Down-Regulation of the Mineralocorticoid Receptor (MR) and Up-Regulation of Hydroxysteroid 11-Beta Dehydrogenase Type 2 (HSD11B2) Isoenzyme in Critically Ill Patients.

Objective: The mineralocorticoid receptor (MR) has two ligands, aldosterone and cortisol. Hydroxysteroid 11-beta dehydrogenase (HSD11B) isoenzymes regulate which ligand will bind to MR. In this study we aimed to evaluate the expression of the MR and the HSD11B isozymes in peripheral polymorphonuclear cells (PMNs) in critical illness for a 13-day period.Design: Prospective studySetting: One multi-disciplinary intensive care unit (ICU)Participants: Forty-two critically ill patientsMethods: Messenger RNA (mRNA) expression of MR, HSD11B1, and HSD11B2, aldosterone levels, and plasma renin activity (PRA) were measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age and sex-matched healthy subjects were used as controls.Results: Compared to healthy controls, MR expression in critically ill patients was lower during the entire study period. HSD11B1 expression was also lower, while HSD11B2 expression was higher. In patients, PRA, aldosterone, the aldosterone:renin ratio, and cortisol remained unaltered during the study period.Conclusion: Our results suggest that, in our cohort of critically ill patients, local endogenous cortisol availability is diminished, pointing towards glucocorticoid resistance. Aldosterone probably occupies the MR, raising the possibility that PMNs might be useful to study to gain insights into MR functionality during pathological states.

Cardiometabolic Disease Burden and Steroid Excretion in Benign Adrenal Tumors : A Cross-Sectional Multicenter Study.

BACKGROUND: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. OBJECTIVE: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. DESIGN: Cross-sectional study. SETTING: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). PARTICIPANTS: 1305 prospectively recruited persons with benign adrenal tumors. MEASUREMENTS: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: <50 nmol/L, nonfunctioning adrenal tumor [NFAT]; 50 to 138 nmol/L, possible MACS [MACS-1]; >138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. RESULTS: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. LIMITATIONS: Cross-sectional design; possible selection bias. CONCLUSION: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes. PRIMARY FUNDING SOURCE: Diabetes UK, the European Commission, U.K. Medical Research Council, the U.K. Academy of Medical Sciences, the Wellcome Trust, the U.K. National Institute for Health Research, the U.S. National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

Cushing's disease: risk of recurrence following trans-sphenoidal surgery, timing and methods for evaluation.

The treatment of choice for Cushing's disease (CD) is trans-sphenoidal surgery (TSS). However, TSS is not always curative and, even when curative it is associated with a substantial rate of recurrence. Published recurrence rates vary between 5 and 20%; half of these recurrences appear within 5-years and the remaining half within or even after 10 years post-surgery. A low or undetectable cortisol in the immediate post-op period is regarded as the best criterion of remission. However, low post-op cortisol levels do not accurately predict long-term remission. Moreover, there are no other robust predictors providing certainty about the long-term outcomes. Interestingly, several studies have shown that the desmopressin test performed in the early post-op period may have some promise in predicting more precisely the risk of recurrence. In view of the lack of robust ways to predict long-term outcomes, current guidelines suggest that every patient in remission should be monitored for the possibility of recurrence. The methods used to detect recurrence are similar to those used to assess the cortisol secretory status and include assessment of: (i) abnormal circadian rhythm by late night salivary cortisol (LNSC) or midnight serum cortisol; (ii) impaired cortisol feedback by the dexamethasone suppression test and; (iii) increased 24-h bioavailable cortisol by urinary free cortisol. The timing of evaluation begins when HPA axis recovers, and then annually or sooner in case of clinical suspicion. Currently LNSC is regarded as the earliest and most sensitive biochemical alteration in detecting recurrence; a major caveat for LNSC, however, is its great variability. In practice, the diagnosis of recurrence is a challenge due to the fact that recurrence is usually a slow process with apparent clinical manifestations that may be delayed and alterations of classical biomarkers that may be delayed as well.

Levoketoconazole in the treatment of patients with endogenous Cushing's syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS).

