"The healthcare system did fail me repeatedly": a qualitative study on experiences of healthcare among Canadian women with Cushing's syndrome.

BACKGROUND: As a rare endocrine disorder, Cushing's Syndrome (Cushing's) is characterized by numerous symptoms and a non-specific presentation, leading to a delay to diagnosis for patients with this disease. To date, research examining the lived experiences of patients with Cushing's in healthcare is absent in the literature. This preliminary inquiry into the healthcare experiences of women with Cushing's aimed to examine the utility of this line of inquiry to support the patient centered care of individuals with Cushing's. METHODS: Seven women from across Canada with endogenous Cushing's participated in the study. Semi-structured interviews were conducted examining participants' healthcare and body-related experiences with Cushing's. Results pertaining to healthcare experiences were analyzed for the current study using reflexive thematic analysis. RESULTS: Four themes emerged whereby women with Cushing's experienced (1) a lack of patient centered care, characterized by provider miscommunication and medical gaslighting; (2) a misunderstanding of their symptoms as related to weight gain; (3) weight stigma in healthcare encounters; and (4) a shift in their quality of care following diagnosis. CONCLUSIONS: The results highlight the importance of patient centered care as well as the negative impact of commonly reported barriers to patient centered care. Cushing's specific barriers to patient centered care may include weight stigma as well as the rare incidence of Cushing's. Further research is needed to better understand the healthcare experiences of people with Cushing's in Canada.

Evaluating the efficacy of surgical and conservative approaches in mild autonomous cortisol secretion: a meta-analysis.

Introduction: The management of Mild Autonomous Cortisol Secretion (MACS) remains a topic of debate among clinicians, with differing opinions on the effectiveness of surgical intervention compared to conservative treatment methods. This meta-analysis provides a comprehensive assessment of available literature to determine the most effective approach for treating this condition. Methods: On December 1, 2023, an exhaustive literature search of English databases Embase, PubMed, the Cochrane Library, Scopus, Web of Science, as well as the Chinese databases China HowNet, Wanfang Database, SinoMed Database, and Weipu Database using the keywords "Mild Autonomous Cortisol Secretion", "Subclinical Cushing's Syndrome", "Subclinical Hypercortisolism", "Mild Cortisol Autonomous Secretion", "Adrenal Incidentaloma", "Surgical Treatment" and "Adrenalectomy". The data were statistically analyzed using STATA version 15.0. Results: In this comprehensive analysis involving 629 patients with MACS, the therapeutic efficacy of adrenalectomy was evident. The meta-analysis results indicate that compared to conservative treatment, surgical intervention more effectively improves obesity indicators in patients: waist circumference (SMD=-0.62, 95% CI: -1.06 to -0.18), BMI (SMD=-0.41, 95% CI: -0.62 to -0.20), enhances glycemic control: fasting blood glucose (SMD=-0.47, 95% CI: -0.68 to -0.26), glycated hemoglobin (SMD=-0.66, 95% CI: -0.95 to -0.38), improves lipid metabolism: triglycerides (SMD=-0.45, 95% CI: -0.73 to -0.16), lowers blood pressure: systolic blood pressure (SMD=-1.04, 95% CI: -1.25 to -0.83), diastolic blood pressure (SMD=-0.89, 95% CI: -1.12 to -0.65), and ameliorates hormonal metabolic disorder: 24h urinary free cortisol (SMD=-1.10, 95% CI: -1.33 to -0.87), ACTH (SMD=2.30, 95% CI: 1.63 to 2.97). All these differences are statistically significant. Conclusion: This meta-analysis shows that, compared to conservative treatment, surgical treatment is more effective in improving obesity indicators, glycemic control, lipid metabolism, reducing blood pressure, and ameliorating hormonal metabolic disorders in patients with MACS. These statistically significant results highlight the importance of considering surgical intervention in the management of patients with MACS. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023492527.

Epicardial adipose tissue volume highly correlates with left ventricular diastolic dysfunction in endogenous Cushing's syndrome.

