post-DST Cortisol Research Articles

Diagnostic Accuracy of Dehydroepiandrosterone Sulfate and Corticotropin in Autonomous Cortisol Secretion.

Autonomous cortisol secretion (ACS) affects up to 50% of patients with adrenal adenomas. Despite the limited evidence, clinical guidelines recommend measurement of serum concentrations of dehydroepiandrosterone-sulfate (DHEA-S) and corticotropin (ACTH) to aid in the diagnosis of ACS. Our objective was to determine the accuracy of serum concentrations of DHEA-S and ACTH in diagnosing ACS. We conducted a retrospective single center study of adults with adrenal adenoma evaluated between 2000−2020. Main outcome measure was diagnostic accuracy of DHEA-S and ACTH. ACS was defined as post-dexamethasone cortisol >1.8 mcg/dL. Of 468 patients, ACS was diagnosed in 256 (55%) patients with a median post-DST cortisol of 3.45 mcg/dL (range, 1.9–32.7). Patients with ACS demonstrated lower serum concentrations of DHEA-S (35 vs. 87.3 mcg/dL, p < 0.0001) and ACTH (8.3 vs. 16 pg/mL, p < 0.0001) compared to patients with non-functioning adrenal tumors (NFAT). Serum DHEA-S concentration <40 mcg/dL diagnosed ACS with 84% specificity and 81% PPV, while serum ACTH concentration <10 pg/mL diagnosed ACS with 75% specificity and 78% PPV. The combination of serum concentrations of DHEA-S <40 mcg/dL and ACTH <10 pg/mL diagnosed ACS with the highest accuracy with 92% specificity and 87% PPV. Serum concentrations of DHEA-S and ACTH provide additional value in diagnosing ACS.

SUBTLE CORTISOL HYPERSECRETION IS ASSOCIATED WITH GLUCOSE HOMEOSTASIS AND INSULIN RESISTANCE IN NON-DIABETIC ESSENTIAL HYPERTENSIVE PATIENTS

Abstract Objective: Patients with Cushing's syndrome (CS) and subclinical Cushing's syndrome (SCS) have a higher prevalence of cardiovascular complications than general population. Increased prevalence of impaired glucose tolerance has been reported in patients with SCS. Excess cortisol secretion can inhibit insulin secretion and impair insulin sensitivity and glucose uptake. We sought that a mild cortisol hypersecretion or an impairment in circadian cortisol rhythm might be associated with glucose homeostasis or insulin-resistance in essential hypertensive (EH) patients. Design and method: In 155 non-diabetic EH patients we measured fasting glucose and insulin, calculated the HOMA-index, performed an oral glucose tolerance test (OGTT), calculated the area under the curve for glucose (GAUC) and insulin (IAUC), glucose level at 2-h of OGTT (G120), plasma cortisol level at 8 AM, 5 PM and 11 PM, and after overnight suppression with 1 mg of dexamethasone (DST), 24-h free urinary cortisol and plasma ACTH. Results: GAUC and G120 were associated with both 11 PM and post-DST cortisol levels. Fasting insulin level, HOMA-index and IAUC were associated with post-DST cortisol level. These associations were independent of age, adiposity, plasma potassium and ACTH levels, alcohol intake and physical activity. Conclusions: In non-diabetic EH patients free of overt CS or SCS, glucose uptake and insulin resistance are associated with subtle cortisol hypersecretion.

MILD CORTISOL HYPERPRODUCTION IS ASSOCIATED WITH IMPAIRED GLUCOSE HOMEOSTASIS AND INSULIN-RESISTANCE IN NON-DIABETIC ESSENTIAL HYPERTENSIVE PATIENTS

