9:30 am), during which a short Synacthen test (250 µg IV bolus) and thyroid function assessments were performed. RESULTS: All patients had a peak cortisol ≥450 nmol/L after Synacthen, consistent with adequate adrenal reserve. Basal and peak serum cortisol did not differ according to disease severity or history of dexamethasone treatment during COVID-19. There was no difference in baseline or peak cortisol after Synacthen or in thyroid function tests, or thyroid status, in patients with fatigue (n = 44) compared to those without (n = 26). CONCLUSION: Adrenal and thyroid function ≥3 months after presentation with COVID-19 was preserved. While a significant proportion of patients experienced persistent fatigue, their symptoms were not accounted for by alterations in adrenal or thyroid function. These findings have important implications for the clinical care of patients after COVID-19.

New onset adrenal insufficiency in a patient with COVID-19.

SARS-CoV-2 is the cause of COVID-19. Since the outbreak and rapid spread of COVID-19, it has been apparent that the disease is having multi-organ system involvement. Still its effect in the endocrine system is not fully clear and data on cortisol dynamics in patients with COVID-19 are not yet available. SARS-CoV-2 can knock down the host's cortisol stress response. Here we present a case of a 51-year-old man vomiting for 10 days after having confirmed COVID-19 infection. He had hypotension and significant hyponatraemia. Work-up was done including adrenocorticotropic hormone stimulation test. He was diagnosed as suffering from adrenal insufficiency and started on steroids with subsequent improvement in both blood pressure and sodium level. COVID-19 can cause adrenal insufficiency. Clinicians must be vigilant about the possibility of an underlying relative cortisol deficiency in patients with COVID-19.

Approach to the Patient with Primary Aldosteronism: Utility and Limitations of Adrenal Vein Sampling.

Several studies over the past 3 decades document a higher prevalence of primary aldosteronism (PA) among hypertensive patients than generally presumed. PA exists as a spectrum from mild to severe aldosterone excess. Although a variety of PA subtypes exist, the 2 most common are aldosterone-producing adenomas (APAs) and bilateral hyperaldosteronism (BHA). The distinction is important, because APA-and other subtypes, with aldosterone production mostly from 1 adrenal-can be cured surgically, and BHA should be treated medically with mineralocorticoid-receptor antagonists (MRAs). The major shortcomings in the tailored management of patients with possible PA are the low rates of screening for case identification and the expensive and technically challenging imaging and interventional procedures required to distinguish APA from BHA, especially adrenal vein sampling (AVS). When AVS identifies an APA and allows the patient to be cured surgically, the procedure is of great value. In contrast, the patient with BHA is treated with MRA whether AVS is performed or not. Consequently, it is prudent to gauge how likely it is to benefit from imaging and AVS in each case prior to embarking on these studies. The explosion of information about PA in the past decade, including predictors of APA and of surgical benefit, are useful in limiting the evaluation for some patients with a positive PA screening test. This article will review our suggestions for approaching these patients in a pragmatic style, recognizing the limitations to even the best resources and facilities.

Cortisol and Dehydroepiandrosterone Response to Adrenocorticotropic Hormone and Frailty in Older Women.

BACKGROUND: The response to adrenocorticotropic hormone (ACTH) is poorly characterized in old-old adults and may provide insight into the physiologic response to stress. METHOD: We performed a standard 250 µg ACTH stimulation test in a home-based substudy of 51 women aged 85-96 years enrolled in the Women's Health and Aging Study II who were not taking corticosteroids. We examined the cortisol and dehydroepiandrosterone (DHEA) responses at 0, 30, 60, and 120 minutes, overall and by frailty status. RESULTS: The peak cortisol response to ACTH could not be determined, with the highest levels at the 120-minute time point. Pre- and post-ACTH stimulated cortisol levels did not differ by frailty status over this time frame, with no difference in the characteristics of the dose-response curves. Pre- and post-ACTH stimulated DHEA levels also did not differ by frailty status, though the dose-response curves suggested divergence after stimulation, with a more rapid DHEA response with increasing frailty. CONCLUSIONS: Our data demonstrate a robust cortisol response to ACTH challenge testing, but inadequate negative feedback in old-old women, resulting in prolonged exposure to cortisol. Future studies should examine dynamic cortisol and DHEA responses in this age group, using a less potent ACTH stimulus and longer collection period.

Abnormal Dexamethasone Suppression Tests in a Rifapentine-Treated Patient With Primary Aldosteronism.