PURPOSE: The efficacy of levoketoconazole for endogenous Cushing's syndrome was demonstrated in a phase 3, open-label study (SONICS). This study (LOGICS) evaluated drug-specificity of cortisol normalization. METHODS: LOGICS was a phase 3, placebo-controlled, randomized-withdrawal study with open-label titration-maintenance (14-19 weeks) followed by double-blind, randomized-withdrawal (~ 8 weeks), and restoration (~ 8 weeks) phases. RESULTS: 79 patients received levoketoconazole during titration-maintenance; 39 patients on a stable dose (~ 4 weeks or more) proceeded to randomization. These and 5 SONICS completers who did not require dose titration were randomized to levoketoconazole (n = 22) or placebo (n = 22). All patients with loss of response (the primary endpoint) met the prespecified criterion of mean urinary free cortisol (mUFC) > 1.5 × upper limit of normal. During randomized-withdrawal, 21 patients withdrawn to placebo (95.5%) lost mUFC response compared with 9 patients continuing levoketoconazole (40.9%); treatment difference: - 54.5% (95% CI - 75.7, - 27.4; P = 0.0002). At the end of randomized-withdrawal, mUFC normalization was observed among 11 (50.0%) patients receiving levoketoconazole and 1 (4.5%) receiving placebo; treatment difference: 45.5% (95% CI 19.2, 67.9; P = 0.0015). Restoration of levoketoconazole reversed loss of cortisol control in most patients who had received placebo. Adverse events were reported in 89% of patients during treatment with levoketoconazole (dose-titration, randomized-withdrawal, and restoration phases combined), most commonly nausea (29%) and hypokalemia (26%). Prespecified adverse events of special interest with levoketoconazole were liver-related (10.7%), QT interval prolongation (10.7%), and adrenal insufficiency (9.5%). CONCLUSIONS: Levoketoconazole reversibly normalized urinary cortisol in patients with Cushing's syndrome. No new risks of levoketoconazole treatment were identified.

Increased Glucocorticoid Receptor Alpha Expression and Signaling in Critically Ill Coronavirus Disease 2019 Patients.

OBJECTIVES: Critical illness is characterized by increased serum cortisol concentrations and bioavailability resulting from the activation of the hypothalamic-pituitary-adrenal axis, which constitutes an essential part of the stress response. The actions of glucocorticoids are mediated by a ubiquitous intracellular receptor protein, the glucocorticoid receptor. So far, data on coronavirus disease 2019 and glucocorticoid receptor alpha expression are lacking. DESIGN: Prospective observational study. SETTING: One academic multidisciplinary ICU. SUBJECTS: Twenty-six adult coronavirus disease 2019 patients; 33 adult noncoronavirus disease 2019 patients, matched for age, sex, and disease severity, constituted the control group. All patients were steroid-free. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Glucocorticoid receptor alpha, glucocorticoid-inducible leucine zipper expression, and serum cortisol were measured on ICU admission. In coronavirus disease 2019 patients, glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper messenger RNA expression were upregulated (4.7-fold, p < 0.01 and 14-fold, p < 0.0001, respectively), and cortisol was higher (20.3 vs 14.3 µg/dL, p < 0.01) compared with the control group. CONCLUSIONS: ICU coronavirus disease 2019 patients showed upregulated glucocorticoid receptor alpha and glucocorticoid-inducible leucine zipper expression, along with cortisol levels, compared with ICU noncoronavirus disease 2019 patients. Thus, on ICU admission, critical coronavirus disease 2019 appears to be associated with hypercortisolemia, and increased synthesis of glucocorticoid receptor alpha and induced proteins.

Histology is more ιmportant than persistent anti-Tg antibodies for progression of differentiated thyroid cancer.