Objective: Patients with Cushing syndrome (CS) and subclinical Cushing syndrome (SCS) have higher risk of cardiovascular events than the general population. Excess cortisol secretion might reduce insulin secretion, insulin sensitivity, glucose uptake, and increase gluconeogenesis. Data on cortisol secretion in patients with essential hypertension and on its relationships with glucose homeostasis are scanty. The aim of the study was to evaluate cortisol secretion and its relationship with glucose homeostasis and insulin-sensitivity in essential hypertensive (EH) patients. Design and method: In 155 EH patients (age 43 ± 13 years, 81 men) we measured fasting glucose and insulin, HOMA index, plasma cortisol levels at 8 AM, 5 PM and 11 PM, and after an overnight suppression test (DST) with 1 mg of dexamethasone, 24-h free urinary cortisol, and ACTH, and performed a standard oral glucose tolerance test (OGTT), calculating the area under the curve for glucose (G-AUC) and insulin (I-AUC). Results: Fasting glucose was positively related to 11 PM cortisol level (r = 0.221, P = 0.019) and post-DST cortisol levels (r = 0.244, P = 0.002). Post-DST cortisol level was positively related with fasting insulin (r = 0.264, P = 0.001), HOMA (r = 0.273, P = 0.001) and I-AUC (r = 0.185, P = 0.023). G-AUC was positively related to 11 PM cortisol (r = 0.246, P = 0.008) and post-DST cortisol levels (r = 0.216, P = 0.007). These associations were independent of age, body mass index, alcohol intake, physical activity, plasma potassium and ACTH levels. Conclusions: In non-diabetic patients with EH, relative cortisol hypersecretion is independently associated with impaired glucose homeostasis and insulin resistance.

HPA axis regulation and epigenetic programming of immune-related genes in chronically stressed and non-stressed mid-life women

Hypothalamic-pituitary-adrenal (HPA) axis dysregulation has been associated with altered immune function, but the underlying molecular mechanisms are unclear. Epigenetic processes, including DNA methylation, respond to the glucocorticoid end-products of the HPA axis (cortisol in humans) and could be involved in this neuroendocrine-immune crosstalk. Here we examined the extent to which variations in HPA axis regulation are associated with peripheral blood DNA (CpG) methylation changes in 57 chronically stressed caregivers and 67 control women. DNA methylation was determined with the Illumina 450k array for a panel of genes involved in HPA axis and immune function. HPA axis feedback was assessed with the low-dose dexamethasone suppression test (DST), measuring the extent to which cortisol secretion is suppressed by the synthetic glucocorticoid dexamethasone. After multiple testing correction in the entire cohort, higher post-DST cortisol, reflecting blunted HPA axis negative feedback, but not baseline waking cortisol, was associated with lower DNA methylation at eight TNF and two FKBP5 CpG sites. Caregiver group status was associated with lower methylation at two IL6 CpG sites. Since associations were most robust with TNF methylation (32% of the 450k-covered sites), we further examined functionality of this epigenetic signature in cultured peripheral blood mononuclear cells in 33 participants; intriguingly, lower TNF methylation resulted in higher ex vivo TNF mRNA following immune stimulation. Taken together, our findings link chronic stress and HPA axis regulation with epigenetic signatures at immune-related genes, thereby providing novel insights into how aberrant HPA axis function may contribute to heightened inflammation and disease risk.

Are the thyroid and adrenal system alterations linked in depression?

BackgroundDisturbances in the hypothalamic-pituitary-thyroid (HPT) and hypothalamic-pituitary-adrenal (HPA) axes have been frequently found in major depression. Given that glucocorticoids may inhibit thyrotropin (TSH) and thyrotropin-releasing hormone (TRH) secretion, it has been hypothesized that hypercortisolemia could lead to HPT axis abnormalities. So far, data on interactions between the HPA and HPT axes in depression remain inconclusive. MethodsIn order to investigate this issue, we examined circadian rhythms of serum TSH and cortisol (sampled at 4 -hly intervals throughout a 24 -h span), TSH responses to 0800 h and 2300 h protirelin (TRH) tests and cortisol response to dexamethasone suppression test (DST) in 145 unmedicated inpatients meeting DSM-IV criteria for major depressive disorder (MDDs) and 25 healthy hospitalized control subjects (HCs). ResultsThe secretion of TSH and cortisol exhibited a significant circadian rhythm both in HCs and MDDs. However, compared to HCs, MDDs showed: 1) reduced TSH mesor and amplitude values; 2) blunted 2300 h-ΔTSH and ΔΔTSH values (i.e. differences between 2300 h and 0800 h TRH-TSH responses); and 3) increased cortisol mesor and post-DST cortisol values. DST nonsuppresssors (n = 40, 27 %) showed higher cortisol mesor than DST suppressors (n = 105, 73 %). There was no difference between DST suppressors and nonsuppressors in their TSH circadian parameters and TRH-TSH responses. In addition, cortisol values (circadian and post-DST) were not related to TRH test responses. ConclusionOur results do not confirm a key role for hypercortisolemia in the HPT axis dysregulation in depression.