BACKGROUND: Cushing's syndrome (CS) is associated with increased risk for heart failure, which often initially manifests as left ventricular diastolic dysfunction (LVDD). In this study, we aimed to explore the potential risk factors of LVDD in CS by incorporating body composition parameters. METHODS: A retrospective study was conducted on patients diagnosed with endogenous CS no less than 18 years old. The control group consisted of healthy individuals who were matched to CS patients in terms of gender, age, and BMI. LIFEx software (version 7.3) was applied to measure epicardial adipose tissue volume (EATV) on non-contrast chest CT, as well as abdominal adipose tissue and skeletal muscle mass at the first lumbar vertebral level. Echocardiography was used to evaluate left ventricular (LV) diastolic function. Body compositions and clinical data were examined in relation to early LVDD. RESULTS: A total of 86 CS patients and 86 healthy controls were enrolled. EATV was significantly higher in CS patients compared to control subjects (150.33 cm3 [125.67, 189.41] vs 90.55 cm3 [66.80, 119.84], p < 0.001). CS patients had noticeably increased visceral fat but decreased skeletal muscle in comparison to their healthy counterparts. Higher prevalence of LVDD was found in CS patients based on LV diastolic function evaluated by E/A ratio (p < 0.001). EATV was proved to be an independent risk factor for LVDD in CS patients (OR = 1.015, 95%CI 1.003-1.026, p = 0.011). If the cut-point of EATV was set as 139.252 cm3 in CS patients, the diagnostic sensitivity and specificity of LVDD were 84.00% and 55.60%, respectively. CONCLUSION: CS was associated with marked accumulation of EAT and visceral fat, reduced skeletal muscle mass, and increased prevalence of LVDD. EATV was an independent risk factor for LVDD, suggesting the potential role of EAT in the development of LVDD in CS.

This study explored the potential risk factors of LVDD in endogenous CS by incorporating body composition parameters. EATV was identified as an independent risk factor for LVDD. Targeted therapeutic interventions to reduce excessive cortisol-induced EAT accumulation may be promising to mitigate the risk of LVDD development in patients with CS.

[The value of serum dehydroepiandrosterone sulfate in the functional evaluation of adrenal space-occupying lesions in adults].

Objective: To evaluate the function of serum dehydroepiandrosterone sulfate (DHEAS) in adult adrenal space-occupying lesions. Methods: In this cross-sectional study, 395 patients with adrenal space-occupying lesions who had their DHEAS levels measured were collected from the First Medical Center of Chinese PLA General Hospital from January 2010 to June 2021. They were divided into the adrenal Cushing syndrome (ACS) group (n=100) and non-ACS group (n=295). The former was divided into the cortisol-producing adrenal adenoma (CPA) group (n=67) and primary bilateral macronodular adrenal hyperplasia (PBMAH) group (n=33). Clinical data of each group were collected and compared among groups by independent samples t-test, chi-square test, and Mann-Whitney U test. Serum DHEAS ratio corrected for age and sex was further constructed to identify the receiver operating characteristic curve and the optimal tangent point value for different adrenal occupation. Results: Patients in the ACS group were younger (44.9±13.7 vs. 49.9±12.5, P=0.001); had a larger proportion of women (79/100 vs.139/295, P=0.001); and had higher cortisol levels [8∶00Am, 497.31 (343.52, 606.50) vs. 353.11 (267.50, 487.91) nmol/L, P<0.001] than those in the non-ACS group. The serum DHEAS level and ratio in the ACS group were significantly lower than those in the non-ACS group [0.50 (0.40, 1.21) vs. 2.68 (1.56, 4.32) µmol/L, 1.00 (0.43, 1.68) vs. 3.17 (2.21, 4.54), both P<0.001]. When the serum DHEAS ratio cut-off point was 1.29, the sensitivity and specificity for differential diagnosis of ACS and non-ACS were 72.0% and 91.5% respectively. The ratio of DHEAS in the CPA group was lower [0.58 (0.27, 1.05) vs. 1.14 (1.04, 2.40), P<0.001] than that in the PBMAH group. When the serum DHEAS ratio cut-off point was 0.99, the sensitivity and specificity for differential diagnosis of CPA and PBMAH were 64.2% and 81.2% respectively. Conclusion: Corrected age-sex DHEAS ratio can assist in the functional assessment of adrenal space-occupying lesions.

Dielectric characterisation of human adrenal glands and adrenal tumours for the development of microwave ablation technologies for hypertension treatment.