CONTEXT: Anti-thyroglobulin antibodies (anti-Tg), present in 20%-25% of differentiated thyroid cancer (DTC) patients, interfere with thyroglobulin measurements posing a challenge in the follow-up. OBJECTIVES: The aim of this study was to identify clinical-histological factors that may affect anti-Tg persistence and disease outcome in DTC with positive anti-Tg. METHODS: We retrospectively studied 234 DTC patients, with positive anti-Tg at diagnosis (females: 82.1%, age at diagnosis: 46.0 ± 14.4 yrs, median follow-up: 5 yrs (1.5-32 yrs). 221/234 (94.4%) received radioiodine (RAI) ablation. Patients were divided into two subgroups: those whose anti-Tg became undetectable (anti-Tg-NEG) and those whose anti-Tg remained positive (anti-Tg-POS) at the end of the follow-up period. RESULTS: Anti-Tg-POS patients (n = 80, 34.2%) compared to anti-Tg-NEG (n = 154, 65.8%) had more frequently lymph node infiltration (36.3% vs 20.1%, P = .01), extrathyroidal extension (ETE, 35.0% vs 22.1%, P = .04), poorly differentiated DTC and increased tumour size (P ≤ .004). They received higher total RAI dose (P < .001). In most cases, additional RAI administration and/or additional surgeries did not lead to anti-Tg elimination. These had more frequently structural disease persistence/progression compared to anti-Tg-NEG (remission: 78.8% vs 95.5%, persistence: 13.8% vs 3.9%, progression: 7.5% vs 0.6%, P < .001). In Kaplan-Meier analysis, the probability of disease progression was higher in anti-Tg-POS. In Cox proportional hazard analysis, the predictors of disease progression were size (P = .002) and ETE (P = .006). CONCLUSIONS: Worse histological features are more frequent in patients with anti-Tg persistence during follow-up. Further additional RAI administration and/or surgeries do not affect anti-Tg elimination in most cases. Anti-Tg persistence correlates with structural persistence although tumour size and extrathyroidal extension are the main predictors of disease progression.

Pituitary-Adrenal Responses and Glucocorticoid Receptor Expression in Critically Ill Patients with COVID-19.

The hypothalamus-pituitary-adrenal (HPA) axis was described as the principal component of the stress response 85 years ago, along with the acute-phase reaction, and the defense response at the tissue level. The orchestration of these processes is essential since systemic inflammation is a double-edged sword; whereas inflammation that is timely and of appropriate magnitude is beneficial, exuberant systemic inflammation incites tissue damage with potentially devastating consequences. Apart from its beneficial cardiovascular and metabolic effects, cortisol exerts a significant immunoregulatory role, a major attribute being that it restrains the excessive inflammatory reaction, thereby preventing unwanted tissue damage. In this review, we will discuss the role of the HPA axis in the normal stress response and in critical illness, especially in critically ill patients with coronavirus disease 2019 (COVID-19). Finally, a chapter will be dedicated to the findings from clinical studies in critical illness and COVID-19 on the expression of the mediator of glucocorticoid actions, the glucocorticoid receptor (GCR).

Glycemia, Beta-Cell Function and Sensitivity to Insulin in Mildly to Critically Ill Covid-19 Patients.

Background and objectives: Critically and non-critically ill patients with SARS-CoV-2 infection (Covid-19) may present with higher-than-expected glycemia, even in the absence of diabetes. With this study we aimed to assess glucose, glycemic gap (GlyG) and insulin secretion/sensitivity measures in patients with Covid-19. Materials and Methods: We studied, upon admission, 157 patients with Covid-19 (84: in wards and 73: in intensive care units; ICU); 135 had no history of diabetes. We measured blood glucose upon admission as well as glycated hemoglobin (A1c), plasma insulin and C-peptide. We calculated the GlyG and the Homeostasis Model Assessment 2 (HOMA2) estimates of steady state beta cell function (HOMA2%B) and insulin sensitivity (HOMA2%S). Statistical assessment was done with analysis or the Kruskal-Wallis test. Results: Compared to patients in the wards without diabetes, patients with diabetes in the wards, as well as patients in the ICU (without or with diabetes) had higher admission glycemia. The GlyG was significantly higher in patients without diabetes in the ICU compared to patients without diabetes in the wards, while HOMA2%B based on glucose and insulin was significantly higher in the ICU patients compared to patients in the wards. Of all the parameters, HOMA2%S based on C-peptide/glucose was higher in survivors (n = 133). Conclusions: In our series of patients with Covid-19, a substantial number of patients with and without diabetes had admission hyperglycemia and those who were critically ill may have had compromised insulin secretion and lowered sensitivity to insulin. These findings lend credence to reports of association between Covid-19 and hyperglycemia/secondary diabetes.

Decreased glucocorticoid receptor expression during critical illness.

