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Abstract Context Signs and symptoms of Cushing’s syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. Objective The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. Data Sources A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. Study Selection Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. Data Extraction Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. Data Synthesis Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere. Conclusions Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.

Context Once hypercortisolemia is confirmed, differential diagnosis between Cushing’s syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing’s syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed. Objective Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH. Methods Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist. Data synthesis A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87–94%; I 2 0%) and 82% (73–88%; I 2 50%), desmopressin test 86% (81–90%; I 2 28%) and 90% (84–94%; I 2 15%), MSC 91% (85–94%; I 2 66%) and 81% (70–89%; I 2 71%), and LNSC 80% (67–89%; I 2 57%) and 90% (84–93%; I 2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate. Conclusion Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians’ confidence when deciding which test to perform.

We report a case of spontaneous resolution of Cushing disease (CD). A 20-year-old female individual, previously healthy, was referred for investigation of galactorrhea and a prolactin level of 31 ng/mL (<20 ng/mL) (SI: 31 µg/L, <20 µg/L). A magnetic resonance imaging (MRI) scan revealed an 11 mm pituitary lesion. Cabergoline was commenced to address symptomatic hyperprolactinemia. Over the following months, signs of hypercortisolism evolved. Initial tests revealed a positive 1-mg dexamethasone suppression test (DST), prompting further evaluation. Midnight salivary and 24-hour urinary free cortisol tests confirmed hypercortisolism, consistent with a pituitary source which was confirmed with a peripheral corticotropin-releasing hormone (CRH) stimulation test. While cabergoline successfully resolved the galactorrhea, an MRI scan 6 months later showed an increase in the pituitary lesion’s size, leading to neurosurgical referral. However, a preoperative MRI surprisingly revealed complete resolution of the pituitary mass, which coincided with the normalization of hypercortisolism symptoms and laboratory results. This rare case of spontaneous remission, while possibly influenced by cabergoline or undetected pituitary apoplexy, contributes valuable insights into the unpredictable nature of CD and its treatment.

Abstract It is held that the condition of endogenous chronic hypersecretion of cortisol (Cushing syndrome, CS), causes several comorbidities, including cardiovascular and metabolic disorders, musculoskeletal alterations, as well as cognitive and mood impairment. Therefore, CS has an adverse impact on the quality of life and life expectancy of affected patients. What remains unclear is whether disease remission may induce a normalization of the associated comorbid conditions. In order to retrieve updated information on this issue, we conducted a systematic search using the Pubmed and Embase databases to identify scientific papers published from January 1, 2000, to December 31, 2022. The initial search identified 1907 potentially eligible records. Papers were screened for eligibility and a total of 79 were included and classified by the main topic (cardiometabolic risk, thromboembolic disease, bone impairment, muscle damage, mood disturbances and quality of life, cognitive impairment, and mortality). Although the limited patient numbers in many studies preclude definitive conclusions, most recent evidence supports the persistence of increased morbidity and mortality even after long-term remission. It is conceivable that the degree of normalization of the associated comorbid conditions depends on individual factors and characteristics of the conditions. These findings highlight the need for early recognition and effective management of patients with CS, which should include active treatment of the related comorbid conditions. In addition, it is important to maintain a surveillance strategy in all patients with CS, even many years after disease remission, and to actively pursue specific treatment of comorbid conditions beyond cortisol normalization.

Cushing’s disease (CD), caused by an adrenocorticotropic hormone-secreting pituitary adenoma, is challenging to diagnose, especially in obese patients post-bariatric surgery. This report discusses a misdiagnosed case of CD in a 42-year-old obese male with hypertension. CD was suspected only after surgery, confirmed by magnetic resonance imaging (MRI) showing a pituitary macroadenoma. Despite transsphenoidal surgery and ketoconazole therapy, the patient suffered liver failure and died. Among 20 CD reviewed cases in the literature, 65% were misdiagnosed. MRI and immunohistochemistry confirmed tumors, with 55% achieving remission post-surgery. Screening for CD before bariatric surgery may prevent mismanagement and complications.

Abstract Background Treatment of naturally occurring Cushing’s syndrome includes surgery or medical management but there is little information on how primary care veterinarians (PCVs) select and monitor such treatment. Hypothesis/Objectives Determine how PCVs from selected European countries treat and monitor Cushing’s syndrome in dogs. Methods Cross-sectional survey study assessing treatment and monitoring protocols used by PCVs when managing dogs with Cushing’s syndrome. Results A total of 2178 responses from 9 European countries were included. Overall, 1694 (77.8%) respondents attempted to differentiate functional adrenal tumor (FAT) from pituitary-dependent hypercortisolism (PDH). Adrenalectomy and hypophysectomy were recommended in 67.8% and 30.5% dogs with FAT and PDH, respectively. When surgery was not considered, 23.9% of respondents did not always suggest medical management. Of those recommending medical treatment, 1895/2163 (87.6%) respondents used trilostane either once (60.7%) or twice (39.3%) daily. Time to first follow-up was < 10, 10-14, and 15-30 days for 6.1%, 59.8%, and 31.1% of respondents, respectively. Long-term follow-up was every 3-4 (41.7%) or 5-6 months (37.9%). Monitoring is performed using ACTH stimulation test (54.6%), pre-pill plasma cortisol concentration (18.4%), and both pre- and post-pill plasma cortisol concentration (13.3%). Conclusions and clinical importance Approximately one-third of PCVs do not recommend adrenalectomy for FAT and two-thirds do not recommend hypophysectomy in PDH. Despite demonstrated benefits of medical treatment, one-quarter of respondents do not always recommend it, which may adversely affect life expectancy and quality of life. Treatment and monitoring protocols vary among PCVs. These results suggest that further education of PCVs about management of Cushing’s syndrome in dogs may be warranted.