Adrenal gland-induced hypertension results from underlying adrenal gland disorders including Conn's syndrome, Cushing's syndrome, and Pheochromocytoma. These adrenal disorders are a risk for cardiovascular and renal morbidity and mortality. Clinically, treatment for adrenal gland-induced hypertension involves a pharmaceutical or surgical approach. The former presents very significant side effects whereas the latter can be ineffective in cases where the adrenal disorder reoccurs in the remaining contralateral adrenal gland. Due to the limitations of existing treatment methods, minimally invasive treatment options like microwave ablation (MWA) have received significant attention for treating adrenal gland disorders. A precise comprehension of the dielectric properties of human adrenal glands will help to tailor energy delivery for MWA therapy, thus offering the potential to optimise treatments and minimise damage to surrounding tissues. This study reports the ex vivo dielectric properties of human adrenal glands, including the cortex, medulla, capsule, and tumours, based on the data obtained from four patients (diagnosed with Conn's syndrome, Cushing's syndrome, and Pheochromocytoma) who underwent unilateral adrenalectomy at the University Hospital Galway, Ireland. An open-ended coaxial probe measurement technique was used to measure the dielectric properties for a frequency range of 0.5-8.5 GHz. The dielectric properties were fitted using a two-pole Debye model, and a weighted least squares method was employed to optimise the model parameters. Moreover, the dielectric properties of adrenal tissues and tumours were compared across frequencies commonly used in MWA, including 915 MHz, 2.45 GHz, and 5.8 GHz. The study found that the dielectric properties of adrenal tumours were influenced by the presence of lipid-rich adenomas, and the dielectric properties of Cushing's syndrome tumour were lowest in comparison to the tumours in patients diagnosed with Conn's syndrome and Pheochromocytoma. Furthermore, a notable difference was observed in the dielectric properties of the medulla and cortex among patients diagnosed with Conn's syndrome, Cushing's syndrome, and Pheochromocytoma. These findings have significant implications for the diagnosis and treatment of adrenal tumours, including the optimisation of MWA therapy for precise ablation of adrenal masses.

Primary unilateral macronodular adrenal hyperplasia with concomitant glucocorticoid and androgen excess and KDM1A inactivation.

BACKGROUND: Primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. Individuals with PBMAH and glucose-dependent insulinotropic polypeptide (GIP)-dependent Cushing's syndrome due to ectopic expression of the GIP receptor (GIPR) typically harbor inactivating KDM1A sequence variants. Primary unilateral macronodular adrenal hyperplasia (PUMAH) with concomitant glucocorticoid and androgen excess has never been encountered or studied. METHODS: We investigated a woman with a large, heterogeneous adrenal mass and severe adrenocorticotropic hormone-independent glucocorticoid and androgen excess, a biochemical presentation typically suggestive of adrenocortical carcinoma. The patient presented during pregnancy (22nd week of gestation) and reported an 18-month history of oligomenorrhea, hirsutism, and weight gain. We undertook an exploratory study with detailed histopathological and genetic analysis of the resected adrenal mass and leukocyte DNA collected from the patient and her parents. RESULTS: Histopathology revealed benign macronodular adrenal hyperplasia. Imaging showed a persistently normal contralateral adrenal gland. Whole-exome sequencing of 4 representative nodules detected KDM1A germline variants, benign NM_001009999.3:c.136G > A:p.G46S, and likely pathogenic NM_001009999.3:exon6:c.865_866del:p.R289Dfs*7. Copy number variation analysis demonstrated an additional somatic loss of the KDM1A wild-type allele on chromosome 1p36.12 in all nodules. RNA sequencing of a representative nodule showed low/absent KDM1A expression and increased GIPR expression compared with 52 unilateral sporadic adenomas and 4 normal adrenal glands. Luteinizing hormone/chorionic gonadotropin receptor expression was normal. Sanger sequencing confirmed heterozygous KDM1A variants in both parents (father: p.R289Dfs*7 and mother: p.G46S) who showed no clinical features suggestive of glucocorticoid or androgen excess. CONCLUSIONS: We investigated the first PUMAH associated with severe Cushing's syndrome and concomitant androgen excess, suggesting pathogenic mechanisms involving KDM1A.

Comparable cognitive impairment was detected in MACS and CS and alleviated after remission of hypercortisolism in MACS.