The Quantitative Relationship Between Autonomous Cortisol Secretion, Dysglycemia and the Metabolic Syndrome

Autonomous cortisol secretion (ACS) is the most common endocrine abnormality in the evaluation of adrenal incidentalomas. The categorization of ACS is derived from a 1 mg dexamethasone suppression test (DST). Impaired DST is associated with several metabolic derangements. In this study we analyzed the association between post-DST cortisol level, analyzed as a continuous parameter, and indices of glycemic metabolism. We prospectively collected data of 1,976 patients evaluated for adrenal incidentalomas in a large tertiary medical center between December 1, 2017, and August 31, 2019. Seventy-three patients completed the evaluation process. Post-DST cortisol levels were analyzed for correlation with various metabolic parameters, including fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) among the general cohort and for subgroups stratified by the number of metabolic syndrome (MS) criteria. Post-DST cortisol demonstrated a linear association with FPG and HbA1c across its entire cortisol range (R = 0.51 and 0.41, respectively; P≤.01). The association between post-DST cortisol and FPG was strengthened with an increased number of metabolic syndrome criteria. Patients with 4 MS criteria show a stronger association (R = 0.92) compared to patients with only a single criterion (R = 0.509). Furthermore, mean post-DST cortisol levels increased as the number of MS criteria accumulated. Post-DST cortisol should be viewed as a continuous parameter in risk stratification algorithms for the development of MS and particularly dysglycemia.

SUN-162 Isolated Primary Pigmented Micronodular Adrenal Disease. Unilateral or Bilateral Adrenalectomy? Two Cases Report

Background: Isolated primary pigmented nodular adrenal disease (i-PPNAD) is a particular case of micronodular bilateral hyperplasia (MiBAH) leading to Cushing syndrome (CS). We present two patients with i-PPNAD who undergone unilateral adrenalectomy with different disease outcomes. Case 1: A 56 yo man presented with typical signs and symptoms of CS, including central weight gain, proximal muscle weakness, hypertension and marked osteoporosis. A biochemical investigation showed an assessment of late-night salivary cortisol - 23 nmol/l (n <9), 24h urinary free cortisol (UFC)- 1206 nmol/24h (n-60–413). The 1 mg DST showed post-DST cortisol 617 nmol/l (n<50). ACTH concentration was suppressed at 1.1 pg/ml (n-7–66). Adrenal CT-scan was normal. PPNAD was assumed and the screening for Carney complex components was negative. After left adrenalectomy, histological examination confirmed the diagnosis of PPNAD. However, biochemical remission wasn’t achieved: postoperative UFC-860 nmol/24h. Thus, the right adrenalectomy was conducted. Case 2: A 40 yo female presented with long term drug-corrected (beta-blockers, ACE inhibitor) arterial hypertension, menstrual dysfunction and clinical features of CS (central obesity, proximal muscle weakness, hirsutism), without osteoporosis. Baseline hormonal evaluation documented slightly increased level of salivary cortisol- 9,8 nmol/l (n <9), post 1 mg DST cortisol - 470 nmol/l (n<50) and ACTH-concentration below detection <1 pg/ml (n-7–66). However, UFC was normal – 215 nmol/l (n-60–413). Abdominal CT-scan revealed micronodular hyperplasia of the left adrenal and was suggestive of possible right adrenal gland hyperplasia. We performed left adrenalectomy. In the early postoperative period, adrenal insufficiency was diagnosed and thus it required hydrocortisone replacement. Discussion: We obtained two opposite results: in case 1, an expected remission after unilateral adrenalectomy was not achieved, while patient No.2 developed adrenal insufficiency, which was a more favourable prognostic sign and attested to the successful outcome of surgical treatment. A possible explanation of the ineffectiveness of surgical intervention in patient No.1 was primary more severe hypercortisolism. It is also necessary to take into account that according to the CT data of the patient No.1, both adrenal glands were within normal ranges and did not differ from one another, while in the patient No.2, the lesion was more prominent on the right side. Conclusion: Diagnostic of i-PPNAD and choice of intervention can be precarious, consequently more studies are needed to define to which patients unilateral adrenalectomy could be an efficient treatment modality. It is possible to perform unilateral adrenalectomy with subsequent assessment of cortisol levels, in case of lack of remission the contralateral adrenalectomy is required.

Dexamethasone Suppression Test May Predict More Severe/Violent Suicidal Behavior.

