One of the recommended initial tests for diagnosing neoplastic hypercortisolism is the measurement of late-night salivary cortisol (CortisolLNSa). Published cut-off values for CortisolLNSa and late-night salivary cortisone (CortisoneLNSa) vary widely between studies. This study aims to establish cut-off values for CortisolLNSa and CortisoneLNSa using liquid chromatography-tandem mass spectrometry and to determine which salivary hormone performs better in distinguishing between people with and without neoplastic hypercortisolism.

A retrospective study was conducted on subjects screened for endogenous hypercortisolism at Amsterdam UMC between December 2015 and February 2022. 25 subjects with and 430 subjects without neoplastic hypercortisolism were included. The diagnosis neoplastic hypercortisolism was confirmed by histology and postoperative clinical features, not on biochemical tests, and excluded based on a follow-up of at least 12 months without progressive clinical signs of neoplastic hypercortisolism. Salivary samples were collected between 22:00-23:59 h and CortisolLNSa and CortisoneLNSa concentrations were measured using liquid chromatography-tandem mass spectrometry.

The median CortisolLNSa was 7.8 nmol/L for subjects with and 0.8 nmol/L for subjects without neoplastic hypercortisolism (p < 0.001). The median CortisoneLNSa was 35.5 nmol/L and 5.3 nmol/L, respectively (p < 0.001). Optimal diagnostic accuracy was established at 2.25 nmol/L for CortisolLNSa (sensitivity 92 %, specificity 89 %, positive predictive value 32.9 %, negative predictive value 99.5 %) and 15.5 nmol/L for CortisoneLNSa (sensitivity 93.8 %, specificity 94.5 %, positive predictive value 46.9 %, negative predictive value 99.7 %).

We established cut-off values for CortisolLNSa and CortisoneLNSa for the diagnosis of neoplastic hypercortisolism. CortisoneLNSa provided the highest diagnostic accuracy and we therefore recommend it as the preferred salivary measurement.

Cushing's disease with inconclusive MRI findings presents a significant diagnostic and surgical challenge due to the difficulty in localizing the causative pituitary adenoma. This case report highlights the use of intraoperative ultrasound as an adjunct for tumor detection and successful resection in a Cushing disease patient with hidden adenoma. A 55-year-old female with a history of hypertension, diabetes, and a recent cerebral infarction presented with clinical and biochemical features of Cushing's disease. Brain MRI revealed a 10 mm non-enhancing cystic lesion in the sella, making it difficult to confirm the underlying pathology. Inferior petrosal sinus sampling suggested a right-sided lesion, leading to an endoscopic endonasal transsphenoidal surgery. Intraoperatively, ultrasound was employed to assess the sellar region, initially identifying a cystic structure consistent with a Rathke's cleft cyst. Following fluid drainage, ultrasound revealed an iso-echoic lesion with a distinct margin, which was subsequently resected and confirmed as a pituitary adenoma on histopathological examination. The patient experienced postoperative biochemical remission, with normalization of ACTH levels and resolution of hypertension and diabetes. This case demonstrates that intraoperative ultrasound can be a valuable tool for tumor localization in suspicious MRI-negative Cushing's disease. By aiding in the identification of adenomas obscured by cystic lesions or surrounding structures, intraoperative ultrasound may improve surgical outcomes. Further studies are warranted to validate its efficacy in routine clinical practice.

We aim to review the most recent literature on demographic features and diagnostic workup of children with secondary hypertension, in order to provide a framework for health providers to determine which hypertensive pediatric patients warrant further investigation for secondary causes. By highlighting the utility of various diagnostic investigations, we aim to minimize unnecessary testing burden.

A recent meta-analysis revealed that hypertensive children and adolescents with any of the following features were at increased risk of secondary hypertension: < 6 years of age, history of prematurity, family history of secondary hypertension, body mass index (BMI) < 10th percentile. Based on available evidence, we suggest a testing schema that is stratified by both age and BMI. Limited evidence suggest renal ultrasound may be one of the most useful initial investigations for secondary causes in asymptomatic hypertensive children. Lipid profile in overweight/obese children, and echocardiogram for end organ involvement may have high yield of abnormal results. Further studies on the diagnostic utility of tests for secondary hypertension are required, as the current body of evidence is limited.

The ubiquitin-specific protease 8 (USP8) gene mutations are the most common driver changes in Cushing disease (CD). However, few studies have investigated the association between USP8 mutation and recurrence, and the results have been inconclusive.

To identify the predictors of recurrence and evaluate the prognostic role of USP8 mutation.

One hundred and seven patients with pathologically confirmed corticotroph adenomas were included. Somatic USP8 mutations were identified using Sanger sequencing. Recurrence predictors were estimated using multivariate Cox models, followed by receiver operating characteristic curves and Kaplan-Meier analysis.

Thirteen patients (12.6%) experienced recurrence, with a mean follow-up period of 65 months after surgery. The recurrence rate was significantly higher in USP8-mutated tumors than in USP8 wildtype tumors (26.5% vs 5.8%; P = .009). Multivariate Cox models revealed that USP8 mutation, high postsurgical morning serum cortisol (MSC), and high 1-mg dexamethasone suppression test (DST) were associated with an increased 5-year recurrence risk. Furthermore, Kaplan-Meier survival analysis showed that patients with USP8 mutation, combined with either high postsurgical MSC (>2.5 μg/dL) or high 1-mg DST (>0.78 μg/dL), were more prone to recurrence (log-rank P < .001). The negative predictive values were 98% and 100%, while the positive predictive values improved from 33% to 55% and from 47% to 86%, respectively.

Our study corroborates USP8 mutational status in combination with postsurgical MSC or 1-mg DST as independent predictors of long-term remission, highlighting their potential role in stratifying patients at risk for suboptimal outcomes.

The diagnosis of Cushing's syndrome is challenging and often fraught with many pitfalls depending on several factors. We compare the diagnostic performance of AM serum cortisol (SC), 24-hour urinary free cortisol (UFC) and 0800 h, 1400 h and 2400 h salivary cortisol curve (SCC) in dexamethasone suppression test 1mg (1mg-DST) positive and negative patients.

83 subjects performed measurements of SCC by Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS) method, exploiting the circadian rhythm of cortisol.

The reproducibility and specificity of the test identify patients with hypercortisolism in 95% of cases at midnight. Interestingly, when considering two specific points (1400 h and 2400 h) on the SCC, the success rate rises to 100%.

