Adrenal function in relation to cytokines and outcome in non-critically ill patients with COVID-19.

PURPOSE: We aimed to identify whether hypothalamic-pituitary-adrenal (HPA) axis dysfunction is related to deterioration in a percentage of patients who progress to severe COVID-19. METHODS: In this cohort observational study, we evaluated HPA axis activation by measuring cortisol, adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate (DHEA-S) levels, whole blood expression levels of the key glucocorticoid receptor, GCR-α, and the glucocorticoid-induced leucine zipper (GILZ), and cytokines, as markers of the inflammatory phase, in 149 patients with respiratory infection admitted in the ward, without known adrenal disease and/or confounding medications (glucocorticoids). One hundred and four (104) patients were SARS-CoV-2 positive (C +) and controls consisted of 45 SARS-CoV-2-negative patients (NC). RESULTS: No differences in cortisol levels were observed between the C + and the NC patients. Cortisol levels correlated with ACTH (r = 0.284, p = 0.001) and IL-6 (r = 0.289, p = 0.04). In C + patients, cortisol levels mainly correlated with IL-6 levels (r = 0.28; p = 0.017). GCR-α expression was significantly higher in C + patients compared to NC. Patients with higher cortisol levels were more likely to progress to respiratory function deterioration or die. Both GCR-α and GILZ expression were significantly higher in C + non-survivors. CONCLUSION: Our findings indicate that cortisol serves as an indicator of disease severity. GILZ expression appears to be a more effective marker of mortality prediction in moderate COVID-19 cases. However, routine measurement of GILZ levels is currently unavailable. Elevated levels of cortisol may be indicative of patients with moderate COVID-19 who are at a higher risk of deterioration. This information can aid in identifying individuals who require early medical attention.

Inferior petrosal sinus sampling in Cushing's syndrome: usefulness and pitfalls.

In patients with ACTH-dependent Cushing's syndrome (CS), the differentiation between Cushing's disease (CD) and ectopic ACTH secretion (EAS) can often be challenging. The traditionally used biochemical tests have limited diagnostic accuracy and imaging modalities may fail to detect the culprit lesion. Inferior petrosal sinus sampling (IPSS) was introduced more than 3 decades ago as a test with optimal diagnostic accuracy and has since become the gold standard in the differential diagnosis between CD and EAS. However, several, albeit rare, pitfalls may limit its diagnostic accuracy and awareness is needed to avoid incorrect interventions. Moreover, it is an invasive and demanding procedure, available in a limited number of centers worldwide. This review aims to critically present the usefulness and pitfalls of IPSS and define strategies for its optimal place in the contemporary management of CS.

Cushing's disease: the desmopressin test as a compelling predictive marker of long-term remission after transsphenoidal surgery.

Transsphenoidal surgery (TSS) is the treatment of choice in Cushing's disease. However, recurrence rates are substantial and currently there are no robust predictors of late prognosis. As accumulating evidence challenge the accuracy of the traditionally used early postoperative cortisol values, alternative tests are required. The study of Cambos et al., published in a recent issue of the European Journal of Endocrinology, adds to the existing data that support a role of the desmopressin test as an early and reliable predictive marker in successfully TSS-treated patients. However, despite these promising data, the use of this test is hampered by the fact that it can be applied only in patients with a documented preoperative positive test. Moreover, the lack of robust criteria to define positive postoperative responses represents another major limitation.

The Desmopressin Test Predicts Better Than Basal Cortisol the Long-Term Surgical Outcome of Cushing's Disease.