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Abstract Context The risk of vertebral fractures (VFx) in patients with adrenal incidentalomas (AI) and mild autonomous cortisol secretion (MACS) is debated. Objective To evaluate the VFx prevalence and incidence in patients with AI and MACS. Methods This cross-sectional and longitudinal study using retrospective data from 4 Italian endocrinology units included 444 patients (cross-sectional arm) and 126 patients (longitudinal arm, 24.9 ± 5.3 months follow-up) to evaluate prevalent and incident VFx, respectively, in patients with MACS (MACS-yes) and without MACS (MACS-no). The main outcome measures were serum cortisol after a 1-mg dexamethasone test (F-1mgDST), bone mineral density (BMD) by dual-energy x-ray absorptiometry at spine (LS) and femur (FN), and VFx presence by x-ray. Results Cross-sectional arm: 214 and 230 patients were MACS-yes and MACS-no, respectively, based on F-1mgDST >1.8 µg/dL (50 nmol/L). Patients with MACS had higher VFx prevalence (62.6%) than those without MACS (22.9%, P < .001); MACS was associated with prevalent VFx (odds ratio, 5.203; 95% CI, 3.361-8.055; P < .001; relative risk [RR] 2.07), regardless of age, body mass index, gender distribution, LS-BMD, and presence of type 2 diabetes mellitus (T2D). Longitudinal arm: 66 and 60 patients were MACS-no and MACS-yes, respectively. Patients without MACS showed higher number of incident VFx (36.4%) than patients without MACS (10.0%, P < .001); MACS was associated with the presence of an incident VFx (RR 4.561; 95% CI, 1.600-13.003; P = .005) regardless of age, LS-BMD, gender distribution, presence of prevalent VFx, and T2D. Results were confirmed in women and men when separately evaluated. Conclusion Women and men with AI and MACS are at higher risk of VFx.

Abstract Context Mild autonomous cortisol secretion (MACS) is diagnosed based on postdexamethasone cortisol >1.8 µg/dL. Scarce evidence exists on steroid circadian secretion and steroid metabolome in MACS. Objective To characterize 24-hour (h) urine steroid metabolome in patients with MACS and determine circadian differences in urine steroid profiling and cortisol concentrations in patients with MACS vs referent subjects. Methods Cross-sectional study, 2018-2023, at a referral center. Patients with MACS and age-, sex-, body mass index–, and menopausal status–matched referent subjects were included. Urine was collected over a 24 hour period as separate daytime and nighttime collections. High-resolution mass spectrometry assay was used to measure 25 steroids. A subgroup of patients and referent subjects was admitted for serum measurements of free and total cortisol every 2 hours. Outcomes were steroids, steroid sums, and ratios. Results Patients with MACS (n = 72) had lower µg/24 hour median androgens (2084 vs 3283, P < .001), higher glucocorticoids (15 754 vs 12936, P < .001), and higher glucocorticoid/androgen ratio (8.7 vs 3.9, P < .001) than referent subjects. Patients also had lower steroid day/night ratios than referent subjects, reflecting a higher relative nocturnal steroid production in MACS. In a subgroup of 12 patients with MACS and 10 referent subjects, the 24-hour areas under the curve for total and free serum cortisol were similar. However, evening mean total (5.3 vs 4.0 µg/dL, P = .056) and free (0.2 vs 0.1 µg/dL, P = .035) cortisol was higher in patients vs referent subjects. Conclusion Patients with MACS demonstrate an abnormal urine steroid metabolome, with a high glucocorticoid to androgen ratio, and a higher nocturnal steroid production.

Abstract Background The dexamethasone suppression test (DST) is the recommended first-tier test for suspected Cushing syndrome (CS). Missed dexamethasone intake or insufficient dexamethasone serum exposure may yield false positive results. Quantification of serum dexamethasone in DST samples may therefore improve test performance. Methods Simultaneous quantification of dexamethasone and cortisol by liquid chromatography-tandem mass spectrometry in 400 DST serum samples (100 overt CS, 200 excluded CS, 100 adrenal incidentalomas with (possible) autonomous cortisol secretion, AI-ACS) randomly selected within the indication groups. The 2.5th percentile of dexamethasone in patients with excluded CS was considered the lower limit of normal (LLN). Results Serum dexamethasone varied from undetectable to 20.2 ng/mL with a median of 4.8 ng/mL (95% CI 4.5-5.1 ng/mL). Dexamethasone was undetectable in only 16 patients (4%), suggesting non-compliance. The dexamethasone LLN was 1.8 ng/mL (4.6 nmol/L). Decreased glomerular filtration rate and diabetes mellitus were associated with higher serum dexamethasone concentration, while body mass index, sex, age, nicotine, and oral contraceptives had no significant effect. By excluding the 27 samples with dexamethasone

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