INTRODUCTION: In critically ill patients, the hypothalamic-pituitary-adrenal axis is activated, resulting in increased serum cortisol concentrations. However, in some patients, especially those with sepsis, cortisol levels are relatively low for the degree of illness severity. Therefore, in the present project, we aim to characterize the time course of glucocorticoid receptor (GCR) alpha and beta expression in peripheral polymorphonuclear cells of critically ill septic or nonseptic patients using real-time PCR. DESIGN: A prospective observational study conducted on 32 critically ill adults not receiving steroids, in a university-affiliated, multidisciplinary intensive care unit (ICU). Blood samples were collected for measurement of glucocorticoid receptor expression within 24-48 hours of admission to the ICU and at days 4, 8 and 13 after admission, reflecting the acute and chronic phase of the illness. RESULTS: During ICU stay, patients expressed over time reduced levels of both GCR-α and GCR-ß mRNA. More specifically, GCR-α mRNA expression was decreased fourfold 4 days after admission (P < 0.0001) and remained low up to 2 weeks after admission (P < 0.001). On the other hand, GCR-ß mRNA levels remained stable shortly after admission, but approx. one week after admission, its levels decreased threefold (P < 0.01) and remained reduced up to 2 weeks after admission (P < 0.001). DISCUSSION: Our results suggest that critically ill patients have highly variable expression of alpha and beta GCR, and moreover, the levels of both receptors decrease during ICU stay. Taken together, these might explain the differential responsiveness of patients to exogenous steroid administration or to endogenous cortisol secretion.

Traumatic brain injury induced neuroendocrine changes: acute hormonal changes of anterior pituitary function.

PURPOSE: It is estimated that approximately 69 million individuals worldwide will sustain a TBI each year, which accounts for substantial morbidity and mortality in both children and adults. TBI may lead to significant neuroendocrine changes, if the delicate pituitary is ruptured. In this review, we focus on the anterior pituitary hormonal changes in the acute post-TBI period and we present the evidence supporting the need for screening of anterior pituitary function in the early post-TBI time along with current suggestions regarding the endocrine assessment and management of these patients. METHODS: Original systematic articles with prospective and/or retrospective design studies of acute TBI were included, as were review articles and case series. RESULTS: Although TBI may motivate an acute increase of stress hormones, it may also generate a wide spectrum of anterior pituitary hormonal deficiencies. The frequency of post-traumatic anterior hypopituitarism (PTHP) varies according to the severity, the type of trauma, the time elapsed since injury, the study population, and the methodology used to diagnose pituitary hormone deficiency. Early neuroendocrine abnormalities may be transient, but additional late ones may also appear during the course of rehabilitation. CONCLUSIONS: Acute hypocortisolism should be diagnosed and managed promptly, as it can be life-threatening, but currently there is no evidence to support treatment of acute GH, thyroid hormones or gonadotropins deficiencies. However, a more comprehensive assessment of anterior pituitary function should be undertaken both in the early and in the post-acute phase, since ongoing hormone deficiencies may adversely affect the recovery and quality of life of these patients.

CLINICAL PRESENTATION AND LONG-TERM OUTCOME OF PATIENTS WITH ECTOPIC ACTH SYNDROME DUE TO BRONCHIAL CARCINOID TUMORS: A ONE-CENTER EXPERIENCE.

OBJECTIVE: To describe the diagnostic features and long-term outcome of patients with bronchial carcinoid tumors with ectopic adrenocorticotropic hormone (ACTH) syndrome (EAS), treated in our department. METHODS: We studied 10 cases with EAS and histologically confirmed bronchial carcinoid tumors, diagnosed from 1992 until 2006. Diagnosis was based upon blood, urine, radiologic, and interventional tests. Disease status at the time of the last follow-up was the primary outcome measure. RESULTS: Clinical manifestations included Cushingoid features (100%), psychiatric symptoms (90%), hypertension (70%), diabetes/impaired glucose tolerance (40%), osteoporosis (10%), and hypokalemia (10%). The average time from the onset of symptoms until diagnosis was 14.2 ± 17.0 months. None of the patients exhibited a positive cortisol or ACTH response to corticotropin-releasing hormone (CRH) test, and none showed a positive gradient on bilateral inferior petrosal sinus sampling (BIPSS). All tumors were identified by computed tomography and by octreotide scintigraphy in 8 patients. All patients underwent surgical resection of the tumor, and 2 patients had adjuvant radiation therapy. The mean follow-up was 126.6 ± 63.3 months. At latest follow-up, 8 patients were in remission and 2 had recurrence of the EAS; both had a multifocal tumor. The 2 patients submitted to adjuvant radiation therapy were in remission at their latest follow-up, despite local invasion and lymph node metastases. CONCLUSION: CRH test and BIPSS are the most useful methods in diagnosing EAS. For localization, repeated imaging studies are necessary. Surgical treatment is effective in most cases. Adjunctive radiotherapy may be useful in patients with lymph node metastases. Patients with multifocal disease should be monitored for potential recurrence.