The evaluation of the 1400 h and 2400 h assays lead to detection of the total number of patients with Cushing's syndrome. SCC is a non-invasive diagnostic strategy associated with elevated positive predictive value for hypercortisolism capable of enabling diagnosis. In addition, it can be considered for management of patient outcomes and monitoring of Cushing's syndrome pharmacological treatment.

The clinical manifestations of Cushing syndrome are variable, but an important number of patients present a metabolic syndrome, strongly associated with hepatic steatosis.

The aim of this study was to determine the prevalence of metabolic dysfunction associated steatotic liver disease (MASLD) at the diagnosis of Cushing syndrome.

We conducted a single-center retrospective study at Angers Hospital (France) between 2010 and 2020. Forty-nine patients followed for Cushing syndrome with available abdominal imaging at diagnosis were included. A mean liver/spleen density ratio < 1 on computed tomography was diagnostic of hepatic steatosis. Simple clinico-biological scores predictive of hepatic fibrosis (FIB-4, NAFLD Fibrosis Score, and eLIFT) were calculated for patients with hepatic steatosis.

Of the 49 patients, 13 (26.5%) had hepatic steatosis at diagnosis of Cushing syndrome. All 13 had MASLD. These patients had a higher prevalence of type 2 diabetes and higher triglyceride levels in multivariate analysis. There was no difference according to the intensity or duration of Cushing syndrome. Among the 13 patients with MASLD, 2 (15.4%) had a significant fibrosis predictive score. Of the 4 patients with follow-up imaging after remission of Cushing syndrome, 3 had remission of steatosis between 1 and 5 years after remission of Cushing syndrome. No patient without MASLD at diagnosis had a worsening liver/spleen ratio after remission.

We estimated the prevalence of hepatic steatosis at the diagnosis of Cushing syndrome at 26.5%. The presence of metabolic factors was associated with the occurrence of hepatic steatosis.

Androgen excess is common in women and refers to clinical or biochemical evidence of elevated androgenic steroids such as testosterone. It is associated with underlying polycystic ovary syndrome in the majority of cases. However severe androgen excess is less common and may indicate the presence of underlying adrenal or ovarian neoplasms, genetic disorders or severe insulin resistance syndromes. Currently there are few consensus guidelines to assist clinicians with a standardised management approach to the patient with severe androgen excess.

Clinical practice guideline.

This guideline has been developed with expertise from colleagues in endocrinology, gynaecology, clinical biochemistry and nursing, and furthermore provides a unique patient perspective to guide clinicians.

The Society for Endocrinology commissioned this new guideline to collate multi-disciplinary guidance for clinical practitioners in the investigation of severe androgen excess. Recommendations have been made in the areas of clinical assessment, biochemical work up, dynamic testing and imaging, informed where possible by the best available evidence.

This guideline will provide guidance for clinicians in their approach to patients with severe androgen excess.

Pituitary radiotherapy (RT) is used for persistent/recurrent Cushing's disease (CD) after pituitary surgery. The utility of late-night salivary cortisol (LNSC) in evaluating endocrine remission after RT is unclear.

To identify the clinical characteristics and outcomes of patients with CD after RT, in endocrine remission based on normal LNSC (group 1) or 24 h urinary free cortisol (UFC; group 2).

Retrospective cohort, observational study in academic medical centre. Patients (16-86 years old, n = 75) with CD who underwent RT were studied; group 1 (n = 16), group 2 (n = 18), and 41 patients not in remission. Outcome measures included within-group and between-group changes (group 1 vs. group 2) in clinical characteristics, endocrine data and time to remission.

Seventy-five patients with CD, aged (median [range]: 50 years [16, 86], 71% female, BMI: 34.7 kg/m2 [19.1, 62.5], 63% with macroadenomas) underwent RT and 34 (45.3%) entered endocrine remission, including 16 (21.3%) in group 1 and 18 (24%) in group 2 (median: 56 months). From RT to remission, there were decreases in BMI (group 1: -3.9 ± 0.7 kg/m2, p = 0.0001; group 2: -5.2 ± 1.9 kg/m2, p = 0.0123) and systolic blood pressure (group 1: -7.9 ± 3.9 mmHg, p = 0.03; group 2: -10.1 ± 4.5 mmHg (p = 0.008). There were no between-group differences in BMI, blood pressure, HbA1c, number of antihypertensive or antihyperglycemic agents, UFC, median time to remission, recurrence risk.

In patients with CD following RT, LNSC appears to be clinically equivalent to UFC in the assessment of endocrine remission. These patients can be followed with LNSC, which is easier for patients to collect.

Cushing's disease is a rare endocrine disorder that presents many systemic complications, and its initial phase management can be difficult in atypical and severe cases or at institutes with limited experience. It is a disease in which several complications may have already progressed at the time of diagnosis, and complications may become more severe during the initial management phase, potentially becoming life-threatening. In addition, many patients are young, and depending on this phase management, their quality of life will significantly decline later on. Therefore, this review summarizes the evidence accumulated to date and outlines strategies for disease management, focusing on the initial stages from detection, diagnosis, and referral of patients to surgery.

Adrenal surgery is an established, critical tool in the management of various adrenal gland pathologies. Complete or partial adrenalectomy is employed to manage both benign lesions and malignant tumors. Beyond a technical understanding of surgical and anatomic principles, an understanding of adrenal endocrine function is essential for all surgeons who care for patients with adrenal pathologies. In this article, we provide an overview of adrenal surgery, discussing key anatomic and functional considerations, various surgical approaches, perioperative management strategies, and potential complications.

Adrenal Cushing syndrome (CS) has been rarely studied in recent years in Japan. This study aimed to investigate clinical characteristics and their changes over time in patients with adrenal CS. We analyzed 101 patients with adrenal CS caused by adenoma, dividing them into two groups based on diagnosis period: December 2011-November 2016 (later group, n = 50) and August 2005-November 2011 (earlier group, n = 51). Differences between the groups and comparisons with previous reports were assessed. Patients with subclinical CS were excluded. Adrenal incidentalomas were the most frequent reason for CS diagnosis (34%). Most patients exhibited few specific cushingoid features (2.5 ± 1.3), with moon faces and central obesity being the most common. Compared to earlier reports, specific cushingoid features were less frequent; nonetheless, no significant differences were observed between the earlier and later groups. All patients had midnight and post-dexamethasone suppression test serum cortisol levels exceeding 5 μg/dL. No significant differences were found between the groups regarding non-specific symptoms, endocrinological findings related to cortisol secretion, cardiometabolic commodities or infections, except for glucose intolerance and bone complications. The prevalence of metabolic disorders other than glucose intolerance and osteoporosis fluctuated over time. Sixteen patients developed cardiovascular diseases or severe infections. In conclusion, adrenal CS became less florid in the 2000s, showed no improvement in the following years, and remained associated with a high complication rate. Further research is needed to establish an early detection model for CS.

