Development and validation of a preoperative "difficulty score" for laparoscopic transabdominal adrenalectomy: a multicenter retrospective study.

BACKGROUND: A difficulty score for laparoscopic adrenalectomy (LA) is lacking in the literature. A retrospective cohort study was designed to develop a preoperative "difficulty score" for LA. METHODS: A multicenter study was conducted involving four Italian tertiary centers for adrenal disease. The population was randomly divided into two subsets: training group and validation one. A multicenter study was undertaken, including 964 patients. Patient, adrenal lesion, surgeon's characteristics, and the type of procedure were studied as potential predictors of target events. The operative time (pOT), conversion rate (cLA), or both were used as indicators of the difficulty in three multivariate models. All models were developed in a training cohort (70% of the sample) and validated using 30% of patients. For all models, the ability to predict complicated postoperative course was reported describing the area under the curve (AUCs). Logistic regression, reporting odds ratio (OR) with p-value, was used. RESULTS: In model A, gender (OR 2.04, p = 0.001), BMI (OR 1.07, p = 0.002), previous surgery (OR 1.29, p = 0.048), site (OR 21.8, p < 0.001) and size of the lesion (OR 1.16, p = 0.002), cumulative sum of procedures (OR 0.99, p < 0.001), extended (OR 26.72, p < 0.001) or associated procedures (OR 4.32, p = 0.015) increased the pOT. In model B, ASA (OR 2.86, p = 0.001), lesion size (OR 1.20, p = 0.005), and extended resection (OR 8.85, p = 0.007) increased the cLA risk. Model C had similar results to model A. All scores obtained predicted the target events in validation cohort (OR 1.99, p < 0.001; OR 1.37, p = 0.007; OR 1.70, p < 0.001, score A, B, and C, respectively). The AUCs in predicting complications were 0.740, 0.686, and 0.763 for model A, B, and C, respectively. CONCLUSION: A difficulty score based on both pOT and cLA (Model C) was developed using 70% of the sample. The score was validated using a second cohort. Finally, the score was tested, and its results are able to predict a complicated postoperative course.

Association Between Aldosterone and Parathyroid Hormone Levels in Patients With Adrenocortical Tumors.

OBJECTIVE: Patients with primary aldosteronism (PA) can present with high PTH levels and negative calcium balance, with some studies speculating that aldosterone could directly stimulate PTH secretion. Either adrenalectomy or mineralocorticoid receptor blockers could reduce PTH levels in patients with PA. The aim of this study was to assess the relationship between aldosterone levels and parathyroid hormone (PTH)-vitamin D-calcium axis in a cohort of patients with PA, compared with patients with nonsecreting adrenocortical tumors in conditions of vitamin D sufficiency. METHODS: We enrolled a series of 243 patients retrospectively, of whom 66 had PA and 177 had nonsecreting adrenal tumors, and selected those with full mineral metabolism evaluation and 25(OH) vitamin D levels >20 ng/mL at the time of initial endocrine screening. The final cohort was composed of 26 patients with PA and 39 patients, used as controls, with nonsecreting adrenal tumors. The relationships between aldosterone, PTH levels, and biochemistries of mineral metabolism were assessed. RESULTS: Aldosterone was positively associated with PTH levels (r = 0.260, P < .05) in the whole cohort and in the PA cohort alone (r = 0.450; P = .02). In the multivariate analysis, both aldosterone concentrations and urinary calcium excretion were significantly related to PTH levels, with no effect of 25(OH) vitamin D or other parameters of bone metabolism. CONCLUSION: PTH level is associated with aldosterone, probably independent of 25(OH) vitamin D levels and urinary calcium. Whether aldosterone interacts directly with the parathyroid glands remains to be established.

Minimally invasive adrenalectomy: a comprehensive systematic review and network meta-analysis of phase II/III randomized clinical controlled trials.