Impact of early vs late postoperative radioiodine remnant ablation on final outcome in patients with low-risk well-differentiated thyroid cancer.

OBJECTIVE: Postoperative radioiodine remnant ablation (RRA) represents an adjunctive therapeutic modality in patients with differentiated thyroid cancer (DTC). The impact of late vs early RRA on the outcome of DTC is currently unclear. The aim of the study was to evaluate the outcome of patients with DTC according to RRA timing. DESIGN RETROSPECTIVE STUDY PATIENTS: A total of 107 TNM stage 1 DTC patients were divided into two groups. In group A (n = 50), RRA was administered in less than 4·7 months median 3·0 (range 0·8-4·7), while in group B (n = 57) in more than 4·7 months median 6 (4·8-30·3) after thyroidectomy. Remission was achieved when stimulated serum Tg levels were undetectable, in the absence of local recurrence or cervical lymph node metastases on the neck ultrasound. RESULTS: All patients underwent near-total thyroidectomy. The mean age at diagnosis was 49·3 years (range: 18-79 years). There were no statistically significant differences in the histological subtype, the TNM stage, the dose of radioiodine and the time of follow-up, between the two groups. After the RRA treatment, 44 group A patients (88%) were in remission and 6 (12%) in persistence; while in group B, 52 (91·2%) were in remission, 1 (1·8%) in persistence and 4 (7%) in recurrence. At their latest follow-up median 87·3 (23·3-251·6 months), all patients were in remission, either as a result of further iodine radioiodine therapy (in 11 patients) or watchful monitoring. CONCLUSIONS: The timing of RRA seems to have no effect on the long-term outcome of the disease. Therefore, urgency for radioiodine ablation in patients with low-risk thyroid cancer is not recommended.

Approach to the Patient With Bilateral Adrenal Masses.

Bilateral adrenal masses, increasingly encountered in clinical practice, manifest across diverse contexts, including incidental discovery, malignancy staging, and targeted imaging after hormonal diagnosis of adrenal disorders. The spectrum encompasses various pathologies, such as cortical adenomas, macronodular adrenal disease, pheochromocytomas, myelolipomas, infiltrative disorders, and primary and secondary malignancies. Notably, not all masses in both adrenal glands necessarily share the same etiology, often exhibiting diverse causes. Recently, the European Society of Endocrinology and the European Network for the Study of Adrenal Tumors updated guidelines, introduced a 4-option schema based on imaging, aiding in targeted hormonal testing and management. This "Approach to the Patient" review delves into the latest advancements in imaging, biochemical, and genetic approaches for the diagnostic and management nuances of bilateral adrenal masses. It provides insights and a contemporary framework for navigating the complexities associated with this clinical entity.

Effects of gender and age on hypothalamic-pituitary-adrenal reactivity after pharmacological challenge with low-dose 1-µg ACTH test: a prospective study in healthy adults.