Context: Few studies have directly compared the cognitive characteristics of patients with mild autonomous cortisol secretion (MACS) and Cushing's syndrome (CS). The effect of surgical or conservative treatment on cognitive function in patients with MACS is still unclear. Objective: To compare the differences in cognitive function between patients with MACS and CS and evaluate the effect of surgery or conservative treatment on cognitive function. Methods: We prospectively recruited 59 patients with nonfunctional adrenal adenoma (NFA), 36 patients with MACS, and 20 patients with adrenal CS who completed the global cognition and cognitive subdomains assessments. Seventeen MACS patients were re-evaluated for cognitive function after a 12-month follow-up period; of these, eleven underwent laparoscopic adrenalectomy and six received conservative treatment. Results: Patients with MACS and CS performed worse in the global cognition and multiple cognitive domains than those with NFA (all P<0.05). No statistical difference was found in cognitive functions between patients with MACS and CS. Logistic regression analysis showed that patients with MACS (odds ratio [OR]=3.738, 95% confidence intervals [CI]: 1.329-10.515, P=0.012) and CS (OR=6.026, 95% CI: 1.411-25.730, P=0.015) were associated with an increased risk of immediate memory impairment. Visuospatial/constructional, immediate and delayed memory scores of MACS patients were significantly improved at 12 months compared with pre-operation in the surgical treatment group (all P<0.05), whereas there was no improvement in the conservative treatment group. Conclusion: Patients with MACS have comparable cognitive impairment as patients with CS. Cognitive function was partially improved in patients with MACS after adrenalectomy. The current data support the inclusion of cognitive function assessment in the clinical management of patients with MACS.

Circulating miR-28-5p is overexpressed in patients with sarcopenia despite long-term remission of Cushing's syndrome: a pilot study.

Introduction: Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS. Patients and methods: Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m2, and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems). Results: In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%. Conclusion: MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo, may serve as an independent non-invasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission.

Case report: A challenging case of severe Cushing's syndrome in the course of metastatic thymic neuroendocrine carcinoma with a synchronous adrenal tumor.

Ectopic ACTH syndrome (EAS) remains one of the most demanding diagnostic and therapeutic challenges for endocrinologists. Thymic neuroendocrine tumors account for 5%-10% of all EAS cases. We report a unique case of a 31-year-old woman with severe EAS caused by primary metastatic combined large-cell neuroendocrine carcinoma and atypical carcinoid of the thymus. The patient presented with severe hypercortisolemia, which was successfully controlled with continuous etomidate infusion. Complex imaging initially failed to detect thymic lesion; however, it revealed a large, inhomogeneous, metabolically active left adrenal mass infiltrating the diaphragm, suspected of primary disease origin. The patient underwent unilateral adrenalectomy, which resulted in hypercortisolemia resolve. The pathology report showed an adenoma with adrenal infarction and necrosis. The thymic tumor was eventually revealed a few weeks later on follow-up imaging studies. Due to local invasion and rapid progression, only partial resection of the thymic tumor was possible, and the patient was started on radio- and chemotherapy.

The clinical characteristics and pathogenic variants of primary pigmented nodular adrenocortical disease in 210 patients: a systematic review.

Aims: Primary pigmented nodular adrenocortical disease (PPNAD), as a rare kind of Cushing's syndrome, is frequently misdiagnosed. To get a better understanding of the disease, we analyzed the clinical characteristics and pathogenic variants of PPNAD. Methods: Databases were searched, and the pathogenic variants and clinical manifestations of patients were summarized from the relevant articles. Results: A total of 210 patients in 86 articles were enrolled with a median age of 22 and a female-to-male ratio of 2:1. Sixty-six (31.43%) patients were combined with Carney complex (CNC) and 94.29% were combined with osteoporosis/osteopenia. Among 151 patients who underwent genetic testing, 87.42% (132/151) had pathogenic variants. Six gene mutations (PRKAR1A, PDE11A, PRKACA, CTNNB1, PDE8B, and ARMC5) were detected in the patients. The most common mutation was PKAR1A, accounting for 79.47% (120/151). There was a significant correlation between PRKAR1A pathogenic variant and spotty skin pigmentation in CNC concurrent with PPNAD (p < 0.05). Among pregnant patients with PPNAD, those without surgical treatment and with bilateral adrenalectomy suffered from a high-risk perinatal period. However, patients with unilateral adrenalectomy presented a safe perinatal period. Conclusions: For young patients with Cushing's syndrome, especially female patients with spotty skin pigmentation and osteoporosis/osteopenia, PPNAD should be considered. Unilateral adrenal resection may be considered as an option for women with fertility needs. In view of the difficulty of PPNAD diagnosis, genetic testing before surgery might be a reasonable option. Patients with PPNAD with spotty skin pigmentation should consider the PRKAR1A pathogenic variant and pay attention to CNC. Systematic review registration: https://www.crd.york.ac.uk/prospero, identifier CRD42023416988.