Our study found that one-sixth of patients with adrenal Cushing syndrome continued to develop severe complications in this century despite their specific cushingoid features being less pronounced than in the past. Notably, the findings provide clinical insights that may aid in earlier disease diagnosis.

Cyclic Cushing syndrome (CS) is a rare form of CS characterized by intermittent episodes of hypercortisolism. We report the case of a 30-year-old female who was diagnosed with ACTH-dependent Cushing disease, confirmed by initial biochemical tests and pituitary imaging. Although surgery was planned, she experienced spontaneous remission for several months, followed by pregnancy, and subsequently relapsed in the early postpartum period. Transsphenoidal resection of a left-sided pituitary adenoma was then performed, confirming an ACTH-secreting tumor. A review of the literature revealed that this case contributes to the increasing number of patients with cyclic CS, with particular attention to the challenges of diagnosing hypercortisolism during pregnancy. While cases of Cushing disease recurrence after pituitary surgery in the immediate postpartum period have been documented, this is the first reported case of early postpartum relapse in cyclic CS. This case highlights the importance of long-term follow-up in patients with a high index of suspicion for cyclic CS, as well as the diagnostic challenges in managing the condition during pregnancy and the peripartum period.

Leukocytosis frequently noted in Cushing's syndrome (CS), along with other blood cell changes caused by direct and indirect cortisol effects.

Assess baseline white blood cell (WBC) profile in CS patients compared to controls and WBC changes pre- and post-remission after surgical treatment for CS.

A comparative nationwide retrospective cohort study.

Data from Clalit Health Services database.

297 patients (mean age 51 ± 16.1 years, 73.0% women) with CS and 997 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS or adrenal cancer patients were excluded.

Mean WBC, neutrophils, and neutrophil-to-lymphocyte ratio (NLR) two-years before and after pituitary or adrenal surgery. WBC and neutrophils are expressed as Kcells/µl.

At baseline, leukocytosis was observed in 21.5% of patients with CS vs. 8.9% of controls (P < 0.001). Patients with CS had significantly higher WBC (8.8 ± 2.88 vs. 7.54 ± 2.45, p < 0.0001), neutrophils (5.82 ± 2.38 vs. 4.48 ± 1.97, p < 0.0001), and NLR (3.37 ± 2.63 vs. 2.27 ± 1.86, p < 0.0001) compared to controls, regardless of pituitary or adrenal source of hypercortisolemia. Post-surgery, patients with CS experienced significant decreases in mean WBC (-0.57 ± 2.56, p < 0.0001), neutrophils (-0.84 ± 2.55, p < 0.0001), and NLR (-0.63 ± 2.7, p < 0.0001). Despite achieving disease remission, patients with CS still had higher WBC (8.11 ± 2.4 vs. 7.46 ± 2.17, p = 0.0004) and neutrophils (4.71 ± 2.10 vs. 4.41 ± 1.87, p = 0.03) compared to controls. Patients with CD and baseline leukocytosis had lower remission rate than those with normal WBC (36.7% vs. 63.9%, p = 0.01).

At diagnosis, CS patients have elevated WBC, neutrophils, and NLR compared to controls. Remission does not normalize WBC levels in all patients, and baseline leukocytosis predicts a poorer remission prognosis in CD.

Adrenal masses are commonly encountered as incidental findings in urologic practice. Many of these lesions do not undergo appropriate testing, likely because guidelines have historically been complex and contradictory. However, the workup for the vast majority of these lesions is actually straightforward. Here we present a practical, guidelines-based approach to the workup of adrenal lesions. We focus on distinguishing between benign, nonhormonally active adenomas (which require no further imaging or intervention) from those which are concerning for malignancy or are hormonally active.

This article covers rare adrenal tumors including functional adenomas, myelolipomas, ganglioneuromas and neuroblastomas, and metastasis to the adrenal gland. It explores their clinical presentation and behavior, hormonal activity, imaging features, other diagnostic considerations, and approaches to management. The variety of rare tumors and their unique behaviors covered in this article underscores the need to maintain up-to-date knowledge and surgical skills, as well as the importance of a multidisciplinary approach to patient care.

Successful first-line treatment of Cushing's syndrome by resection of the underlying tumor is usually followed by adrenal insufficiency.

The aims of this study were to determine the recovery rate and time to recovery of adrenal function after treatment for different forms of endogenous Cushing's syndrome and to identify factors associated with recovery.

In this retrospective study of 174 consecutive patients with Cushing's syndrome, the recovery rate and time to recovery of adrenal function after surgery were assessed.

The 1-year, 2-year and 5-year recovery rates of patients with Cushing's disease were 37.8, 70.1 and 81.1%, respectively. For patients with adrenal Cushing's syndrome, the 1-year, 2-year and 5-year recovery rates were higher: 49.3, 86.9 and 91.3%, respectively. Median time to recovery for patients with Cushing's disease and adrenal Cushing's syndrome was 13.9 and 12.1 months, respectively. The median time to recovery of adrenal function in patients with Cushing's disease with and without recurrence was 9.9 versus 14.4 months, respectively. Higher age was associated with a lower probability of recovery of adrenal function: HR 0.83 per decade of age (95% CI 0.70-0.98).

The recovery rate of adrenal function after successful surgery as first-line treatment in patients with Cushing's syndrome is high. However, it may take several months to years before recovery of adrenal function occurs. In case of early recovery of adrenal function, clinicians should be aware of a possible recurrence of Cushing's disease.