PURPOSE: The best approach for minimally invasive adrenalectomy is still under debate. METHODS: A systematic search of randomized clinical trials was carried out. A frequentist random-effects network meta-analysis was made reporting the surface under the cumulative ranking (SUCRA). The primary endpoint regarded both in-hospital mortality and morbidity. The secondary endpoints were operative time (OP), blood loss (BL), length of stay (LOS), conversion, incisional hernia, and disease recurrence rate. RESULTS: Eight studies were included, involving 359 patients clustered as follows: 175 (48.7%) in the TPLA arm; 55 (15.3%) in the RPLA arm; 10 (2.8%) in the Ro-TPLA arm; 25 (7%) in the TPAA arm; 20 (5.6%) in the SILS-LA arm; and 74 (20.6%) in the RPA arm. The RPLA had the highest probability of being the safest approach (SUCRA 69.6%), followed by RPA (SUCRA 63.0%). TPAA, Ro-TPLA, SILS-LA, and TPLA have similar probability of being safe (SUCRA values 45.2%, 43.4%, 43.0%, and 38.5%, respectively). Analysis of the secondary endpoints confirmed the superiority of RPA regarding OP, BL, LOS, and incisional hernia rate. CONCLUSIONS: The best choice for patients with adrenal masses candidate for minimally invasive surgery seems to be RPA. An alternative could be RPLA. The remaining approaches could have some specific advantages but do not represent the first minimally invasive choice.

Impact of Clomiphene Citrate on the Steroid Profile in Dysmetabolic Men with Low Testosterone Levels.

Clomiphene citrate (CC) in male hypogonadism increases testosterone (T) and estrogen levels by stimulating pituitary gonadotropin release. Our group confirmed these hormonal changes in a randomized, cross-over, double-blind trial of CC versus placebo in addition to metformin, conducted in 21 obese dysmetabolic men with low T levels. However, we hypothesize that based on its mechanism of action, CC may directly or indirectly affect adrenal steroidogenesis. The aim of this sub-study was to better understand the changes in steroid levels and metabolism induced by CC treatment. We assessed 17α-hydroxypregnelone (17αOH-P5), dehydroepiandrosterone (DHEA), progesterone (P4), 17α-hydroxyprogesterone (17αOH-P4), androstenedione (A), T, dihydrotestosterone (DHT), estrone (E1), 17ß-estradiol (E2), 11-deoxycortisol (11 S), cortisol (F), and cortisone (E) by LC-MS/MS, and corticosteroid binding globulin (CBG) by ELISA, before and after each treatment. In addition, free-F and steroid product/precursor ratios were calculated. We observed a significant change in serum levels induced by CC compared with placebo for 17αOH-P4, DHT, T, E2, E1, F, E, and CBG, but not free-F. In addition, compared to placebo, CC induced higher 17αOH-P4/P4, E2/E1, 17αOH-P4/17αOH-P5, A/17αOH-P4, T/A, E1/A, F/11 S, and F/E ratios. Therefore, besides the CC stimulating effect on testis steroidogenesis, our study showed increased F, E, but not free-F, levels, indicating changes in steroid metabolism rather than adrenal secretion stimulation. The steroid profiling also revealed the CC stimulation of the Δ5 rather than the Δ4 pathway, thus indicating considerable testicular involvement in the increased androgen secretion.

The learning curve for the second generation of laparoscopic surgeons: lesson learned from a large series of laparoscopic adrenalectomies.

BACKGROUND: Laparoscopic adrenalectomy has a well-demonstrated learning curve in the first generation of laparoscopic surgeons. Data about the second generation of laparoscopic surgeons are lacking. METHODS: In this retrospective observational study, data from patients undergoing laparoscopic adrenalectomy from 2000 to 2019 in a high-volume center were collected and analyzed. The cumulative sum of procedures of each surgeon and the operating time were evaluated. A multivariate analysis with backward stepwise logistic regression was carried out to define which factors influenced the operative time. Three surgeons performed the analyzed procedures: a senior surgeon who began his laparoscopic activity without receiving specific training or supervision and two young surgeons, who performed their procedures under the guidance of the "senior" experienced surgeon. The first 38 procedures of the three surgeons were then compared. RESULTS: A total of 244 laparoscopic adrenalectomies were performed. Age, clinical diagnosis, side of the lesion, body mass index, comorbidities, Charlson index, American Society of Anaesthesiologists (ASA) score, and lower abdominal surgery were found to have no significant relationship with the operative time (p > 0.05). Gender, symptoms, previous upper abdominal surgery, size of the lesion, and cumulative sum of procedures were independent predictors of operative time. In the comparison between different surgeons, operative time resulted significantly longer for the senior (165 min; 140-180) than for the two junior surgeons (137.5 min; 115-160; p = 0.003 and 130 min; 120-170; p = 0.001). CONCLUSIONS: The presence of a mentor in operative theater and specific training programs could be useful during the learning period. The cumulative sum of procedures related to the operative time represents a good parameter to measure the acquired expertise of a surgeon.