IntroductionSeveral studies demonstrated that the hypothalamic-pituitary-adrenal (HPA) axis is dysregulated in suicide attempters. Prospective studies found that people with an abnormal response at the dexamethasone suppression test (DST) are more likely to commit suicide. However, whether DST may predict suicide attempts remains less clear. A possible strategy to address this question is to consider the suicide attempt lethality.Objectives(1) To compare the pre- and post-DST cortisol levels in serious/violent suicide attempters and in non-serious/non-violent suicide attempters, and (2) to investigate whether cortisol level can predict new suicide attempts or their lethality.MethodsThe study included 70 recent suicide attempters (25 with a serious or violent attempt) who were followed for two years. Three saliva samples for cortisol measurement were obtained at 8a.m., 3p.m., and 9p.m. before the DST (pre-DST). Then, at 11 p.m., 1 mg of dexamethasone was given orally. The following day (post-DST), three saliva samples were collected at the same hours as before. The post-DST–pre-DST salivary cortisol Δ index was calculated for each collection time. The Risk-Rescue Ratio Scale (RRRS) and the Suicidal Intent Scale (SIS) were used to characterize the suicide attempt at inclusion and those occurring during the follow-up.ResultsPost-DST cortisol level at 9 p.m. was higher in patients with an initial violent or serious suicide attempt than in non-violent/non-serious attempters (p < .010). Higher post-DST cortisol at 9p.m. was associated with lower RRRS rescue score and higher clinical impression of suicide severity at inclusion. Among the 66 patients who completed the follow-up, 26 attempted suicide again at least once. Higher pre-DST cortisol at 8a.m. predicted new suicide attempts during the follow-up (OR = 2.15 [1.11, 4.15]), and higher cortisol Δ index at 9p.m. was associated with higher suicide intent during the follow-up.ConclusionsOur results suggest that HPA axis hyper-reactivity monitored with the DST is a marker of violent/serious suicide attempt with lower rescue possibility. Furthermore, higher changes between pre-DST and post-DST cortisol levels may predict higher suicide intent. These findings might help to characterize the biological features of nearest suicide phenotypes.

The Steroid Profile of Adrenal Incidentalomas: Subtyping Subjects With High Cardiovascular Risk.

Steroid profiling by mass spectrometry has shown implications for diagnosis and subtyping of adrenal tumors. To investigate steroid profiles and their cardiovascular correlates in a large cohort of patients with nonsecreting (NS) adrenal incidentalomas and autonomous cortisol secretion (ACS). Cohort study. University hospital. Patients (n = 302) with incidentally discovered adrenal masses, divided into unilateral adenoma and hyperplasia with ACS (n = 46 and n = 52, respectively) and NS (n = 120 and n = 84, respectively). Post-dexamethasone suppression test (DST) cortisol <50 or >50 nmol/L defined NS and ACS, respectively. Analysis of 10-steroid panel by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and clinical data (mean follow-up 39 months). Difference in baseline and post-DST steroid profiles between groups. Correlation with cardiovascular profile. Patients with unilateral adenomas and ACS showed higher cortisol, 11-deoxycortisol, and corticosterone and lower dehydroepiandrosterone than those with NS adenomas. Patients with ACS hyperplasia showed higher cortisol and lower androgens in women than those with NS. Patients with ACS had reduced suppression of post-DST cortisol, 11-deoxycortisol, and corticosterone, irrespective of adrenal morphology. Post-DST cortisol and corticosterone were associated with higher prevalence of severe/resistant hypertension. Patients with ACS unilateral adenomas showed higher incidence of worsening of hypertensive disease and novel cardiovascular events than those with NS, with post-DST cortisol [hazard ratio (HR) 1.02; 95% CI, 1.01 to 1.03; P < 0.001] and baseline corticosterone (HR 1.06; 95% CI, 1.01 to 1.12; P = 0.031) among the main predictors. Patients with adrenal incidentalomas showed different steroid profiles, depending on functional status and adrenal morphology, with implications for their cardiovascular status.