BackgroundAs cortisol and metanephrine are involved in the stress response, it is often recommended that individuals are relaxed at the time of venepuncture, however, evidence behind these recommendations is lacking. We investigated the effects of acute psychological stress on serum cortisol and plasma metanephrine concentrations in healthy individuals exposed to varying levels of psychological stress and compared these results to self-reported measures of stress.MethodsTen medical students completed two medical in-person simulations (one low-complexity, one high-complexity) in a random order. At four times, participants completed the State-Trait Anxiety Inventory (STAI) and serum cortisol and plasma metanephrine/normetanephrine were tested.ResultsMedian (interquartile range) STAI prior to the low-complexity simulation was 44 (18) versus 33 (13) afterwards (P = 0.050). STAI prior to the high-complexity simulation was 33 (10) versus 48 (17) afterwards (P = 0.007). Cortisol prior to the low-complexity simulation was 272 nmol/L (115) versus 247 (115) afterwards (P = 0.333). Prior to the high-complexity simulation, cortisol was 246 (70) versus 261 (137) afterwards (P = 0.859). Metanephrine prior to the low-complexity simulation was 242 pmol/L (79) versus 247 (93) afterwards (P = 0.515). Metanephrine prior to the high-complexity simulation was 220 (81) versus 251 pmol/L (120) afterwards (P = 0.074). Normetanephrine prior to the low-complexity simulation was 593 pmol/L (247) versus 682 (281) afterwards (P = 0.047 for the difference). Normetanephrine prior to the high-complexity simulation was 696 (123) versus 705 pmol/L (224) afterwards (P = 0.169).ConclusionsThe trend in cortisol levels largely reflected changes in STAI. We outline some implications of these findings for current practice and future research.

Localizing the source of adrenocorticotropic hormone (ACTH) in patients with ACTH-dependent Cushing's syndrome (CS) poses significant challenges. There is a pressing need for novel imaging modalities that provide both anatomical delineation and functional confirmation of corticotropinomas.

This study utilized a modified form of desmopressin (mDesmo), an agonist of the V1b receptor, which is overexpressed in tumoral corticotrophs. After modification, radionuclide 68Ga was chelated to produce a new radiopharmaceutical for positron emission tomography (PET) imaging. A total of 234 patients with CS were screened and 30 underwent [68Ga]Ga-mDesmo imaging. Patient demographics and hormonal levels (plasma cortisol and ACTH) were recorded, and the diagnostic accuracy of contrast-enhanced MRI (CE-MRI) and [68Ga]Ga-mDesmo was compared, with histopathological evidence of a corticotropinoma serving as the reference standard.

The cohort comprised 10 males (33%, CI: 16-50%) and 20 females (67%, CI: 50-84), with a mean age of 33.5 ± 13.5 years. Of 30 patients with CS, 24 patients had treatment naïve Cushing's disease (CD) of which 17 (71%, CI: 53-89%) had microadenomas and 7 (30%, CI: 12-48%) had macroadenoma; 4 (13%, CI: 0-25%) patients had ectopic Cushing syndrome (ECS). CE-MRI identified lesions in 16 patients (67%, CI: 48-86%), while [68Ga]Ga-mDesmo successfully identified corticotropinomas in all 24 patients (100%, CI: 86-100%). In patients with microadenomas, CE-MRI had a diagnostic accuracy of 53% (CI: 29-77%), whereas [68Ga]Ga-mDesmo achieved 100% (CI: 86-100%). There was no uptake of [68Ga]Ga-mDesmo in the pituitary of patients with ECS.

This study demonstrates that [68Ga]Ga-mDesmo imaging is an effective in vivo molecular imaging technique for delineating corticotropinomas, surpassing the accuracy of CE-MRI and BIPSS, regardless of adenoma size.

CTRI/2022/08/044615 dated 03/08/2022.

Glucocorticoid withdrawal syndrome (GWS) may develop in patients following successful surgery for endogenous hypercortisolism. Effective strategies to minimize GWS and improve quality of life (QoL) are currently lacking. We aimed to determine the impact of hydrocortisone vs prednisone therapy on GWS and QoL during the first 12 weeks postsurgery.

Single-center prospective cohort study (2019-2024) of adults with endogenous hypercortisolism who developed postoperative adrenal insufficiency and treated with either prednisone or hydrocortisone. Quality of life was assessed with Short Form-36 (SF-36) and Cushing QoL questionnaires at baseline and at 12 weeks postsurgery. GWS was assessed using weekly AddiQoL questionnaires for the first 12 weeks postsurgery.

Of 165 patients, 101 (61%) were treated with hydrocortisone and 64 (39%) with prednisone. At baseline, no group differences were found in the hypercortisolism subtype, comorbidities, or QoL assessments. At follow-up, no group differences in final total daily hydrocortisone equivalent dose were seen.When adjusting for the baseline QoL assessment, patients treated with prednisone demonstrated a higher degree of improvement in their QoL, particularly in the SF-36 mental component score (estimate 0.33, 95% CI, 0.04-0.63), SF-36 role-emotional limitation (estimate 0.52, 95% CI, 0.2-0.84), and SF-36 body pain (estimate 0.31, 95% CI, 0.07-0.56) subcomponents. In the multivariable analysis of age, sex, body mass index, glucocorticoid type, baseline clinical severity score, and baseline QoL assessment, prednisone therapy was an independent predictor of better SF-36 mental component at 12 weeks postsurgery.

Prednisone therapy was associated with better mental health QoL than hydrocortisone at 12 weeks postsurgery in patients with hypercortisolism.

Adrenal incidentalomas are adrenal masses ≥ 1 cm discovered on imaging studies for unrelated clinical conditions. The prevalence of adrenal incidentalomas has increased as a byproduct of the widespread use of cross-sectional imaging, particularly in older adults. The clinical significance of adrenal incidentalomas varies based on tumor size, hormonal activity, and imaging characteristics. While most adrenal incidentalomas are benign and asymptomatic, a significant minority are hormonally active or malignant, necessitating careful evaluation and management. Adrenal hormone secretion can have significant clinical implications. Biochemical testing is crucial to assess for hormone excess, including steroid hormones (mineralocorticoids, glucocorticoids, and androgens), which are made in the adrenal cortex, as well as catecholamines, which are made in the adrenal medulla. Non-contrast computed tomography (CT) is the preferred modality for evaluating adrenal nodules as it allows for assessment of tissue density in Hounsfield units (HU). Benign lesions typically have an homogeneous appearance with HU ≤ 10. Contrast-enhanced CT with delayed washout can help differentiate benign tumors from malignant tumors. Tumors ≥ 4 cm, or those with indeterminate features may require further imaging, such as magnetic resonance imaging (MRI) or positron emission tomography (PET)/CT. The management of adrenal incidentalomas is determined by hormonal secretion and imaging characteristics. Surgical resection is recommended for functional tumors and those that are suspicious for malignancy, including tumors ≥ 4 cm in size and those with rapid growth. Non-functional tumors < 4 cm may undergo imaging surveillance. The goal of this review is to summarize the contemporary literature and guidelines on adrenal incidentalomas, and to describe the key principles regarding evaluation and management.