Effect of clomiphene citrate treatment on the Sertoli cells of dysmetabolic obese men with low testosterone levels.

BACKGROUND: Clomiphene citrate (CC) has been shown to restore the hypothalamic-pituitary-gonadal (HPG) axis by increasing testosterone (T) levels to physiological levels in patients with dysmetabolic conditions such as obesity, metabolic syndrome and type 2 diabetes mellitus (T2DM). However, the data are unclear regarding the effects on Sertoli cell (SC) function. AIM: To study SC function by assessing Inhibin B (IB) and anti-Mullerian hormone (AMH) levels at baseline and after 3 months of CC treatment. MATERIALS AND METHODS: This is an ancillary study of a cross-over, randomised, double-blind, placebo-controlled trial performed to evaluate androgen response to CC treatment in dysmetabolic obese subjects with low T levels treated with metformin. We evaluated SC function by assessing IB and AMH levels at baseline and after 3 months of each treatment in ten dysmetabolic obese subjects with low T levels. In all subjects, the influence of the clinical characteristics, metabolic and hormonal baseline parameters on SC and Leydig (LC) function, evaluated respectively with AMH, IB, follicle-stimulating hormone (FSH) and T levels, was tested. RESULTS: No significant changes were observed for IB and AMH concentrations after each treatment period. Whereas T and oestradiol (E2) levels were shown to be significantly higher in the CC plus metformin phase (CC/Met) only. No clinical, metabolic or hormonal parameters showed significant effects on serum AMH at baseline or after treatments. However, baseline T, dihydrotestosterone (DHT) and E2 positively affected IB levels during CC/Met therapy (P = .003, P = .038 and P = .049, respectively). Baseline leptin and FSH had a negative (P = 031) and positive (P = .048) respectively role on T levels during CC/Met, as they were statistically significant compared to the placebo period (Plac/Met). CONCLUSION: Unlike the LC activity, CC was unable to influence SC function, as shown by the lack of IB and AMH serum modifications, thus suggesting an intrinsic nonreversible defect of SC cells in patients with dysmetabolic conditions.

Plasma Steroid Metabolome Profiling for Diagnosis and Subtyping Patients with Cushing Syndrome.

BACKGROUND: Diagnosis of Cushing syndrome requires a multistep process that includes verification of hypercortisolism followed by identification of the cause of adrenocortical hyperfunction. This study assessed whether pituitary, ectopic, and adrenal subtypes of Cushing syndrome were characterized by distinct plasma steroid profiles that might assist diagnosis. METHODS: In this retrospective cross-sectional study, mass spectrometric measurements of a panel of 15 plasma steroids were applied to 222 patient samples tested for Cushing syndrome. Disease was excluded in 138 and confirmed in 51 patients with pituitary Cushing syndrome, 12 with ectopic adrenocorticotropin secretion, and 21 with adrenal disease. Another 277 age- and sex-matched hypertensive and normotensive volunteers were included for comparison. RESULTS: Compared with patients without disease, the largest increases in plasma steroids among patients with Cushing syndrome were observed for 11-deoxycortisol (289%), 21-deoxycortisol (150%), 11-deoxycorticosterone (133%), corticosterone (124%), and cortisol (122%). Patients with ectopic disease showed the most prominent increases, but there was considerable variation for other steroids according to subtype. Patients with adrenal disease had the lowest concentrations of androgens, whereas those with ectopic and pituitary disease showed the lowest concentrations of aldosterone. Plasma 18-oxocortisol was particularly low in ectopic disease. With the use of 10 selected steroids, subjects with and without different Cushing syndrome subtypes could be discriminated nearly as closely as with the use of salivary and urinary free cortisol, dexamethasone-suppressed cortisol, and plasma adrenocorticotropin (9.5% vs 5.8% misclassification). CONCLUSIONS: Patients with different subtypes of Cushing syndrome show distinctive plasma steroid profiles that may offer a supplementary single-test alternative for screening purposes.