SAT-365 Prevalence and Clinical Features of Adrenal Incidentalomas: A Prospective Study in an Unselected Population

Context. The widespread use of cross-sectional imaging in medical practice has increased detection of adrenal tumors, which are most frequently unexpected prior to their discovery (adrenal incidentalomas). Most adrenal incidentalomas (AI) are benign and frequently cause low-grade cortisol excess that may portend adverse clinical consequences. However, this association is subject to confounding by indication since more diagnostic tests are done in diseased patients. Objective. To assess prospectively the prevalence of AI in an unselected adult population performing abdominal CT in our catchment area, and to evaluate the demographic, laboratory and clinical features of AI patients. Design and setting. Monocentric, prospective study. Patients. A consecutive series of 601 unselected patients undergoing abdominal CT as part of their management. Patients with any known adrenal disorder or malignancy were excluded. Results. Of the 601 patients, aged 63.5 ± 14.4 years, 55.4% had hypertension, 15.1% diabetes, 16.8% dyslipidemia and 16% previous CV events. These characteristics are overall comparable to the background general population. We found serendipitously 44 adrenal tumors (7.3%), 43 with radiological features of benign cortical adenoma (density <10 HU) and 1 with indeterminate features, which was a pheochromocytoma. Mass size ranged between 1-5 cm (median 2 cm) and tumors were bilateral in 29.5%. Patients with AI compared to patients without were more frequently suffering from diabetes (31.8% vs 14.2%; p=0.004), showing higher BMI (27.6 ± 6.2 vs. 25.6 ± 4.8; p=0.009) and larger waist (101.2 ± 13.9 cm vs. 95.3 ± 13.9 cm; p=0.007). No differences were found in frequency of hypertension, dyslipidemia or history of CV events. Forty patients underwent a 1-mg overnight dexamethasone test (DST) and 20 (50%) did not suppress cortisol below 1.8 μg/dL (4 had post-DST cortisol >5.0 μg/dL). Post-DST cortisol levels were not different between diabetic and non-diabetic AI patients (3.5 ± 4.0 µg/dL vs. 2.4 ± 2.5 µg/dL). In multivariate analysis, diabetes was significantly associated with AI (p=0.003). Conclusions. We confirm in a prospective study the high prevalence of previously unsuspected adrenal tumors, most of which are benign adenomas. Moreover, we found a significant association between adrenal incidentalomas and diabetes. Since our patients were recruited at the radiology department, this finding is not confounded by selection bias.

Differences in multihormonal responses to the dopamine agonist apomorphine between unipolar and bipolar depressed patients

BackgroundA large number of studies suggest that dopaminergic function may be impaired in depressed patients, particularly in bipolar patients. The dopamine D2/D1 agonist apomorphine (APO) can be useful in the evaluation of dopaminergic function. However, most studies show conflicting results in APO test responses when evaluating unipolar and bipolar depressed patients. Thus, the objective of this study was to apply the APO test to assess whether hypothalamic-pituitary dopaminergic function is altered in unipolar and bipolar depression. MethodsWe evaluated multihormonal responses to APO test (0.75 mg subcutaneous) in 134 drug-free DSM-IV major depressed inpatients (54 with bipolar depression [BD] and 80 with unipolar depression [UD]), compared with 36 healthy controls (HCs). We also examined the cortisol response to the dexamethasone suppression test (DST, 1 mg orally) in all subjects. ResultsNo significant differences in prolactin (PRL), cortisol, adrenocorticotropin (ACTH) or growth hormone (GH) baseline values were found across the three groups. ACTH/cortisol and GH responses to APO were also comparable. BD patients showed lower PRL suppression to APO than did UD patients and HCs (both p < 0.00001). Although responses to DST were comparable between UD and BD patients, the former exhibited higher post-DST cortisol levels than did HCs (p < 0.05). ConclusionsOur results suggest that BD patients, unlike UD patients, have altered post-synaptic D2 receptor sensitivity at the pituitary level. This alteration does not seem secondary to hypercortisolemia. These findings, if confirmed by other studies with larger samples, may support the use of dopamine agents in BD patients treatment.

Cyclic Subclinical Hypercortisolism: A Previously Unidentified Hypersecretory Form of Adrenal Incidentalomas.