This study investigated long-term alterations in cardiometabolic comorbidities among patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) who received surgical or conservative treatments.

A single-center, retrospective study analyzed 132 patients with PBMAH, divided into a surgery group (n = 68) and a control group (n = 64) based on treatment modalities. The main outcomes included changes in blood pressure (BP), blood glucose, lipids, and body weight.

Among the 132 patients, hypertension, abnormal glucose metabolism, dyslipidemia, and overweight/obesity were prevalent in over 50% of cases. The surgery group demonstrated significantly greater improvements in BP, blood glucose, and weight control compared with the control group. Adrenalectomy was associated with enhanced BP control, blood glucose control, and at least one cardiometabolic risk factor control. In a group of 95 patients with mild autonomous cortisol secretion, the surgery group also exhibited higher rates of improvement in BP and blood glucose than the control group. Adrenalectomy was associated with improved BP, blood glucose, and at least one cardiometabolic risk factor.

Our study observed that most patients with PBMAH exhibited at least one cardiometabolic risk factor. Adrenalectomy was associated with improved BP and blood glucose for patients with PBMAH, including those with mild autonomous cortisol secretion.

Adrenal incidentalomas (AIs) and pituitary incidentalomas (PIs) have become frequent findings in the last two decades due to the widespread use of cross-sectional imaging in clinical practice. This review investigates the prevalence of endogenous hypercortisolism in patients with AIs and PIs. We aim to underscore the importance of early detection and management of endogenous hypercortisolism in this subset of patients to mitigate associated cardiometabolic complications and reduce mortality.

We performed a PubMed literature search to provide updates regarding the prevalence of endogenous hypercortisolism in patients with AIs and PIs, the demographic and clinical characteristics of the studied populations, and the diagnostic test accuracy for early identification of endogenous hypercortisolism.

Hypercortisolism, especially mild autonomous cortisol secretion (MACS), was identified in a notable proportion of patients with AIs. MACS was associated with increased cardiometabolic risks, contributing to an elevated overall mortality rate in this cohort. Furthermore, PIs were found to be linked with Cushing's disease in a subset of patients, emphasizing the need for thorough evaluation and monitoring.

Early diagnosis and appropriate management of endogenous hypercortisolism are essential in preventing complications and improving patient outcomes. As the presence of undetected hypercortisolism is associated with clinical complications over time, the accurate identification of high-risk populations to screen remains crucial.

Cushing's syndrome (CS) is characterised by signs and symptoms resulting from excessive and prolonged exposure to exogenous glucocorticoids or endogenous hypercortisolism. In childhood, exogenous CS represents the main cause of CS due to the widespread therapeutic use of glucocorticoids, while endogenous CS is very rare and accounts for about 10% of CS cases. According to the origin of the hypercortisolism, the ACTH-dependent form due to pituitary ACTH-secreting tumours is the most common form of endogenous CS in paediatric age (about 75-80% of cases), following by adrenal causes (about 15-20% of cases) including adenoma, carcinoma (which has a peak of incidence in the first decade), bilateral adrenal hyperplasia or Carney complex, with a different distribution by age. Ectopic ACTH-secreting CS, genetic forms of pituitary adenomas are more uncommon. The insidious onset of hypercortisolism and the absence of salient early signs make the diagnosis of endogenous CS difficult. Facial changes, weight gain with simultaneous growth failure, prepubertal virilisation, or hypogonadism in adolescence represent some of the key features of CS. The diagnostic workup is essentially aimed at confirming hypercortisolism through screening tests whose diagnostic accuracy is not 100% and therefore the combination of more than two tests is mandatory to confirm the diagnosis of CS.

Due to its rare incidence, pituitary adenoma requires high vigilance and suspicion. Therefore, physicians should consider this differential diagnosis and perform the necessary workup, such as an overnight or standard dexamethasone suppression test and brain magnetic resonance imaging (MRI), to rule it out if sudden hormonal changes without any other explanation are observed in children.

The current review aims to summarize and discuss the prevalence of confirmed hypercortisolism in patients with diabetes mellitus or obesity, analysing the screening tests used and their accuracy, in order to better identify whether patients with diabetes mellitus and obesity should be screened for Cushing's syndrome (CS) and how.

A narrative review was performed including publications focusing on the current knowledge on prevalence of confirmed hypercortisolism in patients with type 2 diabetes mellitus (T2DM) or obesity and on screening tests used to detect CS.

The studies reviewed suggest that the prevalence of CS in patients with T2DM is variable, ranging from 0.6 to 9.3%. The most used screening test is the overnight cortisol after 1 mg of dexamethasone suppression test (DST), with a false positive rate ranging from 3.7 to 21%. The prevalence of CS among obese patients is generally about 1%, except for two studies which reported higher prevalence. For obese patients, 1 mg DST and late-night salivary cortisol are the most accurate screening tests for CS.

Clinical expertise remains the mainstay to identify which subjects should be screened for CS. The evaluation of the clinical stigmata of CS and the combination with clinical comorbidities typical of CS are the stronger predictors of CS. In addition, we could hypothesize that in patients with T2DM, overnight 1 mg DST is the more accurate screening test for CS. By contrast, in patients with obesity both LNSC and overnight 1 mg DST could be equally used for the screening of hypercortisolism.

Skeletal comorbidities are frequent and clinically relevant findings in Cushing's syndrome (CS) since an uncoupled suppressed bone formation and enhanced bone resorption leads to a marked skeletal damage with a rapid increase of fracture risk. Reduced Bone Mineral Density (BMD) has been consistently reported and osteopenia or osteoporosis are typical findings in patients with CS. Vertebral Fractures (VFs) are frequently reported and may occur even in patients with an only mild reduction of BMD. Since CS is diagnosed late due to often difficult biochemical and radiological confirmation as well as to signs and symptoms common in other much more frequent diseases an approach suggested for overcoming underdiagnosis is to screen patients with manifestations which may overlap with those of CS such as arterial hypertension, diabetes mellitus and osteoporosis. Our review will focus on the rationale and best practice for screening osteoporotic patients for CS.