CONTEXT: Cushing's disease (CD) has a significant relapse rate after successful transsphenoidal surgery (TSS). Many CD patients respond aberrantly to the desmopressin test (DT). Disappearance of this response after surgery may suggest complete removal of abnormal corticotrophs and a lower possibility of recurrence. OBJECTIVE: The utility of postoperative DT to predict long-term outcome compared to the widely used postoperative cortisol level. DESIGN: Retrospective analysis. SETTING: Tertiary hospital. PATIENTS: Seventy-three patients underwent TSS and postoperative DT; 51 had sustained remission, defined as normal dexamethasone suppression and urinary free cortisol at 6 months. After excluding 12 patients with short follow-up, negative or no preoperative DT, we analyzed 39 patients. INTERVENTION(S): Measurements of morning cortisol at 1-2 weeks and DT within 6 months after TSS. MAIN OUTCOME MEASURE(S): Recurrence or remission at latest follow-up. RESULTS: Mean follow-up was 63 ± 50 months. Recurrence occurred in seven patients. In logistic regression analysis, postoperative cortisol levels were not associated with remission. Apart from the percentage increment of cortisol, all other DT criteria (peak cortisol, peak ACTH, absolute cortisol increment [ΔCort], absolute ACTH change, and percentage absolute ACTH change) were significant predictors of outcome. In receiver operating characteristic analysis, the ΔCort had the best diagnostic performance. ΔCort <7.4 µg/dL had a sensitivity of 97% to detect remission. Comparison of Kaplan-Meier curves showed that ΔCort <7.4 µg/dL was associated with remission, whereas ΔCort ≥7.4 µg/dL had a hazard ratio of recurrence of 24.7 (95% confidence interval, 10.6-448.5) at 60 months (median). CONCLUSION: Loss of desmopressin response indicates favorable prognosis and, if used in addition to basal cortisol levels, improves the accuracy of the postoperative assessment of CD.

The ongoing challenge of discrepant growth hormone and insulin-like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta-analysis.

OBJECTIVE: Growth hormone (GH) and insulin-like growth factor I (IGF-I) are the principal biomarkers used to assess disease activity in acromegaly, and any discrepancy between them renders interpretation of results inconclusive. Purpose of this study was to assess the frequency of this discrepancy and identify parameters that might affect its occurrence. DESIGN: A systematic review of MEDLINE and Scopus was performed (1987-2013) followed by a meta-analysis to address the frequency of discrepant results between GH and IGF-I levels. Meta-regression and subgroup analyses were performed assessing the effects of the year of publication, the different types of GH testing and GH assays used, as well as the impact of treatment with somatostatin analogues (SSAs) on the occurrence of this discrepancy. RESULTS: The analysis retrieved 39 eligible studies totalling 7071 patients. The pooled discordance rate between GH and IGF-I was 25·7% (95% CI: 22·3-29·4), and the predominant format was that of elevated IGF-I with normal GH levels (15·3%, 95% CI: 12·5-18·7). No significant correlation between the discordance rate and the year of publication was shown; whereas, the use of ultrasensitive GH assays resulted in higher discordance rates (30·7%, 95% CI: 25·9-35·9 vs 19·8%, 95% CI: 14·1-27·2, P = 0·04) as did treatment with SSAs (32·5%, 95% CI: 27·8-37·4) vs (21·6%, 95% CI: 17·8-25·6, P = 0·001). CONCLUSIONS: Discrepancy between GH and IGF-I results is encountered in a quarter of treated patients with acromegaly, especially when using ultrasensitive GH assays or in patients receiving SSAs, a fact that the clinician should take into consideration when making clinical decisions.

Biochemical and clinical benefits of unilateral adrenalectomy in patients with subclinical hypercortisolism and bilateral adrenal incidentalomas.