Parallel diurnal fluctuation of testosterone, androstenedione, dehydroepiandrosterone and 17OHprogesterone as assessed in serum and saliva: validation of a novel liquid chromatography-tandem mass spectrometry method for salivary steroid profiling.

BACKGROUND: Salivary androgen testing represents a valuable source of biological information. However, the proper measurement of such low levels is challenging for direct immunoassays, lacking adequate accuracy. In the last few years, many conflicting findings reporting low correlation with the serum counterparts have hampered the clinical application of salivary androgen testing. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) makes it possible to overcome previous analytical limits, providing new insights in endocrinology practice. METHODS: Salivary testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA) and 17OHprogesterone (17OHP) were extracted from 500µL of saliva, separated in 9.5 min LC-gradient and detected by positive electrospray ionization - multiple reaction monitoring. The diurnal variation of salivary and serum androgens was described by a four paired collection protocol (8 am, 12 am, 4 pm and 8 pm) in 19 healthy subjects. RESULTS: The assay allowed the quantitation of T, A, DHEA and 17OHP down to 3.40, 6.81, 271.0 and 23.7 pmol/L, respectively, with accuracy between 83.0 and 106.1% for all analytes. A parallel diurnal rhythm in saliva and serum was observed for all androgens, with values decreasing from the morning to the evening time points. Salivary androgen levels revealed a high linear correlation with serum counterparts in both sexes (T: R>0.85; A: R>0.90; DHEA: R>0.73 and 17OHP: R>0.89; p<0.0001 for all). CONCLUSIONS: Our LC-MS/MS method allowed a sensitive evaluation of androgen salivary levels and represents an optimal technique to explore the relevance of a comprehensive androgen profile as measured in saliva for the study of androgen secretion modulation and activity in physiologic and pathologic states.

Mild Autonomous Cortisol Secretion (MACS) - Related Osteoporosis.

Mild autonomous cortisol secretion (MACS) has thus far been associated with several comorbidities, among which osteoporosis and fractures appear to be highly prevalent. Recent guidelines for adrenal incidentalomas have updated the definition of MACS, currently formulated on serum cortisol after a 1-mg dexamethasone test above 1.8 µg/dL or 50 nmol/L. Previous studies on bone health in adrenal incidentalomas had adopted different definitions of MACS, which produced heterogenous results in terms of fracture prevalence. This review aims to summarize the clinical impact of MACS in relation to fractures, bone quantity and quality, by providing a thorough update on MACS-related osteoporosis (MACS-ROP). Room for research in this area is large, and management of this comorbidity still needs to be elucidated.

Monitoring adrenal insufficiency through salivary steroids: a pilot study.

BACKGROUND: Various glucocorticoid replacement therapies (GRTs) are available for adrenal insufficiency (AI). However, their effectiveness in restoring glucocorticoid rhythm and exposure lacks adequate biochemical markers. We described the diurnal salivary cortisol (SalF) and cortisone (SalE) rhythm among different GRTs and analysed the associations between saliva-derived parameters and life quality questionnaires. METHODS: Control subjects (CSs, n = 28) and AI patients receiving hydrocortisone (HC, n = 9), cortisone acetate (CA, n = 23), and dual-release hydrocortisone once (DRHC-od, n = 10) and twice a day (DRHC-td, n = 6) collected 9 saliva samples from 07:00 to 23:00. Patients compiled Pittsburgh Sleep Quality Index, Hospital Anxiety and Depression Scale, and Addison disease-specific quality-of-life questionnaires. SalE and SalF were measured by liquid chromatography-mass spectrometry. Exposure was monitored using SalE for HC and DRHC and SalF for CA. Area under the curve (AUC) was computed. Different GRTs were compared by Z-scores calculated from saliva-derived parameters. Questionnaire results predictors were evaluated with multiple regression analysis. RESULTS: Compared with controls, all GRTs resulted in glucocorticoid overexposure in the morning. Hydrocortisone, CA, and DRHC-td caused overexposure also in afternoon and evening. Compared with other treatments, CA determined increased Z-score-07:00 (P < .001), DRHC-td determined increased Z-score-AUC07:00→14:00 (P = .007), and DRHC-od induced lower Z-score-AUC14:00→23:00 (P = .015). Z-scores-AUC14:00→16:00 ≥ .619 best predicted questionnaire scores. CONCLUSIONS: None of the GRTs mimics normal glucocorticoid rhythmicity and exposure. SalE, SalF, and Z-score may be useful markers for monitoring and comparing different GRTs. Excess glucocorticoid in early afternoon best associated with depressive symptoms and worse life and sleep quality.