OBJECTIVE: Τhe aim of this study was to observe cortisol responses to a pharmacological challenge with 1 µg ACTH as a function of age and gender. PATIENTS: Twenty-one young (13 women and 8 men; mean age: 43∙48 ± 10∙52 years) and forty elderly (20 women and 20 men; mean age: 79 ± 6∙76 years) volunteers without overt acute or chronic disease participated in this study. MEASUREMENTS: Basal serum cortisol levels were measured, and cortisol values were obtained at 30 and 60 min after administration of 1 µg ACTH. Free thyroxine, triiodothyronine, thyrotrophin, prolactin, dehydroepiandrosterone sulphate (DHEAS), insulin-like growth factor-1, follicle stimulating hormone, luteinizing hormone, oestradiol levels in women and total testosterone levels in men were also measured at baseline. RESULTS: No differences were observed between the groups of older and younger individuals in baseline plasma cortisol levels and mean cortisol responses at 30 and 60 min postchallenge. In the elderly subjects, statistically lower cortisol responses were observed in men at 30 and 60 min after 1-µg ACTH challenge (540∙17 ± 112∙28 vs 670∙11 ± 146∙49 nmol/l in women, P = 0∙003 at 30 min, and 482∙24 ± 108∙14 vs 568∙04 ± 135∙73 nmol/l in women, P = 0∙03 at 60 min). Furthermore, significant lower values in PRL, IGF-1, DHEAS and T3 were detected in older subjects when compared to the younger age group. Interestingly, a higher incidence of individuals who did not achieve normal responses to 1-µg ACTH test (>497 nmol/l) was noted in the group of elderly male subjects. CONCLUSION: This study documents a marked gender effect in the elderly, in the cortisol response levels to 1-µg ACTH stimulation. Elderly men demonstrate a decreased responsiveness compared to women in the same age range.

Post-Thyroidectomy Development of Posterior Reversible Encephalopathy Syndrome (PRES) Due to Calcium Over-Replacement.

Posterior reversible encephalopathy syndrome (PRES) represents a distinct neurological entity characterized by a range of neurological signs and symptoms (seizures, headache, visual abnormalities, altered consciousness, and/or focal neurological signs) and typical neuroimaging findings reflecting reversible subcortical vasogenic edema, usually in the setting of blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and eclampsia. Here we present a case of a 61-year-old woman, with a history of recent total thyroidectomy and postoperative hypoparathyroidism, who was admitted to the Emergency Department with generalized seizures. Although in this clinical setting, hypocalcemia is expected as the most possible underlying pathogenic factor for triggering seizures, the patient was diagnosed with iatrogenic hypercalcemia and milk-alkali syndrome. A brain magnetic resonance imaging (MRI) demonstrated cortical swelling and fluid-attenuated inversion recovery (FLAIR) signal abnormalities in both occipital, parietal, and right frontal lobes, consistent with PRES. The patient's encephalopathy resolved after resolution of hypercalcemia; she had no neurological deficits on discharge, while she was restarted on lower doses of calcium for hypoparathyroidism. This case illustrates the challenges imposed by postoperative hypoparathyroidism and highlights that PRES is a rare but serious complication of hypercalcemia of which endocrinologists should be aware.

Cushing's syndrome in the elderly: data from the European Registry on Cushing's syndrome.

OBJECTIVE: To evaluate whether age-related differences exist in clinical characteristics, diagnostic approach, and management strategies in patients with Cushing's syndrome (CS) included in the European Registry on Cushing's Syndrome (ERCUSYN). DESIGN: Cohort study. METHODS: We analyzed 1791 patients with CS, of whom 1234 (69%) had pituitary-dependent CS (PIT-CS), 450 (25%) adrenal-dependent CS (ADR-CS), and 107 (6%) had an ectopic source (ECT-CS). According to the WHO criteria, 1616 patients (90.2%) were classified as younger (<65 years old) and 175 (9.8%) as older (≥65 years old). RESULTS: Older patients were more frequently males and had a lower Body Mass Index (BMI) and waist circumference when compared with the younger. Older patients also had a lower prevalence of skin alterations, depression, hair loss, hirsutism, and reduced libido, but a higher prevalence of muscle weakness, diabetes, hypertension, cardiovascular disease, venous thromboembolism, and bone fractures than younger patients, regardless of sex (P < .01 for all comparisons). Measurement of urinary free cortisol supported the diagnosis of CS less frequently in older patients when compared with the younger (P < .05). An extrasellar macroadenoma (macrocorticotropinoma with extrasellar extension) was more common in older PIT-CS patients than in the younger (P < .01). Older PIT-CS patients more frequently received cortisol-lowering medications and radiotherapy as a first-line treatment, whereas surgery was the preferred approach in the younger (P < .01 for all comparisons). When transsphenoidal surgery was performed, the remission rate was lower in the elderly when compared with their younger counterpart (P < .05). CONCLUSIONS: Older CS patients lack several typical symptoms of hypercortisolism, present with more comorbidities regardless of sex, and are more often conservatively treated.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis.