A strict association exists between mood disorders and endogenous hypercortisolism, namely Cushing's syndrome (CS). Indeed, CS is characterized by a wide range of mood disorders, such as major depression, generalized anxiety, panic disorders, bipolar disorders up to psychosis, with major depression being the most frequent, with a prevalence of 50-80%, and potentially representing the clinical onset of disease. Despite this observation, the exact prevalence of hypercortisolism in patients with mood disorders is unknown and who/how to screen for endogenous hypercortisolism among patients with mood disorders is still unclear. In this context, an accurate anamnestic and clinical examination are crucial in order to identify those patients who may benefit from CS screening. In particular, the presence of specific signs and symptoms of CS, comorbidities typically associated with CS, and lack of improvement of depressive symptoms with standard treatments can further guide the decision to screen for CS. Anyhow, it is noteworthy that mood disorders represent a cause of functional activation of hypothalamic-pituitary-adrenal (HPA) axis, a condition formerly known as non-neoplastic hypercortisolism (NNH). The differential diagnosis between CS and NNH is challenging. Beyond anamnestic and clinical features, various tests, including measurement of daily urinary cortisol and late-night salivary cortisol, together with low dose-dexamethasone suppression test, are used for initial screening. However, considering their low accuracy, a definitive diagnosis may require a longitudinal follow-up along with second-line dynamic tests like combined dexamethasone-CRH test and desmopressin test. In conclusion, available data suggest the need for a comprehensive assessment and follow-up of individuals with mood disorders to detect possible underlying CS, considering the pitfalls in diagnosis and the overlap of symptoms with other conditions like NNH. Specialized centers with expertise in CS diagnosis and differential testing are recommended for accurate evaluation and management of these patients.

Co-existing primary aldosteronism (PA) and autonomous cortisol secretion (ACS) has been recently recognized as a distinct entity. This study aimed to assess the incidence of ACS in patients with PA, and its impact on clinical and laboratory parameters.

Ninety-two patients diagnosed with PA were included. Demographic data, comorbidities, laboratory and imaging results were retrospectively analyzed. Patients with overnight 1mg dexamethasone suppression test>1.8μg/dL were classified as PA with ACS.

Twenty-four patients (26.1%) were in the PA-with-ACS group, and 68 (73.9%) in the PA-without-ACS group. Mean age (P=0.034), body mass index (P=0.034), number of female patients (P=0.012) and maximum adenoma diameter (P<0.001) were higher in the PA-with-ACS group than in the PA-without-ACS group. Basal (P=0.001) and post-saline infusion plasma aldosterone concentrations (PAC) (P=0.009) were higher in the PA-without-ACS group than in the PA-with-ACS group. No significant differences between groups were found in intensity of antihypertensive treatment, presence of type 2 diabetes, coronary artery disease, proteinuria or glomerular filtration rate (P>0.05). Left ventricular hypertrophy (LVH) was detected in 49.4% of patients. Logistic regression demonstrated that PAC and gender were associated factors for LVH.

Cortisol co-secretion was identified in approximately one-quarter of patients diagnosed with PA. PA patients without ACS had higher PAC than those with co-existing ACS. According to our results, the co-existing ACS may not seem to have a significant negative impact on clinical parameters in patients with PA.

Many review articles have explored data regarding the coexistence of specific types of pituitary adenomas (PAs) and polycystic ovary syndrome (PCOS), particularly focusing on the potential pathogenesis of this intersection and overlapping features. However, a comprehensive evaluation encompassing the full spectrum of PAs and their association with PCOS remains lacking. This review aims to provide a broad assessment of the interactions between these entities, emphasizing pathophysiological mechanisms, clinical presentations, diagnostic challenges and therapeutic implications.

A comprehensive literature search was conducted in the PubMed/MEDLINE database, focusing primarily on publications from the years 2000 to 2024, while also including seminal papers from the 1950s. The reference lists of selected articles were also manually searched. Inclusion criteria encompassed review articles, retrospective studies, clinical trials, case reports and meta-analyses providing data on the pathogenesis, clinical features, diagnostic challenges and therapeutic approaches related to PCOS and different PAs.

PCOS and functioning PAs often exhibit overlapping clinical features, complicating diagnosis and management. PCOS may precede and delay the diagnosis of growth hormone (GH)-secreting adenomas. The prevalence of PCOS or its features in acromegaly is influenced by disease activity, while approximating 13% in cases with controlled disease. Excess GH and insulin-like growth factor 1 (IGF-1) adversely affect ovarian function through direct pathways and by inducing insulin resistance, contributing to acromegaly-associated PCOS. In Cushing's syndrome (CS), findings consistent with PCOS may be present in 46% of patients, with cortisol excess contributing to menstrual dysfunction, hyperandrogenism and insulin resistance. While the prevalence of PCOS in patients with prolactinomas remains under-researched, recent studies indicate a 2.8%-10% prevalence of prolactinomas in PCOS. Elevated prolactin (PRL) levels in these patients may promote insulin resistance, further contributing to PCOS pathogenesis. Moreover, increased androgen bioavailability may be observed in all three aforementioned adenomas. To date, no studies have provided prevalence data for PCOS in other types of PAs.

Distinct clinical features, along with biochemical evaluations and imaging, can help differentiate the presence of both PAs and PCOS. Moreover, excluding other mimicking disorders is essential for an accurate diagnosis of PCOS. The persistence or recurrence of menstrual dysfunction, hyperandrogenism and metabolic disturbances in patients with controlled functioning adenomas may indicate a coexisting PCOS diagnosis. Timely diagnosis may optimize management and improve long-term outcomes for both conditions. Future studies should focus on investigating the clinical differences between patients with co-occurring PCOS and PAs compared to those with PCOS alone, ideally in larger cohorts, to better understand unique diagnostic and therapeutic considerations.