Radioiodine whole body scan pitfalls in differentiated thyroid cancer.

PURPOSE: whole body scan (WBS) performed following diagnostic or therapeutic administration of I-131 is useful in patients with differentiated thyroid carcinoma. However, it can be falsely positive in various circumstances. We aimed to report a series of pitfalls in a clinical perspective. METHODS: A search in the database PubMed utilizing the following terms: "false radioiodine uptake" and "false positive iodine 131 scan" has been made in January 2023. Among the 346 studies screened, 230 were included in this review, with a total of 370 cases collected. Physiological uptakes were excluded. For each patient, sex, age, dose of I-131 administered, region and specific organ of uptake and cause of false uptake were evaluated. RESULTS: 370 cases of false radioiodine uptake were reported, 19.1% in the head-neck region, 34.2% in the chest, 14.8% in the abdomen, 20.8% in the pelvis, and 11.1% in the soft tissues and skeletal system. The origin of false radioiodine uptake was referred to non-tumoral diseases in 205/370 cases (55.1%), benign tumors in 108/370 cases (29.5%), malignant tumors in 25/370 cases (6.7%), and other causes in 32/370 cases (8.7%). CONCLUSIONS: WBS is useful in the follow-up of patients with differentiated thyroid carcinoma, however it can be falsely positive in various circumstances. For this reason, it is critically important to correlate the scintigraphic result with patient's medical history, serum thyroglobulin levels, additional imaging studies and cytologic and/or histologic result.

Sex-driven factors associated with anxiety and depression in autoimmune diabetes.

AIM: To analyze the prevalence of anxiety and depression in a large cohort of adults with autoimmune diabetes, identifying sex-driven associated factors. MATERIALS AND METHODS: In this cross-sectional study, we enrolled 553 consecutive adults with Type 1 diabetes mellitus or latent autoimmune diabetes in adults who came to the Division of Endocrinology of the S.Orsola-Malpighi Polyclinic, Bologna (Italy), to receive their second dose of SARS-CoV-2 vaccine. We administered the questionnaires: Hospital Anxiety and Depression Scale, Diabetes Distress Scale, Diabetes-related Quality of Life, Diabetes Treatment Satisfaction Questionnaire. We collected clinical and biochemical data and 14 days glucose metrics in patients with sensor use > 70% in a time span of ± 4 months from the questionnaires' administration. We excluded 119 patients from our analyses with missing data (final cohort n = 434: 79% of those enrolled). RESULTS: Anxiety and depression prevalence was respectively 30.4% and 10.8%. According to the multivariate analysis, higher diabete-related emotional burden, lower treatment satisfaction, but not physician-related distress, were risk factors for anxiety and depression; female sex was associated with anxiety (OR 0.51, 95% 0.31-0.81; p = 0.005); in women, depression was associated with increasing age (males vs. females OR 0.96 per 1 year increase, 95% CI 0.92-1.00; p = 0.036), whilst in men with HbA1c (OR 1.08 per 1 mmol/mol increase, 95% CI 1.03-1.13; p = 0.002). CONCLUSION: Nearly 1/3 of patients with autoimmune diabetes suffers from anxiety and 1/10 from depression. These conditions are associated with independent modifiable and non-modifiable characteristics. For depression, these characteristics differ between males and females.

Sleep quality and sex-related factors in adult patients with immune-mediated diabetes: a large cross-sectional study.