Aldosterone-producing adenoma (APA) is a main cause of primary aldosteronism (PA). Given that a large benign-appearing unilateral masse (>1 cm in diameter) may represent an aldosterone and cortisol-co-secreting adenoma, dexamethasone suppression testing is required in such patients to exclude or confirm the diagnosis of hypercortisolism. Tuberculosis is highly prevalent in China, and rifamycins are often used in these patients. Rifapentine belongs to the rifamycin family, and we herein for the first time report a case of misdiagnosis of hypercortisolism due to rifapentine use in a patient with APA. Thus, in patients treated with rifapentine, diagnosis of hypercortisolism based on dexamethasone suppression tests can be very misleading.

Human Corticotropin-Releasing Hormone Tests: 10 Years of Real-Life Experience in Pituitary and Adrenal Disease.

CONTEXT: The human corticotropin-releasing hormone (CRH) test (hCRHtest) is used to differentiate Cushing disease (CD) from ectopic adrenocorticotropin (ACTH) secretion (EAS), to assess autonomous cortisol secretion by the adrenal glands, and to characterize pseudo-Cushing syndrome (CS) or adrenal insufficiency (AI). MAIN OUTCOME MEASURE: The main outcome measure of this study was to assess the diagnostic accuracy of the hCRHtest. METHODS: We measured ACTH and cortisol levels; collected the peak values (peakACTH and peakcortisol), and calculated the percentage increases (∆%ACTH and ∆%cortisol) after an intravenous bolus of 100 µg hCRH. DESIGN AND SETTING: This cross-sectional study of hCRH tests from 2010 to 2019 took place in a referral university hospital center. PATIENTS: We enrolled 200 patients: 86 CD, 15 EAS, 18 adrenal CS, 25 mild adrenal autonomous cortisol secretion, 31 pseudo-CS, and 25 suspected AI. RESULTS: The hCRHtest was performed mainly for the differential diagnosis of ACTH-dependent CS or adrenal lesions (P = .048). PeakACTH and peakcortisol were higher in CD, and ∆%ACTH and ∆%cortisol were able to differentiate CD from EAS with a sensitivity and specificity greater than 80%. In patients with low (< 10 pg/mL) or indeterminate (10-20 pg/mL) basalACTH levels, an absent or reduced peakACTH response was able to differentiate adrenal from ACTH-dependent forms. PeakACTH and peakcortisol after hCRHtest were lower in pseudo-CS than in CD, but ∆%ACTH and ∆%cortisol were similar. The role of hCRHtest in patients with AI was limited. CONCLUSIONS: The hCRHtest test is the mainstay of the differential diagnosis of ACTH-dependent CS. It is also useful for pointing to a diagnosis of CD in the event of bilateral adrenal masses, and in patients with low basalACTH.

Reference ranges of late-night salivary cortisol and cortisone measured by LC-MS/MS and accuracy for the diagnosis of Cushing's syndrome.

PURPOSE: International guidelines recommend salivary cortisol for the diagnosis of Cushing's syndrome. Despite mass spectrometry-based assays are considered the analytical gold-standard, there is still the need to define reference intervals and diagnostic accuracy of such methodology. METHODS: 100 healthy volunteers and 50 consecutive patients were enrolled to compare LC-MS/MS and electrochemiluminescence assay for the determination of late-night salivary cortisol and cortisone. Moreover, we aimed to determine reference intervals of salivary steroids in a population of healthy individuals and diagnostic accuracy in patients with suspected hypercortisolism and in a population including also healthy individuals. RESULTS: Method comparison highlighted a positive bias (51.8%) of immunoassay over LC-MS/MS. Reference intervals of salivary cortisol (0.17-0.97 µg/L), cortisone (0.84-4.85 µg/L) and ratio (0.08-0.30) were obtained. The most accurate thresholds of salivary cortisol for the diagnosis of hypercortisolism were 1.15 µg/L in the population with suspected hypercortisolism (AUC 1) and 1.30 µg/L in the population including also healthy individuals (AUC 1). Cut-off values of salivary cortisone (7.23 µg/L; Se 92.9%, Sp 97.2%, AUC 0.960 and Se 92.9%, Sp 99.1%, AUC 0.985 in suspected hypercortisolism and in overall population, respectively) and cortisol-to-cortisone ratio (0.20; Se 85.7%, Sp 80.6%, AUC 0.820 and Se 85.7%, Sp 85.5%, AUC 0.855 in suspected hypercortisolism and in overall population, respectively) were accurate and similar in both populations. CONCLUSION: LC-MS/MS is the most accurate analytical platform for measuring salivary steroids. Obtained reference intervals are coherent with previously published data and diagnostic accuracy for diagnosis of overt hypercortisolism proved highly satisfactory.