PurposeMost adrenal incidentalomas (AIs) are nonfunctioning adenomas (NFAs), but up to 30% may secrete cortisol autonomously without clinical evidence of Cushing syndrome (CS), which nevertheless may increase cardiovascular mortality. This subclinical hypercortisolism (SCH) is confirmed by cortisol resistance to a dexamethasone suppression test (DST). Cyclic cortisol secretion occurs in classic CS but was not reported in SCH.ObjectiveInvestigate cyclic cortisol production/autonomy in AIs using sequential DSTs.MethodsA total of 251 patients with AI underwent 487 DSTs over 12 years; patients with at least three DSTs were selected. DSTs were validated by measuring serum dexamethasone. Cyclic SCH was defined when at least two abnormal and two normal DSTs were documented.ResultsA total of 44 patients had three or more DSTs during follow-up: 9 of 44 patients (20.4%) had all negative test results (post-DST cortisol ≤1.8 μg/dL) and were classified as NFA; another nine patients had all positive results (cortisol >1.8 μg/dL) and were classified as sustained SCH. The remaining 26 (59.2%) had discordant responses: 8 of 44 (18.3%) had at least two positive and two negative tests, matching the criterion for cyclic SCH, whereas 18 of 44 (40.9%) had only one discordant test and were classified as possibly cyclic SCH. Eleven of 20 (55%) patients initially classified as NFA did not maintain their cortisol pattern.ConclusionsExtended follow-up with repeated DSTs uncovered an unusual subset of AIs with cyclic SCH. Recurring production of cortisol may affect determination of AI subtypes if based on just one DST. Lack of recognition of this phenomenon makes follow-up of patients with AI misleading because even cyclic SCH may result in potential cardiovascular risk.

Chemical shift magnetic resonance imaging could predict subclinical cortisol production from an incidentally discovered adrenal mass.

To investigate whether any association between chemical shift magnetic resonance (MRI) findings, cortisol secretion and pathological findings exists that could predict subclinical hypercortisolism (SCH) in patients with adrenal incidentalomas (AI). Retrospective, cross-sectional study in a tertiary centre. Sixty-eight subjects with AIs and 13 patients with Cushing's syndrome (CS). Patients with AIs were categorized according to cortisol levels post 1mg dexamethasone (post-DST). Visual inspection of the lipid content of the adrenal tumour and calculation of adrenal-to-spleen ratio (ASR), the signal intensity index (SII), volume and the assessment of the association between pathological, radiological and hormonal findings in surgically treated patients. Percentage of clear cells was correlated with ASR (r=-.525, P=.01), SII (r=.465, P=.025), post-DST cortisol (r=-.711, P<.001) and ACTH (r=.475, P=.046). By ANOVA and post hoc analysis, patients with CS and five subjects with a post-DST cortisol greater than 137nmol/L differed significantly in ASR and SII from those with a post-DST cortisol less than 50nmol/L. An ASR level higher than 0.245 (OR 19.7, 95% CI 1.5-257.5; P=.023) and a SII level lower than 78.37 (OR 15.6, 95% CI 1.2-20; P=.034) remained as the independent predictors for SCH while age, presence of arterial hypertension or tumour volume did not make significant contribution to the models. Cortisol hypersecretion by adrenal adenomas is associated with distinctive MRI characteristics. The quantitative assessment of intracellular lipid in an AI could help distinguish patients with a clear phenotype of SCH.

Cardiovascular features of possible autonomous cortisol secretion in patients with adrenal incidentalomas

Low-grade incomplete post-dexamethasone cortisol suppression in patients with adrenal incidentalomas - recently defined as possible autonomous cortisol secretion (pACS) - has been associated with increased cardiovascular events and mortality. However, prospective studies documenting cardiac abnormalities in these patients are lacking. Between July 2016 and September 2017, 71 consecutive patients with adrenal lesions were prospectively screened for hypercortisolism by dexamethasone suppression test (NCT 02611258). Complete anthropometric, metabolic and hormonal parameters were recorded along with full cardiac ultrasound assessment and noninvasive measurement of arterial stiffness. All patients underwent chemical-shift magnetic resonance imaging to characterize the lesions. Cardiovascular outcomes were recorded in blind. According to post-dexamethasone suppression cortisol values (post-DST), 34 patients had pACS and 37 non-functioning adenomas (NFA). The two groups were similar in sex, BMI, age distribution, cardiovascular risk factors and comorbidities. Left ventricular mass index (LVMIBSA) was increased in pACS compared to NFA (P = 0.006) and mildly correlated to the post-DST cortisol level (rho = 0.347; P = 0.004). The post-DST cortisol levels explained up to 13.7% of LVMIBSA variance (P = 0.002). Compared to NFA, patients with pACS had a higher prevalence of diastolic dysfunction (35.1% vs 82.6%; P = 0.001) and worse arterial stiffness assessed by pulse wave velocity (P = 0.033). In apparently asymptomatic patients, mild autonomous cortisol secretion can sustain early cardiac and vascular remodeling, independently of other risk factors. The morphological and functional cardiovascular changes observed in pACS underline the need for further studies to correctly define the long-term management of this relatively common condition.