OBJECTIVE: The treatment of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas (AI) is debatable. We aimed to compare the biochemical and clinical outcome of unilateral adrenalectomy vs a conservative approach in these patients. DESIGN: Retrospective study. METHODS: The study included 33 patients with bilateral AI; 14 patients underwent unilateral adrenalectomy of the largest lesion (surgical group), whereas 19 patients were followed up (follow-up group). At baseline and at each follow-up visit, we measured 0800 h plasma ACTH, midnight serum cortisol (MSF), 24-h urinary-free cortisol (UFC) and serum cortisol following a standard 2-day low-dose-dexamethasone-suppression test (LDDST). We evaluated the following comorbidities: arterial hypertension, impaired glucose tolerance or diabetes mellitus, dyslipidemia and osteoporosis. RESULTS: Baseline demographic, clinical characteristics and the duration of follow-up (53.9±21.3 vs 51.8±20.1 months, for the surgical vs the follow-up group) were similar between groups. At the last follow-up visit the surgical group had a significant reduction in post-LDDST cortisol (2.4±1.6 vs 6.7±3.9 µg/dl, P=0.002), MSF (4.3±2 vs 8.8±4.6 µg/dl, P=0.006) and 24-h UFC (50.1±21.1 vs 117.9±42.4 µg/24 h, P=0.0007) and a significant rise in mean±s.d. morning plasma ACTH levels (22.2±9.6 vs 6.9±4.8 pg/ml, P=0.002). Improvement in co-morbidities was seen only in the surgical group, whereas no changes were noted in the follow-up group. CONCLUSIONS: Our early results show that removal of the largest lesion offers significant improvement both to cortisol excess and its metabolic consequences, without the debilitating effects of bilateral adrenalectomy. A larger number of patients, as well as a longer follow-up, are required before drawing solid conclusions.

Increased prevalence of polycystic ovary syndrome in premenopausal women with nonalcoholic fatty liver disease.

OBJECTIVE: Limited data exist concerning the presence of polycystic ovary syndrome (PCOS) in premenopausal women with nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the prevalence of PCOS in overweight and obese premenopausal women with NAFLD. DESIGN: Prospective, observational, and cross-sectional study. METHODS: We studied 110 apparently healthy, overweight, and obese (BMI: 25.1-49.1 kg/m(2)) premenopausal women (age: 18-45 years) reporting no or minimal alcohol consumption for NAFLD with abdominal ultrasonography after excluding causes of secondary liver disease and for PCOS (Rotterdam criteria) with clinical examination, biochemical evaluation, and pelvic ultrasonography. Insulin resistance (IR) was assessed by homeostasis model assessment of IR (HOMA-IR), and free androgen index was calculated. RESULTS: NAFLD was detected in 71/110 women (64.5%). Women with NAFLD compared to women without NAFLD were more commonly diagnosed with PCOS (43.7% vs 23.1%, respectively, P=0.04), metabolic syndrome (30.2% vs 5.3%, respectively, P=0.003), and abnormal lipid profile (81.1% vs 51.3%, P=0.002). All women with abnormal glucose metabolism had NAFLD (P=0.01). Although PCOS was associated with NAFLD (OR 2.6, 95% CI: 1.1-6.2, P=0.04), in a multivariate analysis higher HOMA-IR values (OR 2.2, 95% CI: 1.1-4.4, P=0.02) and triglyceride levels (OR 1.01, 95% CI: 1.00-1.02, P=0.04) independently predicted NAFLD, after adjusting for age, BMI, and waist-to-hip ratio. CONCLUSIONS: These findings indicate an increased prevalence of PCOS in overweight and obese premenopausal women with NAFLD, although it is not supported that the syndrome is primarily involved in NAFLD. Evaluation for PCOS may be considered in these women.

Abnormal Responsiveness to Dexamethasone-Suppressed CRH Test in Patients With Bilateral Adrenal Incidentalomas.