Alcohol Use Disorder Masks the Effects of Childhood Adversity, Lifetime Trauma, and Chronic Stress on Hypothalamic-Pituitary-Adrenal Axis Reactivity.

BACKGROUND: Individuals with alcohol use disorder (AUD) and those who have experienced traumas or chronic stress exhibit dysregulated hypothalamic-pituitary-adrenal (HPA) axis reactivity. Whether and how trauma and stress histories interact with AUD to affect HPA axis reactivity has not been assessed. METHODS: In the present study, 26 healthy male controls and 70 abstinent men with AUD were administered a pharmacologic probe [ovine corticotropin-releasing hormone (oCRH)] and psychosocial stressor to assess HPA axis reactivity. Plasma adrenocorticotropin hormone (ACTH) and cortisol were assessed every 10-20 minutes. Hierarchical clustering of multiple measures of trauma and stress identified 3 distinct clusters: childhood adversity, lifetime trauma, and chronic stress. General linear model procedures were used to examine main effects of group (AUD/control) and interaction effects of the 3 clusters upon net-integrated ACTH and cortisol response. RESULTS: We found that higher levels of childhood adversity, lifetime trauma, and chronic stress were each associated with blunted oCRH-induced ACTH reactivity in controls, but not in the AUD group. Recent chronic stress within the prior 6 months had the strongest influence upon ACTH reactivity in the control group, and lifetime trauma, the least. CONCLUSIONS: Childhood adversity, lifetime trauma, and chronic stress likely exert persistent, measurable effects upon HPA axis functioning in healthy controls. This association appears to be masked in individuals with AUD, potentially confounding studies examining the effects of stress, adversity, and/or trauma upon the HPA axis in this population during the protracted withdrawal phase of recovery. Future work targeting stress exposure and reactivity should consider the heightened effect of previous alcohol use relative to past adversity and trauma.

Axis-specific analysis and predictors of endocrine recovery and deficits for non-functioning pituitary adenomas undergoing endoscopic transsphenoidal surgery.

PURPOSE: Endoscopic transsphenoidal surgery (ETSS) is a well-established treatment for patients with nonfunctioning pituitary adenomas (NFPAs). Data on the rates of pituitary dysfunction and recovery in a large cohort of NFPA patients undergoing ETSS and the predictors of endocrine function before and after ETSS are scarce. This study is purposed to analyze the comprehensive changes in hormonal function and identify factors that predict recovery or worsening of hormonal axes following ETSS for NFPA. METHODS: A retrospective review of 601 consecutive patients who underwent ETSS between 2010 and 2018 at one institution was performed. Recovery or development of new hypopituitarism was analyzed in 209 NFPA patients who underwent ETSS. RESULTS: Patients with preoperative endocrine deficits (59.8%) in one or more pituitary axes had larger tumor volumes (P = 0.001) than those without preoperative deficits. Recovery of preoperative pituitary deficit occurred in all four axes, with overall mean recovery of 29.7%. The cortisol axis showed the highest recovery whereas the thyroid axis showed the lowest, with 1-year cumulative recovery rates of 44.3% and 6.1%, respectively. Postoperative hypopituitarism occurred overall in 17.2%, most frequently in the thyroid axis (24.3%, 27/111) and least frequently in the cortisol axis (9.7%, 16/165). Axis-specific predictors of post-operative recovery and deficiency were identified. CONCLUSIONS: Dynamic alterations in pituitary hormones were observed in a proportion of patients following ETSS in NFPA patients. Postoperative endocrine vulnerability, recovery, and factors that predicted recovery or loss of endocrine function depended on the hormonal system, necessitating an axis-specific surveillance strategy postoperatively.

Low-dose ACTH test for evaluation of hypothalamus-pituitary-adrenal axis preoperatively and 3-month follow-up in non-functioning pituitary adenomas.