AIM: To analyze sleep quality and its relationships with clinical and biochemical features in a large cohort of adults with autoimmune diabetes. METHODS: We administered to 553 patients with autoimmune diabetes the questionnaires: Pittsburgh Sleep Quality Index (PSQI), diabetes distress scale, diabetes-related quality of life and diabetes treatment satisfaction questionnaire. We excluded patients with missing HbA1c ± 4 months from PSQI administration or incorrect PSQI compilation (n = 110). RESULTS: Altered sleep quality was recorded in 142/443 subjects (32%), insufficient total sleep time in 177/443 (40%). The altered sleep quality group had higher HbA1c (median 56 mmol/mol [interquartile range-IQR 49-62] vs 59 [IQR 52-68]; P < 0.001), higher average HbA1c in the previous 36 months (59 mmol/mol [IQR 54-68] vs 56 [IQR 51-62]; P < 0.001), and more individuals with HbA1c > 53 mmol/mol (74.6% vs 62.8%; P = 0.014). Diabetes duration (P = 0.63), type of insulin delivery (P = 0.48) and glucose monitoring (P = 0.35) were uninfluential. Patients with altered sleep quality showed higher prevalence of autoimmune (42 vs 28%; P = 0.005) and mental diseases (12 vs 4%; P = 0.002); there were greater emotional distress, and lower quality of life and treatment satisfaction (P < 0.001 for all), irrespective of sex. Men with altered sleep quality had higher HbA1c and prevalence of autoimmune diseases. Women showed greater prevalence of psychiatric disorders. Average HbA1c of the previous 36 months, autoimmune or psychiatric disorders were independent predictive factors for altered sleep quality. CONCLUSION: One-third of the patients with autoimmune diabetes showed altered sleep quality, which associates with worse glycemic control, and autoimmune and mental disorders, with sex-specific differences.

Mild autonomous cortisol secretion in adrenal incidentalomas and risk of fragility fractures: a large cross-sectional study.

OBJECTIVE: Mild autonomous cortisol secretion (MACS) has been associated with a higher prevalence of osteoporosis, although most data rely on single-center studies with limited sample size. We aimed to assess the prevalence of fragility fractures and contributing factors in a large cohort of patients with adrenal incidentalomas. DESIGN AND METHODS: Medical records of 1023 patients with adrenal incidentalomas from 1990 to 2019 were reviewed, and 735 patients were selected. Clinically obtained electronic radiological images closest to first endocrine evaluation, such as lateral views of spine X-rays or CT thoraco-abdominal scans, were reviewed to screen for asymptomatic morphometric vertebral fractures. Clinical fragility fractures, hormonal, and dual-energy x-ray absorptiometry (DXA) indices were also recorded. RESULTS: Four hundred seventy-four patients had nonfunctioning (NF) adrenal incidentalomas, 238 had MACS and 23 adrenal Cushing's syndrome (AC). Prevalence of fragility fractures was different (P = .018) between groups, respectively, 24.1% (NF), 34.0% (MACS), and 30.4% (AC), with significant difference between NF and MACS (P = .012). When analyzed separately by sex and menopausal status, this difference remained significant in postmenopausal women (P = .011), with a fracture prevalence of 22.2% (NF) and 34.6% (MACS). Fracture prevalence was similar in males. Women with MACS aged ≥65 years reported a 48.8% prevalence of fractures, as compared with 29.5% in NF (P < .01). In postmenopausal women, fragility fractures were associated with age (odds ratio [OR] 1.1, P < .001), smoking (OR 1.8, P = .048), and 1 mg-dexamethasone suppression test (DST) cortisol (OR 3.1, P = .029), while in men, only age was associated with fragility fractures. CONCLUSIONS: A considerable fracture burden was shown in postmenopausal women with adrenal incidentalomas and MACS, with clinical implications for the evaluation and management of bone metabolism.

New Findings on Presentation and Outcome of Patients With Adrenocortical Cancer: Results From a National Cohort Study.