Autonomous cortisol secretion in adrenal incidentalomas and increased visceral fat accumulation during follow-up.

Autonomous cortisol secretion of adrenal incidentalomas (AIs) is associated with poor cardiovascular outcome. Because centripetal obesity is a cardiovascular risk factor, we aimed to investigate whether autonomous cortisol secretion is associated with increased visceral fat accumulation. Retrospective cohort study. Patients with AIs who attended for follow-up between January 2014 and December 2016 were evaluated. Autonomous cortisol secretion was diagnosed when 1mg overnight dexamethasone (post-DST) cortisol was >50nmol/L at baseline and follow-up. Follow-up duration was 34 (12-105) months. Thirty patients with nonfunctioning AIs and 44 patients with autonomous cortisol secretion were included. Adrenalectomy was performed in five patients. Six patients with Cushing's syndrome were also recruited. Hormonal evaluation and assessment of total (T), visceral (V) and subcutaneous (S) fat area by computed tomography and calculation of V:S and V:T ratios at baseline and follow-up. V, V:S and V:T increased (P<.001 for each comparison, Wilcoxon signed rank test for repeated measures) in patients with autonomous cortisol secretion while did not change significantly in patients with nonfunctioning adenomas. Linear regression models including post-DST cortisol, gender, concomitant treatments and follow-up duration showed that both baseline and follow-up DST significantly predicted Δ(V:S) and Δ(V:T) (P<.01 for all models). In patients with AIs, a post-DST cortisol >50nmol/L at both baseline and follow-up, was associated with a significant increase in visceral fat after a follow-up duration of ~3years. This may be of importance to explain the link between autonomous cortisol secretion and poor cardiovascular outcome.

Cortisol-related metabolic alterations assessed by mass spectrometry assay in patients with Cushing's syndrome.

Endogenous hypercortisolism is a chronic condition associated with severe metabolic disturbances and cardiovascular sequela. The aim of this study was to characterize metabolic alterations in patients with different degrees of hypercortisolism by mass-spectrometry-based targeted plasma metabolomic profiling and correlate the metabolomic profile with clinical and hormonal data. Cross-sectional study. Subjects (n = 149) were classified according to clinical and hormonal characteristics: Cushing's syndrome (n = 46), adrenocortical adenomas with autonomous cortisol secretion (n = 31) or without hypercortisolism (n = 27). Subjects with suspicion of hypercortisolism, but normal hormonal/imaging testing, served as controls (n = 42). Clinical and hormonal data were retrieved for all patients and targeted metabolomic profiling was performed. Patients with hypercortisolism showed lower levels of short-/medium-chain acylcarnitines and branched-chain and aromatic amino acids, but higher polyamines levels, in comparison to controls. These alterations were confirmed after excluding diabetic patients. Regression models showed significant correlation between cortisol after dexamethasone suppression test (DST) and 31 metabolites, independently of confounding/contributing factors. Among those, histidine and spermidine were also significantly associated with catabolic signs and symptoms of hypercortisolism. According to an discriminant analysis, the panel of metabolites was able to correctly classify subjects into the main diagnostic categories and to distinguish between subjects with/without altered post-DST cortisol and with/without diabetes in >80% of the cases. Metabolomic profiling revealed alterations of intermediate metabolism independently associated with the severity of hypercortisolism, consistent with disturbed protein synthesis/catabolism and incomplete β-oxidation, providing evidence for the occurrence of metabolic inflexibility in hypercortisolism.

Which type 2 diabetes mellitus patients should be screened for subclinical Cushing's syndrome?