The effect of mass functionality on laparoscopic adrenalectomy outcomes.

PURPOSE: This study aimed to determine the effect of adrenal mass functionality and different hormone subtypes synthesized by the adrenal masses on laparoscopic adrenalectomy (LA) outcomes. MATERIALS AND METHODS: The study included 298 patients, 154 of whom were diagnosed with nonfunctional masses. In the functional group, 33, 62, and 59 patients had Conn syndrome, Cushing's syndrome, and pheochromocytoma, respectively. The variables were analyzed between the functional and nonfunctional groups and then compared among functional masses through subgroup analysis. RESULTS: The incidence of diabetes mellitus, hypertension, and obesity, blood loss, and length of hospital stay (LOH) were significantly higher in the functional group than in the nonfunctional group. In the subgroup analysis, patients with pheochromocytoma had significantly lower body mass index but significantly higher mass size, blood loss, and LOH than the other two groups. A positive correlation was found between mass size and blood loss in patients with pheochromocytoma (p ≤ 0.001, r = 0.761). However, no significant difference in complications was found among the groups. CONCLUSIONS: In this study, patients with functional adrenal masses had higher comorbidity rates and American Society of Anesthesiologists scores. Moreover, blood loss and LOH were longer on patients with functional adrenal masses who underwent LA. Mass size, blood loss, and LOH in patients with pheochromocytoma were significantly longer than those in patients with other functional adrenal masses. Thus, mass functionality did not increase the complications.

Whole blood transcriptomic signature of Cushing's syndrome.

OBJECTIVE: Cushing's syndrome is characterized by high morbidity and mortality with high interindividual variability. Easily measurable biomarkers, in addition to the hormone assays currently used for diagnosis, could reflect the individual biological impact of glucocorticoids. The aim of this study is to identify such biomarkers through the analysis of whole blood transcriptome. DESIGN: Whole blood transcriptome was evaluated in 57 samples from patients with overt Cushing's syndrome, mild Cushing's syndrome, eucortisolism, and adrenal insufficiency. Samples were randomly split into a training cohort to set up a Cushing's transcriptomic signature and a validation cohort to assess this signature. METHODS: Total RNA was obtained from whole blood samples and sequenced on a NovaSeq 6000 System (Illumina). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore the transcriptome profile. Ridge regression was used to build a Cushing's transcriptome predictor. RESULTS: The transcriptomic profile discriminated samples with overt Cushing's syndrome. Genes mostly associated with overt Cushing's syndrome were enriched in pathways related to immunity, particularly neutrophil activation. A prediction model of 1500 genes built on the training cohort demonstrated its discriminating value in the validation cohort (accuracy .82) and remained significant in a multivariate model including the neutrophil proportion (P = .002). Expression of FKBP5, a single gene both overexpressed in Cushing's syndrome and implied in the glucocorticoid receptor signaling, could also predict Cushing's syndrome (accuracy .76). CONCLUSIONS: Whole blood transcriptome reflects the circulating levels of glucocorticoids. FKBP5 expression could be a nonhormonal marker of Cushing's syndrome.

Association between gut microbiota and adrenal disease: a two-sample Mendelian randomized study.