CONTEXT: Because of the rarity of adrenocortical cancer (ACC), only a few population-based studies are available, and they reported limited details in the characterization of patients and their treatment. OBJECTIVE: To describe in a nationwide cohort the presentation of patients with ACC, treatment strategies, and potential prognostic factors. METHODS: Retrospective analysis of 512 patients with ACC, diagnosed in 12 referral centers in Italy from January 1990 to June 2018. RESULTS: ACC diagnosed as incidentalomas accounted for overall 38.1% of cases, with a frequency that increases with age and with less aggressive pathological features than symptomatic tumors. Women (60.2%) were younger than men and had smaller tumors, which more frequently secreted hormones. Surgery was mainly done with an open approach (72%), and after surgical resection, 62.7% of patients started adjuvant mitotane therapy. Recurrence after tumor resection occurred in 56.2% of patients. In patients with localized disease, cortisol secretion, ENSAT stage III, Ki67%, and Weiss score were associated with an increased risk of recurrence, whereas margin-free resection, open surgery, and adjuvant mitotane treatment were associated with reduced risk. Death occurred in 38.1% of patients and recurrence-free survival (RFS) predicted overall survival (OS). In localized disease, age, cortisol secretion, Ki67%, ENSAT stage III, and recurrence were associated with increased risk of mortality. ACCs presenting as adrenal incidentalomas showed prolonged RFS and OS. CONCLUSION: Our study shows that ACC is a sex-related disease and demonstrates that an incidental presentation is associated with a better outcome. Given the correlation between RFS and OS, RFS may be used as a surrogate endpoint in clinical studies.

The Changing Face of Drug-induced Adrenal Insufficiency in the Food and Drug Administration Adverse Event Reporting System.

CONTEXT: Adrenal insufficiency (AI) is a life-threatening condition complicating heterogeneous disorders across various disciplines, with challenging diagnosis and a notable drug-induced component. OBJECTIVE: This work aimed to describe the spectrum of drug-induced AI through adverse drug event reports received by the US Food and Drug Administration (FDA). METHODS: A retrospective disproportionality analysis reporting trends of drug-induced AI was conducted on the FDA Adverse Event Reporting System (FAERS) (> 15 000 000 reports since 2004). AE reports were extracted from FAERS over the past 2 decades. Interventions included cases containing any of the preferred terms in the Medical Dictionary for Regulatory Activities describing AI, and signals of disproportionate reporting for drugs recorded in 10 or more cases as primary suspect. RESULTS: We identified 8496 cases of AI: 97.5% serious, 41.1% requiring hospitalization. AI showed an exponential increase throughout the years, with 5282 (62.2%) cases in 2015 to 2020. We identified 56 compounds associated with substantial disproportionality: glucocorticoids (N = 1971), monoclonal antibodies (N = 1644, of which N = 1330 were associated with immune checkpoint inhibitors-ICIs), hormone therapy (N = 291), anti-infectives (N = 252), drugs for hypercortisolism or adrenocortical cancer diagnosis/treatment (N = 169), and protein kinase inhibitors (N = 138). Cases of AI by glucocorticoids were stable in each 5-year period (22%-27%), whereas those by monoclonal antibodies, largely ICIs, peaked from 13% in 2010 to 2015 to 33% in 2015 to 2020. CONCLUSION: We provide a comprehensive insight into the evolution of drug-induced AI, highlighting the heterogeneous spectrum of culprit drug classes and the emerging increased reporting of ICIs. We claim for the urgent identification of predictive factors for drug-induced AI, and the establishment of screening and educational protocols for patients and caregivers.

Adrenal Insufficiency with Anticancer Tyrosine Kinase Inhibitors Targeting Vascular Endothelial Growth Factor Receptor: Analysis of the FDA Adverse Event Reporting System.

Background: We described clinical features of adrenal insufficiency (AI) reported with tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor receptor (VEGFR) in the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports of AI recorded in FAERS (January 2004-March 2022) were identified through the high-level term "adrenal cortical hypofunctions". Demographic and clinical features were inspected, and disproportionality signals were detected through the Reporting Odds Ratio (ROR) and Information Component (IC) with relevant 95% confidence/credibility interval (CI), using different comparators and adjusting the ROR for co-reported corticosteroids and immune checkpoint inhibitors (ICIs). Results: Out of 147,153 reports with VEGFR-TKIs, 314 cases of AI were retained, mostly of which were serious (97.1%; hospitalization recorded in 44.9%). In a combination regimen with ICIs (43% of cases), VEGFR-TKIs were discontinued in 52.2% of the cases (26% as monotherapy). The median time to onset was 72 days (IQR = 14-201; calculated for 189 cases). A robust disproportionality signal emerged, also in comparison with other anticancer drugs (ROR = 2.71, 95%CI = 2.42-3.04; IC = 0.25, 95%CI = 0.07-0.39). Cabozantinib, sunitinib and axitinib generated robust disproportionality even after ROR adjustment. Conclusions: We call pharmacologists, internists, oncologists and endocrinologists to raise awareness of serious AI with VEGFR-TKIs, and to develop dedicated guidelines, especially for combination regimens with immunotherapy.