BACKGROUND: Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. METHODS: A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. RESULTS: A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. CONCLUSIONS: We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors.

Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the Grading of Recommendations Assessment, Development and Evaluation system and updated systematic reviews on 4 predefined clinical questions crucial for the management of incidentalomas: (1) How to assess risk of malignancy?; (2) How to define and manage mild autonomous cortisol secretion?; (3) Who should have surgical treatment and how should it be performed?; and (4) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: (1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. (2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L [≤1.8 µg/dL]). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality. For this condition, we propose the term "mild autonomous cortisol secretion" (MACS). (3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. (4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. (5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. (6) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of nonoperated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest 10 important research questions for the future.

Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis.

OBJECTIVE: To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; > 1.8 µg/dL (>50 nmol/L) cortisol level cut-off following the 1 mg dexamethasone suppression test). DESIGN: Systematic review and meta-analysis. METHODS: Seven databases were searched up to July 14, 2022. Eligible studies were (randomized) trials, cohort studies, and cross-sectional studies assessing comorbidities potentially attributable to cortisol excess or mortality in patients with adrenal incidentaloma with or without MACS or the effects of conservative or surgical management of MACS. Random-effects meta-analysis was performed to estimate pooled proportions (with 95% CIs). RESULTS: In 30 cross-sectional and 16 cohort studies (n = 17 156 patients in total), patients with MACS had a higher prevalence of diabetes (relative risk [RR] 1.44 [1.23-1.69]), hypertension (RR = 1.24 [1.16-1.32]), and dyslipidemia (RR = 1.23 [1.13-1.34]). All-cause mortality (adjusted for confounders) in patients with MACS, assessed in 4 studies (n = 5921), was increased (hazard ratio [HR] = 1.54 [1.27-1.81]). Nine observational studies (n = 856) and 2 randomized trials (n = 107) suggest an improvement in glucometabolic control (RR = 7.99 [2.95-21.90]), hypertension (RR = 8.75 [3.99-19.18]), and dyslipidemia (RR = 3.24 [1.19-8.82]) following adrenalectomy. CONCLUSIONS: The present systematic review and meta-analysis highlight the relevance of MACS, since both cardiometabolic morbidities and mortality appeared to have increased in patients with MACS compared to patients with non-functioning incidentalomas. However, due to heterogeneous definitions, various outcomes, selective reporting, and missing data, the reported pooled estimates need to be interpreted with caution. The small number of patients in randomized trials prevents any strong conclusion on the causality between MACS and these comorbidities.

High-resolution daily profiles of tissue adrenal steroids by portable automated collection.

Rhythms are intrinsic to endocrine systems, and disruption of these hormone oscillations occurs at very early stages of the disease. Because adrenal hormones are secreted with both circadian and ultradian periods, conventional single-time point measurements provide limited information about rhythmicity and, crucially, do not provide information during sleep, when many hormones fluctuate from nadir to peak concentrations. If blood sampling is attempted overnight, then this necessitates admission to a clinical research unit, can be stressful, and disturbs sleep. To overcome this problem and to measure free hormones within their target tissues, we used microdialysis, an ambulatory fraction collector, and liquid chromatography-tandem mass spectrometry to obtain high-resolution profiles of tissue adrenal steroids over 24 hours in 214 healthy volunteers. For validation, we compared tissue against plasma measurements in a further seven healthy volunteers. Sample collection from subcutaneous tissue was safe, well tolerated, and allowed most normal activities to continue. In addition to cortisol, we identified daily and ultradian variation in free cortisone, corticosterone, 18-hydroxycortisol, aldosterone, tetrahydrocortisol and allo-tetrahydrocortisol, and the presence of dehydroepiandrosterone sulfate. We used mathematical and computational methods to quantify the interindividual variability of hormones at different times of the day and develop "dynamic markers" of normality in healthy individuals stratified by sex, age, and body mass index. Our results provide insight into the dynamics of adrenal steroids in tissue in real-world settings and may serve as a normative reference for biomarkers of endocrine disorders (ULTRADIAN, NCT02934399).