Endogenous Cushing's syndrome (CS) is rare, with an incidence of 0.7-2.4 per million population per year according to population-based studies. However, evaluation of patients presenting disorders potentially related to cortisol excess, and therefore with a 'high risk of clinical suspicion' profile, could bring out several unrecognized cases. CS represents one of the most challenging endocrine diseases, with clinical features overlapping with those of common conditions affecting general population, invariably resulting in potential mis- or delayed diagnosis with negative consequences in terms of morbidity and mortality. CS is remarkably prevalent among young females, variably presenting with menstrual irregularities and/or signs and symptoms of hyperandrogenism. Herein we briefly reviewed literature on prevalence and clinical impact of menses abnormalities, acne and hirsutism -also coexisting in the context of a polycystic ovary syndrome- in CS, aiming at clarifying if, when and how to screen for hypercortisolism young women with these disorders.

Cushing's syndrome (CS) is associated with high morbidity and mortality triggered by increased risk for cardiovascular events. Nevertheless, no screening tool to predict the individual risk for these events in patients with Cushing's syndrome has been established. Nonenhanced electron-beam computed tomography scans with calculation of the Coronary Artery Calcium (CAC) score may offer a non-invasive method. Hence, we evaluated the diagnostic accuracy of Agatston score to predict the risk of a cardiac event in patients with Cushing's syndrome. Single center prospective study of 34 patients with endogenous CS Multidetector computer tomography and calculation of CAC score was performed at diagnosis of CS. Prevalence of cardiovascular events was documented with median follow-up over 5 years and results were compared with data from the Heinz Nixdorf Recall (HNR) Study. In addition, correlations of CAC score with parameters of cortisol excess were evaluated. CAC score was significantly higher in CS patients with a cardiovascular event than in patients without an event (117 vs. 90; p=<0.01). An odds ratio of 31.7 (p=0.03, 95% CI: 1.3-773.0) for a cardiovascular event could be shown in Cushing's syndrome patients with a CAC score>75th risk factor-specific reference percentile, while the odds ratio in the HNR study was 4.5 (p<0.01, 95% CI: 3.0-6.9). No correlation between the degree of cortisol excess and CAC score was evident. The CAC score>75th risk factor-specific reference percentile could offer a useful screening tool to precise the cardiovascular risk in patients with Cushing's syndrome.

We report the case of a 43-year-old male who presented with a 2-year history of frequent frontal headaches, initially attributed to sinus disease. Magnetic resonance imaging revealed a 30 mm mass in the right sphenoid sinus with extension into the cavernous sinus, encasing the internal carotid artery, and invading the sella turcica. Differential diagnosis based on imaging included sphenoid meningioma, low-grade carcinoma, or lymphoma. An endoscopic sphenoid sinus biopsy identified the lesion as a silent corticotroph pituitary neuroendocrine tumor/adenoma (SCA), confirmed by positive immunostaining for ACTH and T-PIT. The patient underwent a successful transsphenoidal resection, followed by a transient postoperative central adrenal insufficiency and diabetes insipidus, which resolved within eight months. Eighteen months postoperatively, the patient retains normal pituitary function with minimal residual tumor. This case illustrates the diagnostic challenge posed by SCAs when presenting as sphenoid sinus masses and highlights the importance of considering SCAs in similar cases.

Mild autonomous cortisol secretion (MACS) is the most common hormonal alteration in patients with adrenal incidentalomas (AIs). Given its prevalence and associated adverse outcomes, reviewing its impact and interventions is essential.

In this article, we provide a comprehensive review on the diagnosis of MACS, the cardiometabolic burden associated with MACS and on its surgical and medical treatment. The diagnosis of MACS requires three criteria: hormonal evidence of hypercortisolism, the absence of typical Cushing's syndrome signs, and the presence of an AI. The most recommended test for MACS diagnosis is the 1 mg dexamethasone suppression test. There is plenty of evidence of the detrimental effect of MACS, including an increased risk of diabetes, hypertension, dyslipidemia and all-cause mortality. Surgery should be considered for patients with significant comorbidities and has been shown to significantly improve anthropometric variables, hyperglycemia and blood pressure. Medical therapy to lower cortisol offers an effective alternative, particularly for patients with bilateral AI, when surgery is contraindicated, or the patient declines surgery.

Based on our expert opinion, steroid profiling has the potential to become the gold standard for MACS diagnosis, and further studies should identify which patients benefit most from specific treatment to guiding evidence-based recommendations.

Patients with endogenous Cushing's syndrome (CS) have elevated mortality, particularly during active disease. A recent meta-analysis reported reduced mortality rates after 2000 in adrenal CS and Cushing disease (CD), though many studies lacked population-matched controls.

Nationwide retrospective study (2000-2023) in Israel using the Clalit Health Services database to assess all-cause mortality in patients with endogenous CS matched 1:5 with controls by age, sex, socioeconomic-status, and body mass index (BMI). Primary outcome was all-cause mortality. Secondary outcomes included cause-specific mortality, impact of hypercortisolism remission, disease source, and mortality risk factors.

The cohort included 609 cases with CS (mean age 48.1 ± 17.2 years; 65.0% women) and 3018 matched controls (47.9 ± 17.2 years; 65.4% women). Over a median follow-up of 16 years, 133 cases (21.8%) and 472 controls (15.6%) died (HR = 1.44, 95% CI, 1.19-1.75). Both patients with CD (HR = 1.73, 95% CI, 1.27-2.36) and adrenal CS (HR = 1.31, 95% CI, 1.00-1.81) had increased mortality risk. Patients without remission within 2 years had a higher mortality risk than those achieving remission (HR = 1.44, 95% CI, 1.00-2.17). Mortality was similar for CD and adrenal CS (HR = .83, 95% CI, .56-1.24). Older age, male gender, and prior malignancy were independent risk factors for mortality.

This is the largest national cohort study on mortality risk in CS over the past 2 decades, showing a significantly higher risk compared to matched controls in a homogeneous database. While etiology had no impact, remission significantly affected mortality, highlighting the importance of disease control for long-term survival.

Endogenous Cushing's syndrome (CS) is characterized by an unfavorable cardiovascular (CV) and metabolic risk profile, but the potential adverse effects of hypercortisolism on myocardial function are not well known. Myocardial Work analysis is a new echocardiographic method that utilizes left ventricular pressure-strain loops to quantify cardiac performance independent of afterload.