Diagnosis and management of hypertension in patients with Cushing's syndrome: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension.

Endogenous/exogenous Cushing's syndrome is characterized by a cluster of systemic manifestations of hypercortisolism, which cause increased cardiovascular risk. Its biological basis is glucocorticoid excess, acting on various pathogenic processes inducing cardiovascular damage. Hypertension is a common feature in Cushing's syndrome and may persist after normalizing hormone excess and discontinuing steroid therapy. In endogenous Cushing's syndrome, the earlier the diagnosis the sooner management can be employed to offset the deleterious effects of excess cortisol. Such management includes combined treatments directed against the underlying cause and tailored antihypertensive drugs aimed at controlling the consequences of glucocorticoid excess. Experts on endocrine hypertension and members of the Working Group on Endocrine Hypertension of the European Society of Hypertension (ESH) prepared this Consensus document, which summarizes the current knowledge in epidemiology, genetics, diagnosis, and treatment of hypertension in Cushing's syndrome.

Age-dependent and sex-dependent disparity in mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: an international, retrospective, cohort study.

BACKGROUND: The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing). METHODS: We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800-0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50-138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants. FINDINGS: Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53-68]; median follow-up 7·0 years [IQR 4·7-10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19-1·94) and autonomous cortisol secretion (1·77, 1·20-2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93-9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values <0·001). INTERPRETATION: Cortisol autonomy is associated with increased all-cause mortality, particularly in women younger than 65 years. However, until results from randomised interventional trials are available, a conservative therapeutic approach seems to be justified in most patients with adrenal incidentaloma. FUNDING: Deutsche Forschungsgemeinschaft, Associazione Italiana per la Ricerca sul Cancro, Università di Torino.

Steroid reference intervals in women: influence of menopause, age and metabolism.

OBJECTIVE: To investigate the impact of age, obesity and metabolic parameters on 13 circulating steroids in reproductive and menopausal age. To define reference intervals (RIs). DESIGN: Cross-sectional. METHODS: Three hundred and twenty five drug-free, healthy and eumenorrheic women were selected from the general population. Independent relationships of LC-MS/MS-determined steroid levels with age, BMI and metabolic parameters were estimated. Reference sub-cohorts were defined for calculating upper and lower limits in reproductive age, menstrual phases and menopause, and these were compared with limits in dysmetabolic sub-cohorts. RESULTS: Lower androgens, pro-androgens and estrogens, but higher cortisol and metabolites were found in menopausal compared to reproductive age women. Androgens and precursors decreased during reproductive age (P < 0.001-P = 0.002) but not after menopause. 17OH-progesterone decreased with BMI (P = 0.006) and glucocorticoids with waist circumference (P < 0.001P = 0.002) in reproductive age, but increased with triglycerides (P=0.011P=0.038) after menopause. Inverse associations of dihydrotestosterone with BMI (P=0.004) and HDL-cholesterol (P=0.010), estrone with total cholesterol (P=0.033) and estradiol with triglycerides (P=0.011) were found in reproductive age. After menopause, estrone increased with waist circumference (P<0.001) and decreased with insulin resistance (P=0.012). Ovarian steroid RIs were estimated in menstrual phases and menopause. Age- and reproductive status-specific RIs were generated for androgens, precursors and corticosteroids. Lower limits for reproductive age cortisol (P=0.020) and menopausal 11-deoxycortisol (P=0.003) in dysmetabolic sub-cohorts were reduced and increased, respectively, compared to reference limits. CONCLUSIONS: Obesity and dysmetabolism differently influence circulating steroids in reproductive and menopausal status. Age, menstrual and menopausal status-specific RIs were provided by LC-MS/MS for a broad steroid panel.