BACKGROUND: Peri-operative glucocorticoids are routinely administered to patients undergoing trans-sphenoidal surgery for non-functional pituitary adenomas (NFPA) irrespective of hypothalamus-pituitary-adrenal (HPA) axis status. PURPOSE: Evaluation of HPA axis before and 12 weeks after endoscopic trans-sphenoidal adenomectomy (E-TSA) utilizing low-dose (1 µg) ACTH stimulation test (LDACTH) to determine the need for glucocorticoid administration in patients with NFPA. We also determined the factors that can predict occurrence of hypocortisolism at 12 weeks after surgery. METHODS: Sixty-three consecutive patients with NFPA requiring surgical excision were enrolled in this study. Glucocorticoids were administered to patients with demonstrable hypocortisolism [preoperative peak cortisol < 16 µg/dL during LDACTH test, postoperative day 3 (POD-3) 0800 hrs Cortisol < 8 µg/dL or stimulated cortisol (LDACTH) < 16 µg/dL at 12 weeks]. RESULTS: Hypocortisolism was present in 43 patients (68.2%) pre-operatively and persisted in 33 patients (52.4%) on POD-3. Thirty-three patients (52.4%) had hypocortisolism at 12 weeks after surgery. Eleven patients (17.4%) did not require glucocorticoids during the entire study period and 30 patients (47.6%) did not require glucocorticoids after 3 months. None of the patients developed adrenal crisis during the study. Hypocortisolism on the third post-operative day was the single significant predictor of hypocortisolism at 12 weeks after the surgery. There was a significant correlation between POD-3 0800 hrs cortisol ≥ 8µg/dL and stimulated cortisol (LDACTH) ≥16µg/dL at 12 weeks (r = 0.62, p < 0.0001). POD-3 0800 hrs cortisol ≥ 8 µg/dL had 73% sensitivity and 79% specificity in predicting eucortisolism at 12 weeks. CONCLUSIONS: HPA function is preserved in significant proportion of NFPA patients undergoing E-TSA. Perioperative glucocorticoids should be given only in patients with demonstrable preoperative hypocortisolism on 1 µg ACTH test. Postoperative day 3 0800 hrs cortisol is a reasonable predictor of HPA axis status at 12 weeks after surgery.

Role of enhanced glucocorticoid receptor sensitivity in inflammation in PTSD: insights from computational model for circadian-neuroendocrine-immune interactions.

Although glucocorticoid resistance contributes to increased inflammation, individuals with posttraumatic stress disorder (PTSD) exhibit increased glucocorticoid receptor (GR) sensitivity along with increased inflammation. It is not clear how inflammation coexists with a hyperresponsive hypothalamic-pituitary-adrenal (HPA) axis. To understand this better, we developed and analyzed an integrated mathematical model for the HPA axis and the immune system. We performed mathematical simulations for a dexamethasone (DEX) suppression test and IC50-dexamethasone for cytokine suppression by varying model parameters. The model analysis suggests that increasing the steepness of the dose-response curve for GR activity may reduce anti-inflammatory effects of GRs at the ambient glucocorticoid levels, thereby increasing proinflammatory response. The adaptive response of proinflammatory cytokine-mediated stimulatory effects on the HPA axis is reduced due to dominance of the GR-mediated negative feedback on the HPA axis. To verify these hypotheses, we analyzed the clinical data on neuroendocrine variables and cytokines obtained from war-zone veterans with and without PTSD. We observed significant group differences for cortisol and ACTH suppression tests, proinflammatory cytokines TNFα and IL6, high-sensitivity C-reactive protein, promoter methylation of GR gene, and IC50-DEX for lysozyme suppression. Causal inference modeling revealed significant associations between cortisol suppression and post-DEX cortisol decline, promoter methylation of human GR gene exon 1F (NR3C1-1F), IC50-DEX, and proinflammatory cytokines. We noted significant mediation effects of NR3C1-1F promoter methylation on inflammatory cytokines through changes in GR sensitivity. Our findings suggest that increased GR sensitivity may contribute to increased inflammation; therefore, interventions to restore GR sensitivity may normalize inflammation in PTSD.

Adrenal insufficiency following nivolumab therapy in patients with recurrent or metastatic head and neck cancer.

Nivolumab, an anti-programmed cell death-1 monoclonal antibody, is currently used to treat many types of advanced cancers including recurrent and metastatic head and neck cancer. However, there are increasing reports concerning immune-related adverse events related to nivolumab therapy. Here, we report three patients who presented with adrenal insufficiency following nivolumab therapy. Two were diagnosed as having isolated adrenocorticotropic hormone (ACTH) deficiency and one was diagnosed as having primary adrenal insufficiency. All three patients complained of progressive fatigue and appetite loss, so we measured their blood cortisol and ACTH levels and diagnosed them as having adrenal deficiency. Treatment with nivolumab was discontinued for all three patients, and replacement therapy using hydrocortisone was successful after a few days in all cases. Two patients subsequently resumed nivolumab therapy because their general condition had improved. Complaints of fatigue and appetite loss during cancer treatment are common and tend to be regarded as unimportant. Although adrenal insufficiency due to nivolumab is relatively rare, complaints of these symptoms could lead to the detection of adrenal insufficiency at an early stage. The present report highlights the importance of the early recognition of adrenal insufficiency.