CONTEXT: The bilateral formation of nodules indicates that the pathogenesis of bilateral adrenal incidentalomas (AI) may differ from that of unilateral AI. A possible role of hypothalamo-pituitary-adrenal (HPA) axis dysregulation in their formation has not been investigated. OBJECTIVE: The objective of the study was to evaluate the presence of altered feedback regulation of HPA axis in patients with bilateral AI. DESIGN: The dexamethasone (DEX) suppression-CRH test was used to assess ACTH and cortisol responses in controls and patients with unilateral and bilateral AI. SETTING: The study was conducted at endocrine departments of two tertiary centers. PATIENTS: We studied 24 controls and 39 patients with unilateral and 46 with bilateral AI. INTERVENTIONS: All subjects underwent standard low-dose dexamethasone suppression followed by iv bolus administration of human CRH (100 µg). RESULTS: Bilateral AI had higher levels of ACTH and cortisol after the DEX-CRH challenge compared with both controls (P < .01 for ACTH and P < .001 for cortisol) and unilateral AI (P < .01 for ACTH and cortisol). A positive response, defined as peak ACTH greater than 10 pg/mL at 15 and/or 30 minutes followed by a significant rise in cortisol levels, was noted in 41.3% of bilateral vs 2.6% in unilateral AI (P < .001). Bilateral responders did not differ from nonresponders in demographic or hormonal characteristics, but they had larger total adrenal size compared with nonresponders. CONCLUSIONS: A significant proportion of patients with bilateral AI demonstrate positive responses to the DEX-CRH test compared with unilateral AI, providing ground for potential involvement of HPA axis dysregulation in the pathogenesis, in at least a subgroup, of bilateral AI patients.

Impact of gsp mutations in somatotroph pituitary adenomas on growth hormone response to somatostatin analogs: a meta-analysis.

OBJECTIVE: Somatic mutations in the GNAS1 gene, which encodes the alpha-subunit of G stimulatory proteins (gsp), are frequently detected in somatotroph pituitary tumors and have been associated to specific clinical and histopathological characteristics. However, the question whether the presence of a somatic gsp mutation affects the response to somatostatin analog treatment remains unresolved. DESIGN: Following a literature search, we performed a meta-analysis, including 8 eligible studies, in order to estimate the effect of gsp mutation on the percent reduction of growth hormone (GH) levels during an acute octreotide suppression test (OST). A total of 310 patients with acromegaly [126 gsp (+) and 184 gsp (-)] were included in the analysis. RESULTS: The presence of the gsp mutation was related with a greater reduction in GH levels on OST [Weighted Mean Difference (WMD): 9.08 % (95 % CI, 2.73, 15.42); p = 0.005; random effects model]. There was significant heterogeneity for this effect estimate (I(2) = 58 %, p value for heterogeneity = 0.02). A sensitivity analysis after exclusion of a study with different methodology of OST provided similar estimates [WMD: 6.93 % (95 % CI, 1.40, 12.46); p = 0.01], albeit with no significant heterogeneity (I(2) = 35 %, p value for heterogeneity = 0.16). CONCLUSIONS: The present meta-analysis suggests a role for gsp mutation as a prognostic factor of treatment response to somatostatin analogs.

Adipose tissue lipolysis and circulating lipids in acute and subacute critical illness: effects of shock and treatment.

PURPOSE: The purpose of this study is to assess lipid metabolism at the tissue level in critically ill subjects. MATERIALS AND METHODS: We studied 182 patients with systemic inflammatory response syndrome/severe sepsis or shock during the acute (day 1) and subacute phase of critical illness (day 6). All subjects had a tissue microdialysis (MD) catheter placed in femoral adipose tissue upon admission to the intensive care unit (ICU). Plasma cholesterol, high-density lipoprotein, low-density lipoprotein, free fatty acids (FFAs), triglyceride, and MD glycerol (GLYC) were measured on days 1 and 6 in the ICU. RESULTS: On admission, 56% of the patients had increased levels (>200 µmol/L) of MD GLYC. Patients with shock displayed more pronounced subcutaneous tissue lipolysis and more profound derangements of circulating lipids vs patients without shock (but no appreciable differences in FFA levels). Furthermore, in patients with shock during the acute period, there were positive, albeit weak, correlations of subcutaneous tissue lipolysis (MD GLYC), plasma FFAs (r=0.260; P=.01), and norepinephrine's dose (r=0.230; P=.01), whereas during the subacute phase, MD GLY levels were higher in patients receiving glucocorticoids (344.7±276.0 µmol/L vs 252.2±158.4 µmol/L; P=.03). CONCLUSIONS: Subcutaneous tissue lipolysis is only one of the many determinants of plasma FFAs. Routinely applied therapeutic modalities in the ICU interfere with adipose tissue metabolism.