In a cross-sectional analysis, we compared four groups: patients with overt endogenous CS (n = 31, mean age 47 ± 12 years, 71% women), patients with endogenous CS in long-term remission after medical cure (CS-LTR; n = 49, 53 ± 12 years, 78% women), healthy subjects (n = 439; 49 ± 11 years, 57% women), and individuals with metabolic syndrome (n = 305, 59 ± 10 years, 37% women). Both CS patient groups exhibited a CV risk pattern and metabolic profile worse than healthy subjects but better than individuals with metabolic syndrome. Analyses adjusted for sex and age revealed higher Wasted Work both in overt CS (median; quartiles: 105 mmHg%; 74, 147) and CS-LTR (97 mmHg%; 69, 158), respectively, when compared to healthy individuals (75 mmHg%; 54, 109, p < 0.01) or individuals with metabolic syndrome (95 mmHg%, 65, 136, p < 0.05), resulting in compromised Work Efficiency (p < 0.05).

Left ventricular performance is compromised in overt CS beyond alterations found in individuals with metabolic syndrome sharing equal CV risk factors and remains so despite biochemical remission during the LTR period. Myocardial Work analysis is suited to detect the subtle yet clinically relevant differences between different phenotypes of myocardial involvement.

Normalization of hypercortisolism is essential to reduce morbidity and mortality in patients with Cushing's syndrome (CS). The aim of this analysis was to assess biochemical control rates in patients with Cushing's disease (CD), ectopic Cushing's syndrome (ECS), and adrenal Cushing's syndrome (ACS).

Patients with confirmed CS (n = 296) treated in a single tertiary care center were retrospectively analyzed (185 CD, 27 ECS, 84 uni- and bilateral ACS).

First-line treatment led to biochemical control in 82% of the patients. Time to biochemical control (median, interquartile range) was longer in CD (11.0 weeks, 5.6-29.8; P < .05) than in ACS (7.7 weeks, 4.1-17.1) and ECS (5.6 weeks, 4.1-23.3). Disease persistence or recurrence after first-line therapy was observed more often in CD (24% and 18%; P < .05) than in ECS (15% and 15%) and ACS (6% and 4%). Total time in hypercortisolism since diagnosis was significantly shorter in patients with CD diagnosed since 2013, after specialized patient care was implemented, compared to patients diagnosed before 2013 (13.5 weeks vs 26.1 weeks; P < .0070). Control of hypercortisolism at last follow-up (76 months, 38-163) was achieved in 94% of patients with ACS, 100% of patients with ECS, and 92% of patients with CD.

Biochemical control can be achieved in most patients with different subtypes of CS within a reasonable time frame. Control of hypercortisolism has improved over time.

Autonomous cortisol secretion (ACS) is linked to a higher prevalence of metabolic abnormalities and an increased risk of major adverse cardiovascular events.

To evaluate glucose and bone metabolism in patients with ACS using a continuous glucose monitoring system (CGMS) and dual-energy X-ray absorptiometry (DXA).

Patients diagnosed with ACS, including Cushing syndrome, mild ACS (MACS), and nonfunctional adrenal incidentaloma (NFAI), were recruited for this study. Glucose variability and glycemic status were assessed using CGMS. Regional bone mineral content (BMC), bone mineral density (BMD), and bone area (BA) were evaluated using DXA. CGMS- and DXA-derived parameters were compared across the subgroups of ACS. Correlation analysis was performed to examine relationships between varying degrees of cortisol secretion, measured by cortisol after 1 mg overnight dexamethasone suppression test (DST) or 24-hour urine free cortisol (24h UFC), and CGMS- or DXA-derived parameters.

A total of 64 patients with ACS were included in this study: 19 with Cushing syndrome, 11 with MACS, and 34 with NFAI. Glucose variability, time above range (TAR), and time in range (TIR) along with specific areal BMC, BMD, and BA, differed significantly between groups of Cushing syndrome and NFAI. A significant positive correlation was observed between glucose variability or TAR and cortisol after 1 mg overnight DST or 24h UFC. By contrast, TIR, along with regional BMC, BMD, and BA, were negatively correlated with varying degrees of cortisol secretion.

Glucose and bone metabolism impairments are on a continuum alteration from NFAI to MACS and Cushing syndrome. Prompt attention should be given to these patients with ACS, especially those with mild hormone secretion. Parameters of glucose variability and glycemic status along with bone condition in regions rich in cancellous bone will provide valuable information.

Hypertension is the leading cause of stroke in the UK and worldwide. In recent years, stroke incidence has increased by 30%-41.5% in people aged under 64 years, with the prevalence of hypertension increasing by 4%-11%. Given that 5%-10% of people with hypertension in the general population have an underlying cause for their elevated blood pressure, it is important that all clinicians should maintain a high clinical suspicion for secondary hypertension. This review provides a clinical perspective of when to consider the underlying causes of secondary hypertension, with investigation algorithms for patients presenting with stroke and hypertension. Early involvement of hypertension specialist services is important to identify secondary causes of hypertension, as its effective control reduces cardiovascular-associated morbidity.

Adrenal vein sampling (AVS) is considered the gold-standard for identifying unilateral primary aldosteronism (PA), but is sensitive to any asymmetry in cortisol production. Subclinical autonomous cortisol production likely contributes to discordance between cross-sectional imaging and AVS.

Retrospective chart review was performed of patients in Calgary, Alberta who (1) had a diagnosis of PA with clear adrenal mass, (2) had discordant AVS and cross-sectional imaging, and (3) underwent dexamethasone-suppressed NP59-iodocholesterol adrenal scintigraphy (n = 25). Postoperative biochemical and clinical outcomes were evaluated. Surgical pathology was analyzed with immunohistochemical staining for CYP11B1 and CYP11B2.

NP59 scanning demonstrated autonomous steroidogenesis from the same side as the computed tomography (CT)-identified lesion, despite discordant AVS results, in 19/25 cases. Out of the 16 patients who underwent adrenalectomy (guided by NP59), 11 cases had a final diagnosis of cortisol-producing adenoma with bilateral PA, while the final diagnosis in the remaining 5 cases was cortisol-producing adenoma with unilateral PA (defined by a complete biochemical response). All cases preoperatively had low/suppressed adrenocorticotropin hormone that rose postadrenalectomy, in keeping with the resolution of cortisol autonomy. Adrenal vein sampling incorrectly diagnosed the subtype of PA or falsely localized the side of aldosterone excess in 10/16 cases.

Discordant CT and AVS results in patients with PA and obvious adrenal mass are often explained by subclinical asymmetric cortisol excess. Clinicians should be aware of the limitations of AVS in the presence of subtle autonomous cortisol secretion and must be able to counsel patients regarding the possible outcomes from surgery when discordant lateralization is present.