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.

Immune checkpoint inhibitor-associated pituitary-adrenal dysfunction: A systematic review and meta-analysis.

With the growing use of immune checkpoint inhibitors (ICIs), case reports of rare yet life-threatening pituitary-adrenal dysfunctions, particularly for hypopituitarism, are increasingly being published. In this analysis, we focus on these events by including the most recent publications and reports from early phase I/II and phase III clinical trials and comparing the incidence and risks across different ICI regimens. PubMed, Embase, and the Cochrane Library were systematically searched from inception to April 2019 for clinical trials that reported on pituitary-adrenal dysfunction. The rates of events, odds ratios (ORs), and 95% confidence intervals (CIs) were obtained using random effects meta-analysis. The analyses included data from 160 trials involving 40 432 participants. The rate was 2.43% (95% CI, 1.73%-3.22%) for all-grade adrenal insufficiency and 3.25% (95% CI, 2.15%-4.51%) for hypophysitis. Compared with the placebo or other therapeutic regimens, ICI agents were associated with a higher incidence of serious-grade adrenal insufficiency (OR 3.19, 95% CI, 1.84 to 5.54) and hypophysitis (OR 4.77, 95% CI, 2.60 to 8.78). Among 71 serious-grade hypopituitarism instances in 12 336 patients, there was a significant association between ICIs and hypopituitarism (OR 3.62, 95% CI, 1.86 to 7.03). Substantial heterogeneity was noted across the studies for the rates of these events, which in part was attributable to the different types of ICIs and varied phases of the clinical trials. Although the rates of these events were low, the risk was increased following ICI-based treatment, particularly for CTLA-4 inhibitors, which were associated with a higher incidence of pituitary-adrenal dysfunction than PD-1/PD-L1 inhibitors.

Hyperstable arousal regulation in multiple sclerosis.

BACKGROUND: Fatigue is common in multiple sclerosis (MS) patients. Exhaustion of physiological reserves and mental stress are postulated causes, the latter supported by more pronounced hypothalamic-pituitary-adrenal (HPA) axis activation in fatigued patients. Divergent dysregulation of arousal appears to play important roles in depression- (hyperstable arousal) and in cancer-related (unstable arousal) fatigue, where HPA axis is hyperactive or hypoactive, respectively. OBJECTIVE: This study assessed arousal regulation in multiple sclerosis patients, explored if fatigue can be physiologically described by altered arousal regulation, and if HPA axis activity corresponds to the type(s) of arousal regulation. METHODS: 51 mildly-affected patients with relapsing-remitting MS (86% on disease-modifying treatment) and 20 healthy controls were analysed via Vigilance Algorithm Leipzig and combined dexamethasone/corticotropin releasing hormone test. RESULTS: Hyperstable arousal pattern was significantly more frequent in patients than in controls (62.7% vs. 45.0%, p = 0.011). Patients scored higher on all fatigue, but not on sleepiness scales. All patients combined showed mild activation of the hypothalamic-pituitary-adrenal axis (p < 0.05 for post-CRH ACTH and AUC ACTH; cortisol n.s.). While fatigue was numerically more pronounced in both hyperstable and unstable arousal, HPA axis activity was highest in hyperstable and lowest in unstable arousal (p = 0.013 for post-CRH ACTH; p = 0.087 for AUC ACTH; cortisol n.s.). CONCLUSION: Frequency of arousal patterns are altered in MS. An association with HPA axis activity was weak, possibly because the present sample was stable on immunotherapy.

Pharmacological and analytical interference in hormone assays for diagnosis of adrenal incidentaloma.

Adrenal incidentaloma refers to an asymptomatic adrenal mass detected through an imaging procedure performed for reasons unrelated to adrenal dysfunction or suspected dysfunction. In general, adrenal incidentalomas are non-functioning adrenal adenomas, but in some cases, may require therapeutic intervention: eg., adrenocortical carcinoma, pheochromocytoma, primary aldosteronism, cortisol hypersecretion, or adrenal insufficiency. Hormone assessment is crucial to characterize adrenal incidentaloma. Nowadays, various hormone assay methods are available, such as immunoassay and mass spectrometry. However, there are several pitfalls that should be considered: e.g., circadian rhythm, gender/age dependency, preanalytical and analytical issues, and drug interactions. Pharmacological or analytical interference can lead to false serum concentrations and may result in misinterpretation of results and thus inappropriate treatment. The purpose of this review was to study the main interferences that may be observed in the different tumor types of adrenal incidentalomas in order to help physicians in their clinical decision-making and for the overall benefit of patients.