Background: Some observational studies and clinical experiments suggest a close association between gut microbiota and metabolic diseases. However, the causal effects of gut microbiota on adrenal diseases, including Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism, remain unclear. Methods: This study conducted a two-sample Mendelian randomization analysis using summary statistics data of gut microbiota from a large-scale genome-wide association study conducted by the MiBioGen Consortium. Summary statistics data for the three adrenal diseases were obtained from the FinnGen study. The study employed Inverse variance weighting, MR-Egger, and MR-PRESSO methods to assess the causal relationship between gut microbiota and these three adrenal diseases. Additionally, a reverse Mendelian randomization analysis was performed for bacteria found to have a causal relationship with these three adrenal diseases in the forward Mendelian randomization analysis. Cochran's Q statistic was used to test for heterogeneity of instrumental variables. Results: The IVW test results demonstrate that class Deltaproteobacteria, Family Desulfovibrionaceae, and Order Desulfovibrionales exhibit protective effects against adrenocortical insufficiency. Conversely, Family Porphyromonadaceae, Genus Lachnoclostridium, and Order MollicutesRF9 are associated with an increased risk of adrenocortical insufficiency. Additionally, Family Acidaminococcaceae confers a certain level of protection against Cushing syndrome. In contrast, Class Methanobacteria, Family Lactobacillaceae, Family Methanobacteriaceae, Genus. Lactobacillus and Order Methanobacteriales are protective against Hyperaldosteronism. Conversely, Genus Parasutterella, Genus Peptococcus, and Genus Veillonella are identified as risk factors for Hyperaldosteronism. Conclusions: This two-sample Mendelian randomization analysis revealed a causal relationship between microbial taxa such as Deltaproteobacteria and Desulfovibrionaceae and Adrenocortical insufficiency, Cushing syndrome, and Hyperaldosteronism. These findings offer new avenues for comprehending the development of adrenal diseases mediated by gut microbiota.

Study protocol for a prospective, multicentre study of hypercortisolism in patients with difficult-to-control type 2 diabetes (CATALYST): prevalence and treatment with mifepristone.

INTRODUCTION: Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hyper c ortisolism in P at ients with Difficult to Control Type 2 Di a betes Despite Receiving Standard-of-Care Therapies: Preva l ence and Treatment with Korl y m® (Mifepri st one) (CATALYST) trial. METHODS AND ANALYSIS: In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%-11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life. ETHICS AND DISSEMINATION: The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05772169.

Endogenous Cushing's syndrome and cancer risk.

OBJECTIVE: Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls. DESIGN: A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel. METHODS: Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event. RESULTS: A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9-20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44-2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies. CONCLUSION: Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population.

Prevalence and outcome of secondary hypogonadism in male patients with Cushing's syndrome and mild autonomous cortisol secretion.

BACKGROUND: Secondary hypogonadism (SH) is common in men with Cushing's syndrome (CS), but its impact on comorbidities is largely unknown and longitudinal data are scarce. If SH also affects men with mild autonomous cortisol secretion (MACS) is unknown. METHODS: We included 30 treatment-naïve adult men with CS and 17 men with MACS diagnosed since 2012. Hypogonadism was diagnosed based on total testosterone (TT) concentrations < 10.4 nmol/L and age-specific cut-offs. Outcomes were compared to age- and BMI-matched controls. In 20 men in remission of CS, a longitudinal analysis was conducted at 6, 12, and 24 months. RESULTS: Men with CS had significantly lower concentrations of TT, bioavailable T, and free T compared to controls (P < .0001) with lowest concentrations in ectopic CS. Likewise, TT was lower in men with MACS compared to controls. At baseline, 93% of men with CS and 59% of men with MACS had SH. Testosterone correlated negatively with late night salivary cortisol and serum cortisol pre- and post-1 mg dexamethasone suppression test. Following successful surgery, TT increased significantly (P = .001), normalising within 6 months. Despite normalisation, several RBC parameters remained lower in men with CS even 2 years after successful surgery. CONCLUSIONS: Secondary hypogonadism is common in men with CS and MACS but usually reversible after successful surgery. The persisting changes observed in RBC parameters need to be further investigated in larger cohorts and longer follow-up durations.

Conundrums of Diagnosis and Management of Cushing's Syndrome in Pregnancy.

Pregnancy is rare in women with Cushing's syndrome (CS), due to hypercortisolism-induced gonadotropin suppression and anovulation. Diagnosis of CS is hampered by physiological cortisol level increases during normal pregnancy; importantly abnormal cortisol secretion circadian rhythm could be diagnostic. Active CS is associated with considerable maternal and fetal complications. Second trimester surgery (pituitary or adrenal) is the main treatment option, however observation in mild cases has been suggested. Medical treatment, although not approved for use in pregnancy, may be considered, after careful discussion and balancing any benefits with potential risks and side-effects.