Elevated adipose tissue lactate to pyruvate (L/P) ratio predicts poor outcome in critically ill patients with septic shock: a microdialysis study.

BACKGROUND: Sepsis is a disease affecting tissue metabolism; in vivo microdialysis (MD) is a bedside technique enabling researchers to monitor tissue metabolic changes. We conducted this study aiming to evaluate the relationship between lactate to pyruvate (L/P) ratio, a sensitive marker of tissue oxygenation and perfusion, and mortality in critically ill septic patients. METHODS: We enrolled 105 patients with septic shock hospitalized in the mixed intensive care unit of a tertiary hospital. A MD catheter was inserted in the subcutaneous adipose tissue of the upper thigh and interstitial fluid samples were collected and analyzed for glucose, lactate, pyruvate, and glycerol. RESULTS: Multivariate regression analysis showed that among variables registered on day 1, APACHE II and SOFA scores, blood lactate and microdialysis-assessed tissue L/P ratio were independently associated with 28-day mortality. Even in patients with normal (<2 mmol/L) blood lactate, adipose tissue L/P ratio showed a strong trend to statistical significance. During the 6-day study period, non-survivors had significantly higher L/P ratios compared to survivors (P=0.001) and mixed model analysis revealed a different pattern of evolution in time with non-survivors experiencing an increase while survivors had a late decline in their L/P ratio. The AUC for L/P ratio was similar to that of APACHE II (P=0.67) and SOFA score (P=0.73). Comparison of the Kaplan-Meier 28-day survival curves of patients with normal (≤ 25) versus elevated (>25) L/P ratios showed that the latter survived significantly less (P=0.02; log-rank test). CONCLUSION: Elevated adipose tissue L/P ratio is associated with poor outcome in critically ill patients with septic shock. Microdialysis deserves to be further studied as a research tool in the multi-modal monitoring of septic critically ill patients.

Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman.

BACKGROUND: Corticosteroid-binding globulin (CBG), encoded by SERPINA6, is the principal plasma binding protein for cortisol. Most nonsynonymous single-nucleotide polymorphisms that alter the production or function of CBG occur rarely, and their clinical significance remains obscure. METHODS: Serum and DNA were obtained from a Greek woman with low morning cortisol levels and from family members. SERPINA6 exons were sequenced, and serum CBG was measured by ELISA and cortisol-binding capacity assay. Recombinant CBG variants were produced for detailed functional studies. RESULTS: A novel heterozygous c.1282G>C transversion in exon 5 of SERPINA6, resulting in a p.Trp393Ser (W371S) substitution, was identified in the proband, who was also heterozygous for single-nucleotide polymorphisms encoding the CBG Lyon (D367N) and CBG A224S variants. The proband had no measurable plasma cortisol-binding activity despite a CBG level of 273 nm by ELISA. She inherited CBG W371S from her mother whose plasma cortisol-binding capacity was approximately 50% lower than the CBG measurements by ELISA (314 nm). The proband's father and four children were heterozygous for CBG D367N; their CBG levels by ELISA were normal, but corresponding cortisol-binding capacity measurements were 50% lower. Pedigree analysis revealed that W371S segregates with A224 and that D367N and W371S segregate separately. Recombinant CBG D367N and CBG W371S had no measureable cortisol-binding activity. CONCLUSION: A new CBG Athens (W371S) variant that lacks cortisol-binding activity has been identified in a carrier of the cortisol-binding deficient CBG Lyon (D367N) variant. Analyses of CBG levels in this pedigree illustrate how immunoassays fail to accurately reflect cortisol-binding activity.