Saliva versus serum cortisol to identify subclinical hypercortisolism in adrenal incidentalomas: simplicity versus accuracy.

PURPOSE: Subclinical hypercortisolism (SCH) leads to metabolic derangements and increased cardiovascular risk. Cortisol autonomy is defined by the overnight 1 mg dexamethasone suppression test (DST). Saliva cortisol is an easier, stress-free, and cost-effective alternative to serum cortisol. We compared 23 h and post-1 mg DST saliva with serum cortisol to identify SCH in adrenal incidentalomas (AI). METHODS: We analyzed 359 DST obtained retrospectively from 226 AI subjects (173F/53 M; 19-83 years) for saliva and serum cortisol. We used three post-DST serum cortisol cutoffs to uncover SCH: 1.8, 2.5, and 5.0 µg/dL. We determined post-DST and 23 h saliva cortisol cutoffs by ROC curve analysis and calculated their sensitivities (S) and specificities (E). RESULTS: The sensitive 1.8 µg/dL cutoff defined 137 SCH and 180 non-functioning adenomas (NFA): post-DST and 23 h saliva cortisol S/E were: 75.2%/74.4% and 59.5%/65.9%, respectively. Using the specific 5.0 µg/dL cortisol cutoff (22 SCH/295 NFA), post-DST and 23 h saliva cortisol S/E were 86.4%/83.4% and 66.7%/80.4%, respectively. Using the intermediate 2.5 µg/dL cutoff (89 SCH/228 NFA), post-DST and 23 h saliva cortisol S/E were 80.9%/68.9% and 65.5%/62.8%, respectively. CONCLUSION: Saliva cortisol showed acceptable performance only with the 5.0 µg/dL cortisol cutoff, as in overt Cushing's syndrome. Lower cutoffs (1.8 and 2.5 µg/dL) that identify larger samples of patients with poor metabolic outcomes are less accurate for screening. These results may be attributed to pre-analytical factors and inherent patient conditions. Thus, saliva cortisol cannot replace serum cortisol to identify SCH among patients with AI for screening DST.

Plasma Free Cortisol in States of Normal and Altered Binding Globulins: Implications for Adrenal Insufficiency Diagnosis.

CONTEXT: Accurate diagnosis of adrenal insufficiency is critical because there are risks associated with overdiagnosis and underdiagnosis. Data using liquid chromatography tandem mass spectrometry (LC/MS/MS) free cortisol (FC) assays in states of high or low cortisol-binding globulin (CBG) levels, including cirrhosis, critical illness, and oral estrogen use, are needed. DESIGN: Cross-sectional. OBJECTIVE: Determine the relationship between CBG and albumin as well as total cortisol (TC) and FC in states of normal and abnormal CBG. Establish the FC level by LC/MS/MS that best predicts TC of <18 µg/dL (497 nmol/L) (standard adrenal insufficiency diagnostic cutoff) in healthy individuals. SUBJECTS: This study included a total of 338 subjects in four groups: healthy control (HC) subjects (n = 243), patients with cirrhosis (n = 38), intensive care unit patients (ICU) (n = 26), and oral contraceptive (OCP) users (n = 31). MAIN OUTCOME MEASURE(S): FC and TC by LC/MS/MS, albumin by spectrophotometry, and CBG by ELISA. RESULTS: TC correlated with FC in the ICU (R = 0.91), HC (R = 0.90), cirrhosis (R = 0.86), and OCP (R = 0.70) groups (all P < 0.0001). In receiver operator curve analysis in the HC group, FC of 0.9 µg/dL (24.8 nmol/L) predicted TC of <18 µg/dL (497 nmol/L; 98% sensitivity, 91% specificity; AUC, 0.98; P < 0.0001). Decreasing the cutoff to 0.7 µg/dL led to a small decrease in sensitivity (92%) with similar specificity (91%). CONCLUSIONS: A cutoff FC of <0.9 µg/dL (25 nmol/L) in this LC/MS/MS assay predicts TC of <18 µg/dL (497 nmol/L) with excellent sensitivity and specificity. This FC cutoff may be helpful in ruling out adrenal insufficiency in patients with binding globulin derangements.