Diabetes or impaired glucose tolerance are common in patients with Cushing's syndrome (CS). In this study we investigated the incidence of subclinical Cushing's syndrome (SCS) in type 2 diabetic patients with poor and good metabolic control and the relationship between blood glucose and cortisol levels. A total of 400 type 2 diabetes mellitus (T2DM) patients (Group A, HbA1c ≥8%, n=250; Group B, HbA1c ≤6.5%, n=150) were included in the study. Biochemical tests followed by the 1 mg dexamethasone suppression test (DST) were performed. If post-DST cortisol levels were above 1.8 μg/dl (non-suppressed group), the 2 mg DST test was performed for 2 days. Among the patients, post-DST cortisol of at least 1.8 μg/dL and midnight serum cortisol levels of at least 7.5 μg/dL confirmed the diagnosis of CS. While SCS was observed in 5 patients (2%) in Group A, no case was observed in group B. There was a statistically significant difference between groups for basal cortisol and post-DST cortisol results (p<0.001 and p<0.001, respectively). Microvascular complication rates were higher in the non-suppressed group (p=0.007). Post-DST cortisol levels had a positive correlation with the number of complications and HbA1c levels (respectively r=0.213, p<0.001, and r=0.191, p<0.001). Multivariate regression analysis revealed that durations of DM, HbA1c level, and post 1 mg DST cortisol levels were associated with the number of complications. This study shows the presence of SCS in a notable number in T2DM patients having poor metabolic control. Screening with 1 mg and 2 mg DST of T2DM patients with poor metabolic control who are also obese and hypertensive and have microvascular complications may be an appropriate method for detection of SCS.

Hyper- and hypocortisolism in bipolar disorder - A beneficial influence of lithium on the HPA-axis?

BackgroundA hyperactive hypothalamic-pituitary-adrenal axis (HPA-axis) is a well-known phenomenon in bipolar disorder (BD). However, hypocortisolism has also been described and found associated with depression, low quality of life and cardiovascular risk factors in BD patients. Although the pathophysiology related to hypocortisolism in BD is largely unknown, hypocortisolism is associated with chronic stress exposure and after inducing an initial rise in cortisol long-term stress may result in a transition to hypocortisolism. BD patients are throughout life often exposed to chronic stress. We therefore hypothesized that higher age would be associated with lower HPA-axis activity especially among patients without previous mood stabilizing treatment. MethodsThis cross-sectional study consisted of 159 bipolar outpatients and 258 controls. A low-dose-dexamethasone-suppression-test (DST) was used to measure HPA-axis activity. ResultsPatients with BD showed a negative association between post DST cortisol and age (−3.0 nmol/l per year; p=0.007). This association gradually increased in subgroups that were naïve to lithium (−7.7 nmol/l per year; p=0.001) and “all mood stabilizers” (−11.4 nmol/l per year; p=0.004). Patients exhibiting hypercortisolism were characterized by younger age and female gender, whereas patients exhibiting hypocortisolism were characterized by long disease duration without prophylactic lithium treatment as well as absence of current lithium medication. LimitationsCross sectional study design. ConclusionsThere was a negative association between HPA-axis activity and age in BD, rendering BD patients at risk for developing hypocortisolism. This association was most pronounced among patients without previous or current lithium prophylaxis.

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

HPA Axis Function as Biomarker for Atypical and Melancholic Depression

Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity.

Preclinical data suggest that chronic stress may cause cellular damage and mitochondrial dysfunction, potentially leading to the release of mitochondrial DNA (mtDNA) into the bloodstream. Major depressive disorder has been associated with an increased amount of mtDNA in leukocytes from saliva samples and blood; however, no previous studies have measured plasma levels of free-circulating mtDNA in a clinical psychiatric sample. In this study, free circulating mtDNA was quantified in plasma samples from 37 suicide attempters, who had undergone a dexamethasone suppression test (DST), and 37 healthy controls. We hypothesized that free circulating mtDNA would be elevated in the suicide attempters and would be associated with hypothalamic–pituitary–adrenal (HPA)-axis hyperactivity. Suicide attempters had significantly higher plasma levels of free-circulating mtDNA compared with healthy controls at different time points (pre- and post-DST; all P-values<2.98E−12, Cohen's d ranging from 2.55 to 4.01). Pre-DST plasma levels of mtDNA were positively correlated with post-DST cortisol levels (rho=0.49, P<0.003). Suicide attempters may have elevated plasma levels of free-circulating mtDNA, which are related to impaired HPA-axis negative feedback. This peripheral index is consistent with an increased cellular or mitochondrial damage. The specific cells and tissues contributing to plasma levels of free-circulating mtDNA are not known, as is the specificity of this finding for suicide attempters. Future studies are needed in order to better understand the relevance of increased free-circulating mtDNA in relation to the pathophysiology underlying suicidal behavior and depression.